In an effort to provide a unifying hypothesis, this handbook analyzes all reports of zinc lozenge for common cold research reported since publication of my 1984 article in Antimicrobial Agents and Chemotherapy which documented a way of reducing the average duration of common colds by seven days using zinc gluconate lozenges. Common colds are mostly caused by rhinoviruses, and zinc gluconate is a good source of Zn²⁺ ions which are antirhinoviral.

The story has been told around the world of how in 1979 my leukemic 3-year old daughter, Karen, started a revolution. She had refused to swallow her 50-mg zinc supplement because she had a severe common cold. Instead, she allowed the zinc gluconate tablet to dissolve slowly in her mouth during an afternoon nap, resulting in the termination of her cold within several hours -- without further treatment or relapse. After this serendipitous discovery, I found similar results in other family members, friends, and co-workers.

Swallowed tablets, nasal ointments, nasal sprays, and nose drops were also tested. Nose drops were expected to work better than lozenges; however, no reduction in duration of common colds was observed. The dichotomy was difficult to understand, as colds are an infection of the nose, not the mouth. In retrospect, these findings are consistent with published literature dating from 1901 on zinc treatment of nasal catarrh via the nasal route as a short-lived nasal decongestant.

Why? A biologically closed electric circuit (BCEC) between the mouth and nose controls local movement of metallic ions. Of the many BCECs described in 1984 by Björn E. W. Nordenström, the mouth-nose BCEC is the most readily observable.

Over a two-year experimental period from 1979 to 1981, I formalized what I thought to be the best protocol for using zinc gluconate lozenges. William W. Halcomb (a general practice physician and allergist now in Mesa, Arizona), Donald R. Davis (a nutrition scientist who worked for National Academy of Science member Roger J. Williams [deceased] at the Clayton Biochemical Institute Foundation at the University of Texas at Austin), and I conducted the original double-blind study using slow-dissolving zinc gluconate tablets -- as lozenges -- in the fall of 1981 to treat wild common colds.

The results showed the expected efficacy. Zinc gluconate lozenges reduced the average duration of common colds by seven days, with exceptionally strong statistical significance from the first few hours, again without relapse of colds. Our article caused others to attempt to replicate our findings.

In 1984, the Medical-Scientific Director of RBS Pharma-Milan (now part of Rôhne-Poulenc Pharma, Italia, S. P. A.), Rinaldo Pellegrini sought my team's advice on how to compound zinc gluconate lozenges. By that time, my team had completed a no-effect zinc orotate (non-ionizable) lozenge for common colds study. On the basis of the conflicting zinc gluconate and zinc orotate results, we recommended avoidance of zinc chelators in lozenges. The pleasant-tasting, fructose-based RBS Pharma lozenges were tested on experimental colds by David A. J. Tyrrell and co-workers at the Great Britain Medical Research Council (MRC) Common Cold Unit. Analysis of the data from the MRC study showed nasal secretions essentially returned to normal in the zinc-treated group by day 4, while colds in the placebo-treated group continued. Analysis of mean clinical scores showed colds were essentially absent in six days with zinc treatment. Compared to the historic average of 10.8 days for untreated colds, a reduction of 4.8 days in common cold duration occurred. For the first time, an internationally recognized common cold research group verified a clinical treatment to shorten common cold symptoms. The positive results were discomfiting to the MRC scientists, because the operative mechanism remained elusive.

The issue became confounded when other studies came up with different findings from the Texas and MRC studies. Some zinc gluconate lozenges had objectionable taste and long-lasting aftertaste, seriously impairing patient compliance. Zinc gluconate developed a reputation for being bitter, and lozenges needed flavor-masking. Actually, bitterness results only when zinc gluconate is combined with dextrose. Zinc gluconate in fructose -- as in the MRC lozenges -- tastes pleasant when flavored and has a mild aftertaste. The wide disagreement between studies caused researchers to assume the positive findings to be faulty. In 1988, letters to the editor of Antimicrobial Agents and Chemotherapy suggested differences in stability constants as being responsible for failures. The letters produced both insightful, and misleading information.

In apparent defense of citric acid flavor-masked zinc gluconate lozenge work, one letter asserted zinc gluconate-citrate lozenges produced a salivary pH of 2.3 (stomach acid pH), contending one hundred percent of the zinc was released as Zn²⁺ ions.

Realizing the improbability of a salivary 2.3 pH from use of the zinc gluconate-citrate lozenges and the improbability of availability of Zn²⁺ ions at physiologic pH, Guy Berthon, Director of Research at INSERM Unit 305 in Toulouse, France, entered the fray. One responsibility of INSERM Unit 305 is to determine the bioavailability of drugs at physiological pH 7.4, the only relevant pH for antivirals and many other chemotherapeutic agents. Determination of bioavailability is a complex and difficult effort involving solution chemistry. After a close collaboration between Guy Berthon and myself from 1988 to 1993, a report was produced thoroughly examining bioavailability of Zn²⁺ ions from the conflicting zinc lozenge articles. The resulting report, -- The "Zinc Lozenge and Common Cold Story" -- is published separately by Marcel Dekker, Inc. in Handbook of Metal-Ligand Interactions in Biological Fluids, edited by Guy Berthon. We all owe Guy Berthon our gratitude. Had he not intervened, the work would have died, and I would have gone on to do something else, disillusioned and disappointed. Worse, an effective cure to the common cold would have been buried and probably never resurrected.

Presentation of comprehensive solution chemistry data is part of the analysis of the various conflicting reports in this handbook. Guy Berthon's research demonstrated Zn²⁺ ions were available at physiologic pH from efficacious zinc gluconate lozenges. More importantly, he clearly and convincingly demonstrated Zn²⁺ ions were not available at physiologic pH from non-efficacious lozenges.

Quantification of the amount of Zn²⁺ ions capable of penetrating oral mucous membranes through lozenge use relies upon Zn ion salivary concentration at pH 7.4 and time of contact, following Fick's laws of membrane diffusion. The zinc ion availability (ZIA) method of analysis discussed in Chapter 3 was developed in 1991 as an application of Fick's laws in a mouth-nose BCEC. ZIA values are determined by the availability of Zn²⁺ ions at pH 7.4 over time of absorption into oral mucosal membranes.

Electrical charge of zinc species is important as Zn²⁺ ions are absorbed into oral tissues and follow a readily measurable mouth-nose BCEC. Neutral and negatively charged species are unaffected or repelled, respectively, and have no known biologic activity in treating colds.

Comparing ZIA values of the zinc lozenges to the resultant changes in duration of colds yields a linear regression having a r (rho) value of 0.96, providing reconciliation of all previously divergent results and a sound statistical basis for a unifying hypothesis. For complete details, see Chapter 5 and examine Figure 19 entitled "Relationship of zinc ion availability (ZIA) values and reduction in duration of common colds." Lozenges having a positive ZIA released Zn²⁺ ions and were beneficial. Lozenges releasing no Zn²⁺ ions produced no results, and lozenges having negative ZIA values usually worsened colds.

The ZIA versus cold duration relationship also demonstrates a method to predict outcome of future studies with assurance of results in clinical trials. Linearity in ZIA -- versus -- cold duration data is the heart of this handbook and forms the foundation for future research.

Chapter 7 discusses zinc acetate lozenges as the successor to zinc gluconate for use in common cold treatment. Zinc acetate has essentially no taste in dextrose or fructose at efficacious ZIA values, and lozenges are flavor-stable when properly formulated. Zinc acetate lozenges release 100 percent of their zinc as Zn²⁺ ions at physiologic pH 7.4. Full ionization of zinc acetate is a significant improvement over zinc gluconate, as zinc gluconate releases only 30 percent Zn²⁺ ions possible at pH 7.4. Chapter 7 details findings relating ZIA-to-lozenge dissolution rates, compressive forces used in tablet manufacture, zinc dosage, lozenge weight, and many other variables. Chapter 7 also shows unexpected non-linearity in ZIA values as zinc acetate content is increased in lozenges.

Without comprehensive solution chemistry and ZIA analyses, understanding differences between the zinc lozenges for common cold studies is impossible, as was found by Y. J. Potter and L. L. Hart, who surveyed literature describing use of zinc lozenges for common colds in the May 1993, issue of The Annals of Pharmacotherapy. Potter and Hart were given an impossible task, as they only had an idea of the complexity of the chemistry involved and did not have sufficient information (particularly critical unpublished lozenge design materials from manufacturers) to arrive at a correct conclusion.

I believe governmental and pharmaceutical company officials, as well as the public, want an inexpensive and safe cure for common colds. Unfortunately, present society has been taught to equate common cold cures to the elusive fountains of youth sought centuries ago. Without this handbook, the literature seems to support that belief. I sincerely hope this handbook will stimulate medical researchers without vested interests in other common cold treatments to conduct clinical trials of ZIA 50 to 200 zinc acetate lozenges for common colds. Before the public can benefit, responsible public and private health officials must find the truth for themselves. Once the -- no cure for the common cold -- fable is universally revealed as false, perhaps governmental and pharmaceutical company officials will listen to my zinc lozenge story and the public will eventually benefit.

Engraved in glistening white marble above the entrance to the University of Texas Main Building in Austin, Texas, which houses comprehensive medical, life science and pharmaceutical libraries, are the encouraging words: "Ye shall know the truth and the truth shall make you free."

Perhaps the full truth about zinc lozenges and common colds established and preserved in this handbook will result in new, focused research and submission of a New Drug Application to the United States Food and Drug Administration for zinc acetate lozenges as cure for common colds. I have done all I can. I must place the future of zinc acetate lozenges as cure for common colds in the hands of others. Let's see what will be done. Assuming availability of appropriate finances and cooperation by common cold authorities and regulatory agencies, we can rightfully expect zinc acetate lozenges to win approval of a Food and Drug Administration New Drug Application, resulting in placement of zinc acetate lozenges as the cure for the common cold on the market within the next five years.

George A. Eby