Zinc Gluconate-Glycine (10-mole) Lozenge Study
Chapter 4.C.3. - Zinc Gluconate-Glycine (1:10-mole) Lozenge Study

In a 1992 double-blind, clinical study involving 87 patients by Godfrey and co-workers at Dartmouth College, zinc gluconate with glycine in 10 molar excess as flavor-mask in 4.5 gram sucrose-corn syrup hard boiled candy lozenges and identically astringent and flavored tannic acid placebos were both reported to have late efficacy against natural common colds.(42)

However, the reported reductions in "average duration of colds" appear in actuality reductions in half-lives. Therefore, the half-life of zinc gluconate-glycine (ZGG)-treated colds, not the average duration (see Figure 2 and explanation in Chapter 3), was 1.27 days shorter (4.86 days) than placebo-treated colds (6.13 days) (t = 2.01, P < 0.05) in patients having colds for an average of 1.34 days before starting treatment. Ordinarily, the half-life for untreated or placebo-treated colds is considered to be 7 days. After the fourth day of treatment, patients using ZGG became symptom-free somewhat faster than volunteers using placebo. Results were reported to be significantly different by day 6 (P = 0.05).

The most frequent symptom in both groups after 7 days of treatment was nasal drainage and nasal congestion. About 13 percent of the ZGG-treated group and about 34 percent of the placebo-treated group still had nasal symptoms after 7 days of treatment. From the half-life data above and Figure 1 of Godfrey and co-workers, it is possible to estimate the over-all effect of ZGG versus placebo on common colds in the whole study group (see Figure 16).

Results seemed better with initiation of treatment of colds starting within 24 hours of the onset of the first symptom (see Figure 17). Severity of symptoms remaining on the seventh day for the sub-group of ZGG-treated patients having been ill for less than 1 day before starting treatment was also less than for the ZGG-treated sub-group having been ill for 2 days prior to starting treatment.

Estimated effect of zinc gluconate-glycine (10 mole) versus placebo Figure 16. Estimated effect of zinc gluconate-glycine and placebo on duration of colds.

The conclusion by Godfrey and co-workers that ZGG lozenge treatment shortened the average duration of cold by 43 percent appears erroneous. Their error results from misinterpreting half-lives of colds (usually 7 days), as the "average durations" of colds (usually about 10 to 11 days), which is an entirely different matter. An accurate assessment of the effect of ZGG lozenges on colds must take these major mathematical and conceptual differences into account.

Effect of pretreatment for cold durationFigure 17. Effect of pretreatment cold duration for zinc gluconate-glycine treated sub-groups. (courtesy of Journal of International Medical Research).

If the assessment of Godfrey and co-workers that colds first treated on their first day have a "total average duration" (in actuality a half-life) of 5.3 days, the half-life must be compared with the historical 7 day half-life of colds, not the 9.2 day average duration figure used in the Godfrey and co-workers report. Therefore, the reduction in half-live was only 1.7 days. If the half-life is divided by the natural log of 2 to give the average reduction in duration of exponentially decaying colds, the result is 2.5 days. However, this method of analysis is inaccurate for these non-exponential decay curves.

The most accurate conclusions are one-half of the ZGG-treated colds ended 1.2 to 1.7 days before normal, and ZGG-treated patients fared better with essentially all colds being absent after seven days of treatment with ZGG when treatment was started on the first day of their colds.

Zinc gluconate-glycine lozenges contained 23.7 mg zinc and 10 molar equivalents of glycine relative to zinc. Average zinc-laden salivary volume was 26.3 ml.(43) Lozenges were used every 2 hours while awake. Total zinc concentration was 14 mMol. Lozenges dissolved in 15 minutes.

Zinc Speciation in the Zinc Gluconate-Glycine System

The stability constants for zinc glycinate complexes are relatively high; for example, log K1 = 4.8 at 37°C.(44) With a 10-mole excess of glycine at the published salivary pH of 5.0, available Zn2+ ion concentration is 20 percent, but it falls rapidly to zero at pH 6.4; and only neutrally and negatively charged zinc glycinate and hydroxide species exist at physiological pH 7.4 and above as shown in Figure 18.

NOTE: Learn about the meaning of "stability constants" here.

Zinc gluconate-glycine Figure 18. Concentration of Zn2+, positively charged zinc gluconate (ZnL+), and various zinc glycinate and zinc hydroxide species in the zinc gluconate - glycinate system. Zinc and gluconate are present at 30 mMol and glycine is present at 300 mMol concentration. Distribution of zinc ionic species is courtesy of Guy Berthon, INSERM U 305, CNRS, Toulouse, France, 1992.



Glycine replaces gluconate in solid state reactions during heated premixing of zinc gluconate and glycine powders and at elevated candy-making temperature, as well as in solutions. According to Berthon, only neutrally and negatively charged zinc glycinate species and excess glycine exist in solution at pH 7.4. Yet, Zarembo and co-workers believe zinc was 90 to 93 percent Zn2+ ion at pH 5.08 because of a previously unknown "catalytic action of saliva."(42,43) However, zinc gluconate with only 60 percent Zn2+ ion content (see Figure 1) added to hard-boiled candy stock at candy-making temperature and pH 5 severely caramelizes and quickly becomes offensively malodorous without added glycine or other strong chelator such as citric acid or acacia.

Effects of Astringency

Because Zn2+ ions, ZGG, and tannic acid are each astringent in saliva, late-occurring efficacy noticed in the zinc gluconate-glycine report for ZGG lozenges is most likely attributable to astringency. The action appears not from antirhinoviral action of Zn2+ ions at physiologic pH 7.4, as no Zn2+ ions are available according to Berthon (see Figure 18).

Any possible Zn2+ ion action on rhinoviruses should occur during the first few days of a cold when rhinoviruses are present, yet no reduction in duration of colds was noted in this study during those early days. In fact, the frequencies of nasal symptoms were the least affected by ZGG lozenges. Effects on individual symptoms during the early phase also were likely to have been caused by astringency, and not Zn2+ ions. Late activity in a cold -- when viruses are essentially absent -- suggests the effect on duration is most likely caused by local astringency, a drying action. This action most likely would not include significant prevention of release of histamine from mast cells considering molecular stabilities.

The suggestion by Godfrey and co-workers that the placebo was active seems implausible, and may not be supported by facts since the half-life of placebo-treated colds was 6.13 days which is essentially the same as the historical half-life of untreated common colds at 7 days, particularly when one adds the pre-treatment day.

Zinc Ion Availability

In this anomaly from the ZIA - day reduction trend, ZIA is unquestionably negative from lack of Zn2+ ions, the presence of neutrally (85%) and negatively (15%) charged zinc glycine species, and glycine in excess at pH 7.4. However, no ZIA data-point can be determined as the results do not fall into the quadrant used to estimate ZIA values for other lozenges having negative ZIA values. This anomaly results in a horizontal line to the left of the origin at a positive 1.27 days.


Year 2001 Addendum: The zinc ion speciation curve for the Quigley Corporation Cold Eeze® product is considerably different than the speciation curve for the Godfrey 1:10 mole product. In the Quigley product at the one to one molar ratio of glycine to gluconate believed specified and applicable in the Annals of Internal Medicine article, positively charged zinc gluconate and glycinate species occur at physiologic pH as shown by Berthon in 1996. However, commercial Cold Eeze® is claimed to have between 2 and 10 moles of glycine per mole of gluconate as described by U. S. Patent Number 4,684,528.

Chapter 4.D. - Summary and Comments