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Context: A zinc preparation that provides a higher concentration of solubilized zinc in a minimally irritating formulation allowing controlled absorption would be of great clinical value for treating oral herpes., Objective: To determine the effect of zinc oxide/glycine cream as a treatment for facial and circumoral herpes infection by measuring duration and intensity of signs and symptoms and assessing adverse effects., Design: Double-blind, placebo-controlled, randomized clinical trial., Setting: Subjects were enrolled from the general community through advertisements., Patients: Forty-six subjects with facial or circumoral herpes infections., Intervention: Application of a zinc oxide/glycine cream or a placebo cream every 2 hours until cold sore resolved or 21 days elapsed., Main Outcome Measures: Duration of cold sore lesions, severity of signs and symptoms, and frequency of adverse effects., Results: Subjects who began treatment with a zinc oxide/glycine cream within 24 hours of onset of signs and symptoms experienced a significantly shorter duration of cold sore lesions (mean, 5.0 days) than did subjects treated with a placebo cream (mean, 6.5 days). Subjects treated with the zinc oxide/glycine cream also experienced reduction in overall severity of signs and symptoms, particularly blistering, soreness, itching, and tingling. Side effects among subjects treated with zinc oxide/glycine cream were those expected from an ionic zinc salt solution. All were completely reversible and of short duration., Conclusion: Zinc oxide/glycine cream is an effective treatment for facial and circumoral herpes infection with predictable adverse effects that are completely reversible.

All eight publications since 1984 that have reported a total of 10 clinical studies of the treatment of common colds with zinc are reviewed. The reasons for the puzzling mix of diametrically opposite results in these studies are elucidated and related to independent in vitro investigations. A theoretical framework is put forth that explains the beneficial effects of zinc and that has a solid foundation based on the known molecular structures of the surface of human rhinovirus and intercellular adhesion molecule-1, the docking point for human rhinovirus present on the surfaces of cells of the nasal epithelium. The results of clinical investigations and theory suggest that consistently beneficial therapeutic effects can be expected of zinc ions from zinc gluconate with glycine in lozenges prepared according to homeopathic principles and procedures. The latest study published used an "intent to treat" statistical model, and the highly beneficial effects of zinc found in that study could not be compared directly with results from any earlier studies. Raw data from that study were therefore reanalyzed on the basis of assessable patients, and the results show an even better effect and can be compared directly with earlier findings. No side effects or adverse experiences due to zinc that were serious, disturbing, or persistent were found in any of the 10 studies.

Clinical studies have shown that ionic zinc (Zn2+) dissolved in the mouth shortened manifestations of the common cold significantly, by an unknown mechanism. The observed immediate effect on symptoms is consonant with osmotic transport of Zn2+, placing a temporary chemical clamp on critical nerves. It is proposed that transient elevation of Zn2+ concentration in and around the nasal cavity facilitates Zn2+ complexation with known intercellular adhesion molecule binding sites on rhinovirus surfaces which prevents rhinovirus binding to cells and interrupts infection. The crystallographically determined surface of rhinovirus-14 has been found to contain binding sites for at least 360 Zn2+. Such binding of Zn2+ would be stabilized by numerous histidine, methionine, tyrosine and carboxyl/carboxylate groups known to line the HRV-14 surface canyons. The resulting blockage of HRV docking with intercellular adhesion molecule binding sites is proposed to be responsible for the observed reduction of the duration of colds by statistically significant and clinically meaningful times.

A report in 1984 on the success of zinc gluconate against common cold symptoms could not be confirmed in three subsequent studies, which are now known to have used formulations that inactivated zinc. A non-chelating formulation including glycine, which releases 93% of contained zinc into saliva, was tested in a randomized, placebo-controlled, double-blind trial in 73 young adults. Efficacy was recorded in symptom diaries using a symptom severity rating. Patients' symptoms first appeared 1.34 days prior to entry to the study in both groups. Disappearance of symptoms occurred after an additional 4.9 days for zinc-treated patients versus 6.1 days for placebo-treated patients. A difference was noted in the efficacy of treatment if it was started 1 day after symptom onset: cold duration was an additional 4.3 days in zinc-treated patients compared with 9.2 days for placebo-treated patients. Cough, nasal drainage and congestion were the symptoms most affected, and only mild side-effects were noted.

A study of the pH of saliva produced by humans sucking hard candy lozenges containing zinc gluconate and citric acid demonstrated the probability that the formulation delivered an insignificant amount of the contained zinc as Zn2+. This could account for the negative results of several clinical studies of this lozenge and similar formulations as treatment for the common cold. Direct measurement of unbound Zn2+ in saliva from this and other zinc gluconate formulations was required to substantiate the inference from the pH study. A specific-ion-electrode assay method was developed. Using this method, it was found that saliva completely suppresses the ionization of zinc to free Zn2+ in the presence of citric acid or a 30-fold molar excess of mannitol plus sorbitol. Under the same conditions, however, the presence of an excess of glycine does not interfere with ionization to produce Zn2+. This finding supports the hypothesis that the positive clinical results of three studies were due to the use of formulations which release ionic zinc.