In 1984, Eby et al. reported that zinc gluconate lozenges containing zinc (Zn) 23 mg slowly dissolved in the mouth every 2 hours while awake (one lozenge nine times per day) were found to shorten the duration of common colds by an average of 7 days in a double-blind, placebo-controlled clinical trial. Zinc2+ ions released from zinc gluconate were suggested to be the active ingredient because they are known to inhibit rhinovirus replication.(1) The original report was confirmed by the Medical Research Council (MRC) Common Cold Unit of Great Britain in 1987.(2) Other reports of follow-up clinical research were published from 1987 through 1992 using "improved" flavor-masked zinc lozenges; these showed conflicting, often negative, results. Whether successful trials were faulty or the chemically different flavor-masked lozenges were faulty was uncertain.
In 1993, Potter and Hart reviewed the literature on zinc lozenge for the common cold. Their review controverted efficacy because they did not include (1) solution chemistry analyses of lozenges used in reviewed trials, (2) unpublished data available only from lozenge manufacturers and authors of the original reports, and (3) analyses of the availability of Zn2+ ions to the oral mucosa.(3) The present reanalysis extends their review by including the omitted information, and shows availability of Zn2+ ions to be associated with positive results and the presence of negatively charged zinc complexes (ZnL1) causes an increase in cold duration and an increase in symptom severity.
Some 60 to 70% of upper respiratory viral infections - that is, common colds - are believed to be caused by rhinoviruses according to new data obtained using polymerase chain reaction techniques.(4) Symptoms of common colds are more specifically caused by the immune system's over-reaction to rhinoviruses and other common cold-causing pathogens.
Zn2+ ions were demonstrated by Korant, Butterworth, and their co-workers to be highly effective antirhinoviral agents inhibiting cleavage of rhinovirus polypeptides in vitro.(5-9) Merluzzi et al. showed antirhinoviral effects of zinc to be related to the concentration of zinc ions available and unrelated to the total amount of zinc complex available.(10) No in vitro effects were found by Geist et al. at less than 0.03 mmol,(11) and changes in cell appearance suggested toxicity of Zn2+ ion to Merluzzi et al.(10) and Geist et al.(11) at higher concentrations. Korant, Pasternak, their co-workers, and others strongly asserted lack of cytotoxicity along with potent stabilization of cell membranes, strong drying effects, astringency, and anti-inflammatory action.(8,12-20) Merluzzi et al. found the antirhinoviral effect of Zn2+ ions to be as strong as the antirhinoviral effect of interferon.(10) Others found Zn2+ ions to be mitogenic to T-cell lymphocytes and to stimulate interferon production.(21-23) In vitro efficacy in each case occurs at about at 0.1 mmol. Recently, the present author also hypothesized Zn2+ ions to be either antibradykinins or inhibitors of bradykinin release.
Reanalysis of clinical trial data was difficult and/or protracted because: (1) common cold researchers studied chemically different lozenges unrelated to the original trial lozenges or to each other; (2) several researchersdid not publish exact formulations for lozenges and their oral dissolution times; (3) most researchers reported results in different terms; and (4) trials of different designs were published over a ten year period (1984-1993). Contact with lozenge manufacturers and clinical researchers to obtain critical missing lozenge and trial data was required in each instance.
All clinical trials reanalyzed here were originally conducted using double-blind, placebo-controlled clinical research methods. Except in two trials, patients were prohibited from using other medications to alleviate particular symptoms. All patients were screened for allergies, bacterial suprainfections, other respiratory diseases, and other diseases or conditions that might produce misleading results. Pregnant women were not allowed in any trial. All but two trials reported results from natural colds. All meaningful characteristics of patients in the zinc- and placebo-treated groups in each trial were believed to be essentially equal and random. The number of patients in the trials varied from 55 to 146.