Linearity in Dose—Response from Zinc Lozenges in Treatment of Common Colds

Abstract

Objective: To test the hypothesis that major variations in daily zinc ion availability (ZIA) between lozenge formulations caused greatly differing results and to describe the biologically closed electric circuit between the mouth and nose. Data Sources: Data sources included clinical and in vitro reports, zinc speciation computations, and unpublished data from the original researchers and manufacturers. Data Extraction: Data were extracted to determine the composition and usage of lozenges and resultant changes in common cold duration. Lozenge ZIA values were determined from Zn2+ ion concentrations and oral contact time. Data Synthesis: Data synthesis disclosed that lozenges releasing Zn2+ ions at physiologic pH (positive ZIA values) shortened the duration of colds. Conversely, lozenges that released negatively charged zinc complexes (ZnLN−) at physiologic pH (negative ZIA values) lengthened the duration of colds. ZIA 100 lozenges reduced the duration of colds by 7 days. ZIA 0 lozenges had no effect. ZIA −55 lozenges lengthened the duration of colds by 4.4 days. Conclusions: The hypothesis is valid that major variations in ZIA from different zinc lozenge formulations used in clinical trials caused greatly differing results. A linear dose-response relationship exists between ZIA values of zinc lozenges and changes in duration of common colds. In agreement with in vitro activity, Zn2+ ions from lozenges inhibit replication of rhinoviruses, induce interferon release, and stabilize cell membranes in common cold treatment. Linearity in dose-response shows efficacy against common cold duration from clinically untested lozenges to be predictable on the basis of readily determined ZIA values of experimental lozenges.

The Role of Zinc Lozenges in Treatment of the Common Cold

“…Since it is known that a concentration of 0.1 mmol/L of unbound zinc ion is required for the antirhinoviral activity of zinc in vitro, it may be important for formulations of zinc lozenges to have the ability to produce adequate concentrations of unbound Zn +2 . Eby 16 proposed that the initial concentration of Zn +2 released from lozenges must greatly exceed 0.1 mmol/L to exert its activity since many Zn +2 ions may be inactivated due to complex formation with components found in saliva, blood, and lymph tissue. Several reports have been published to determine the amount of unbound Zn +2 released from lozenges used in clinical trials.…”

“…Although almost all zinc was unbound in the absence of saliva, consistent with solution chemistry reports, 25 the addition of fresh saliva resulted in no measurable unbound zinc ion. Conversely, when these lozenges were studied in the presence of saliva, and then buffered to a physiologic pH, Eby 16 reported these lozenges to produce 30% unbound Zn +2 . In the clinical trial using these lozenges, although a small reduction in overall severity of symptoms was reported, this benefit was not considered to be clinically significant.…”

“…6 It has also been suggested that the effervescent zinc acetate lozenges containing tartaric acid and sodium bicarbonate used by Douglas et al 5 may have been ineffective due to the possible complexation of zinc ions with these excipients. Eby 16 reported complete absence of zinc as Zn +2 at physiologic pH in the presence of saliva. This finding has also been supported through chemical equations.…”

“…The definition for average duration of colds appears to differ between trials. Eby et al 3, 16 reported average duration as the half-life of the cold (number of days for half the patients to become free of symptoms) divided by the natural log of 2, since the duration of the common cold typically follows a logarithmic model. Godfrey et al 19 reported average duration as the average number of days the zinc-treated patients were symptomatic subtracted from the average number of days the placebo-treated patients were symptomatic.…”

Abstract

“…A direct correlation between daily dosage of all positively charged zinc species at physiologic pH released from lozenges and reductions in duration of common cold has been hypothesized (Eby 1995). Zinc gluconate and zinc acetate have very low chemical stability and release positively charged zinc ions in aqueous solutions at physiological pH, while stronger complexes do not.…”