INVITED OPINION: Zinc Lozenges as Cure for Common Colds
Zinc Lozenges as Cure for Common Colds


Annals of Pharmacotheraphy 1996;30:1336-1338. (used with permission)

Do zinc lozenges cure the common cold? The Cleveland Clinic Foundation announced that zinc gluconate lozenges shorten the duration of colds by half.(1) This finding is of both medical and economic importance because many people lose several weeks from work or school because of colds each year. Lowered immune resistance allows some people with colds to develop bacterial suprainfections and/or lower respiratory tract involvement.

How did the Cleveland Clinic researchers find their way to such startling results? In 1979, my 3-year old daughter (now 20 years old) allowed the remnants of a chewed 50-mg zinc (from zinc gluconate) tablet to dissolve in her mouth rather than swallow it because she had a sore throat from a severe cold. She fell asleep with the chewed tablet remaining in her mouth. Since she was immunosuppressed for acute T-cell lymphocytic leukemia, we expected a long and nasty cold involving antibiotics for probable suprainfections. In about two hours she awoke feeling as if she had never had the cold. With no further treatment, the cold did not return.

This observation was confirmed by field experiments and the original 1984 Texas study of Eby et al.(2) and from those results, the confirming British 1987 study.(3) Respectively, these studies showed a 7- and 5-day average reduction in the duration of common colds from zinc lozenges compared with placebo. The lozenges used in these two studies were astringent. They did not contain dextrose, an ingredient that when mixed with zinc gluconate converts to an extremely bitter substance over time.

Manufacturers discovered the bitterness problem when they incorporated zinc gluconate into candy lozenges or compacts. To determine whether lozenges masked with chemical flavors would work, citric acid,(4) tartaric acid with sodium bicarbonate,(5) and glycine were added.(6) Lozenges from the first 2 studies released pseudoastringent anionic zinc species at pH 7.4, resulting in worsened colds.(7) Lozenges from the third study released mainly neutrally and negatively charged zinc species producing mixed results. Zinc aspartate and zinc orotate lozenges produced no change compared with placebo lozenges.(7) Low dosage, bitter zinc gluconate lozenges produced little if any benefit, with compliance being questionable.(7-9)

Why would results produced from different zinc lozenge compositions differ so greatly? The answer can be found only through solution chemistry analytical techniques, analysis of lozenge zinc ion availability, and by remembering that the only pH of significance in treating colds with zinc lozenges is physiologic pH 7.4 , the pH of tissue, lymph, serum, and blood.(10,11)

Since Zn2+ is required for inhibition of rhinoviral replication, (12,13) cell membrane protective effects,(14,15) and other immune functions in colds, one might expect uncharged zinc species to have no effect on common colds. However, it could not have been expected that colds would be worsened by anionic zinc species at physiologic pH.

For anionic zinc species to worsen colds, Zn2+ must have the same effects in colds as they do in vitro and negatively charged zinc species must neutralize free Zn2+. For colds to be worsened as a result of neutralized zinc ions, considerable amounts of Zn2+ must be native to the infected tissues of the nasal mucosa. Where could Zn2+ originate in common colds? Mast cell granules contain histamine, heparin, other biochemicals, and unsequestered Zn2+.(16)

The release of Zn2+ from healthy, zinc replete mast cells appears to play a significant role in the termination of inflammation and catabolism of histamine in colds and in the prevention of nasal allergy symptoms.(7,17) Their release is a vital source of Zn2+ for inhibition of rhinovirus replication, cell membrane protection, T-cell lymphocyte activation and regulation, and interferon release.(7) In cases where mast cell granules are not fully replete with Zn2+, inflammation is unchecked, with consequences being well known. In human serum, Zn2+ prevents histamine release from mast cell granules. Normal Zn2+ serum concentration is about 0.015 mMol, although in vitro prevention of histamine release is maximal at 0.1 mMol concentration.(18) Supporting the Zn2+ histamine catabolism theory are the findings of lower amounts of histamine in nasal lavages from people with either colds or nasal allergies compared with people without them.(19)

In 1983, Nordenström(20) found that positively charged metallic ions, including Zn2+, adhere to capillary walls changing their charge and thus providing conduits for other positively charged ions to move long distances without losing their positive charge. Loss of most Zn2+ to capillary walls explains why Zn2+ concentration in the mouth from lozenges needs to be at least 50 times rhinovirus replication inhibition concentration. Conversely, negatively charged zinc species from lozenges are not attracted to negatively charged capillary walls, cell membranes, viruses, or zinc binding proteins, leaving native Zn2+ as the main attractant, worsening colds.

Figure 1. Fraction of zinc released as biologically available Zn2+ from zinc compounds used in common cold clinical research. (from data in ref. 7)

Figure 1 shows zinc chloride releases 100% of its zinc as Zn2+ at physiologic pH. In compacts, it reacts with sugars to form brown spots. Zinc chloride lozenges taste caustic and reminiscent of chlorine. Dextrose and other sweet carbohydrates have a first stability constant for zinc ions of about log K1 = 0.0,(21) allowing chemical reaction with hygroscopic zinc chloride. Berthon (7,22,23) showed 30% of zinc from zinc gluconate to be present as Zn2+ at physiologic pH 7.4. Berthon's calculation for the zinc gluconate with a molar proportion of glycine lozenges used by Mossad et al.(1) showed that 9% of zinc was present as Zn2+ ions, 6% was zinc gluconate+, 36% was zinc glycinate+, 25% was zinc gluconate-hydroxide, and 24% was zinc glycine in solution [personal communication, Guy Berthon, PhD, Director of Research, Centre National de la Recherche Scientifique (CNRS) Institut National de la Santé et de la Recherche Médicale (INSERM Unit 305), Toulouse, France, July 16, 1996]. Tighter bound zinc compounds (first stability constants log K1 > 3) release essentially no zinc ions at physiologic pH 7.4.(7)

Prasad(24) suggested that zinc acetate, which releases essentially 100% of its zinc as Zn2+ regardless of pH, be used rather than zinc gluconate due to unresolved taste problems with zinc gluconate. Zinc acetate was stated to be a GRAS substance in a 1973 FDA report.(25) Dextrose, with its extremely low first stability constant for zinc ions (log K1 = 0.0),(21) does not compete with acetate (log K1 = 1.0)(26) or gluconate (log K1 = 1.7).(26) Why zinc acetate lozenges are both chemically and flavor-stable and zinc gluconate lozenges without glycine are not remains unknown. However, I believe zinc gluconate-hydroxide is the source of oral irritation, objectionable taste and aftertaste, and lozenge bitterness from plain zinc gluconate candy lozenges.(7,22,23)

Zinc ion availability (ZIA) is the term used to define zinc lozenge strength. Lozenge ZIA values are linearly related to duration of colds in clinical trials (Figure 2). Efficacy depends completely on lozenge ZIA value and compliance.(7,22,23)

The ZIA concept is an application of Fick's laws of diffusion as they are extended to include flow of charged particles in bioelectric fields.(20) The unidirectional mouth-nose biologically closed electric circuit (BCEC) moves Zn2+ from the mouth toward the nose. The same BCEC also repels Zn2+ from nasal application, rendering Zn2+ nose drops useless. This is the only BCEC observable from outside the human body.

ZIA is defined as the potential for daily absorption of Zn2+ into oral and oropharyngeal mucosal membranes at pH 7.4. Mathematically, ZIA = KZiT, where K = 0.7697, and Zi = initial concentration of Zn2+ (mMol), and T = time (min). For comparison between lozenge formulas, ZIA equals the constant 0.7697 times zinc dosage (mg), times fraction as Zn2+ at pH 7.4, times lozenge oral dissolution time (min), times number of lozenges used per day, divided by volume of saliva produced (mL).(7,22,23)

Figure 2. Relationship of zinc ion availability (ZIA) values and reduction in duration of common colds in days.(7,23)

Average duration of exponentially decaying colds equals their median duration (half-life) divided by the natural logarithm of 2.(7,22,23) From Figure 2, efficacy starts at ZIA 25 with colds lasting 1 day less than those of people using placebo. Using Figure 2 as the basis for estimating the ZIA value of the zinc gluconate-glycine lozenges tested by Mossad et al.,(1) their ZIA value is about 70, shortening average duration of colds by about 4.6 days. Zinc acetate lozenges having a ZIA value of 50 were sufficiently effective for the U.S. Patent and Trademark Office to issue U.S. patent 5,409,905 (Cure for Common Cold).

Zinc acetate USP seems to have a far brighter future than zinc gluconate without glycine in treating common colds for reasons of efficacy, safety, and taste. Fast dry zinc acetate lozenges have an average ZIA value of 100 and can terminate incipient colds, or shorten existing colds by 1 week. They are flavor-stable, pleasant tasting, sweet, minty and cooling. Their minor astringency is evident to people with healthy oral tissues, but not to people with colds. This difference in response occurs because tissues are more permeable in colds, allowing rapid removal of Zn2+ from oral tissues.(7,23)

Selye, in 1965, admitted that his thorough review of the mast cell literature failed to solve the "riddle of the mast cells".(27) In 1996, we know much more about the role of Zn2+ in health and disease, and if Zn2+ from mast cell granules has the same effects in human beings as Zn2+ has in vitro,(12-15,17,18,20,24,) then the release of mast cell granule Zn2+ is a newly recognized, vital part - foundation - of our immune system, and helps solve the "riddle of the mast cell".

Supplementing the diet with zinc can restore the function of zinc deficient T-cell lymphocytes and the thymus,(24,28) and refill mast cells granules greatly improving human health. Using lozenges releasing considerable Zn2+ to effectively treat colds, mononeucleosis, and acute nasal allergies is one unique way.(7) Golden et al. showed zinc-deficient children to have greatly increased susceptibility to severe infection, and restoration of thymic function and regrowth occurs only when large doses of zinc (2 mg zinc / kg body weight) are administered daily for a few weeks.(28) Parenteral or oral administration of sufficient zinc to temporarily raise Zn2+ serum concentration to about 0.1 mMol should prevent sequela and death from otherwise lethal viruses, toxins and venoms (including brown recluse spider bites) in accordance with the Pasternak et al. in vitro findings,(7,14,15) and in the treatment or prevention of anaphylactic shock and systemic edema.(7,27)

In my opinion, the old adage, "When you find the cure for the common cold, you can cure anything", now has vastly increased merit. I believe we are definitely on the right track in the study of zinc in health and disease, and much more research is vital to preserve and improve human health.

References

1. Mossad BS, Macmillan ML, Medendorp SV , Mason P. Zinc gluconate Lozenge for Treating the Common Cold - A randomized, double-blind, placebo-controlled study. Annals of Internal Medicine. 1996; 125: 81-88.

2. Eby GA, Davis DR, Halcomb WW. Reduction in duration of common cold symptoms by zinc gluconate lozenges in a double blind study. Antimicrobial Agents and Chemotherapy. 1984;25: 20-24.

3. Al-Nakib W, Higgins PG, Barrow I. Prophylaxis and treatment of rhinovirus colds with zinc gluconate lozenges. Journal of Antimicrobial Chemotherapy. 1987;20:893-901.

4. Farr BM, Conner EM, Betts RF. Two randomized controlled trials of zinc gluconate lozenge therapy of experimentally induced rhinovirus colds. Antimicrobial Agents and Chemotherapy. 1987;31: 1183-1187.

5. Douglas RM, Miles HB, Moore BW. Failure of effervescent zinc acetate lozenges to alter the course of upper respiratory tract infections in Australian adults. Antimicrobial Agents and Chemotherapy. 1987;31:1263-1265.

6. Godfrey JC, Conant Sloane B, Smith DS. Zinc Gluconate and the Common Cold. The Journal of International Medical Research. 1992; 20:234-246.

7. Eby GA. Handbook for Curing the Common Cold - The Zinc Lozenge Story. Austin: George Eby Research, 1994.

8. Weismann K, Jakobsen JP, Weismann JE, Hammer UM, NyhoLm SM, Hansen B, et al. Zinc gluconate for common cold. Danish Medical Bulletin. 1990;37:279-281.

9. Smith DS, Helzner EC, Nuttall CE Jr, Collins M, Rofman BA, Ginsberg D, Goswick GB, Magner A, 1989, Failure of zinc gluconate in treatment of acute upper respiratory tract infections. Antimicrobial Agents and Chemotherapy. 1989;33:646-648.

10. Adler S, Fraley DS. Acid-base regulation: cellular and whole body. In: AI Arieff, RA DeFronzo, eds., Fluid, Electrolyte, and Acid-Base Disorders. New York:Churchhill Livingstone. 1985;1:221-257.

11. Guyton AC. Regulation of acid-base balance. In: Textbook of Medical Physiology. New York:W. B. Saunders Company. 1986;37:438-451.

12. Korant BD, Kaurer JC, Butterworth BE. Zinc ions inhibit replication of rhinoviruses. Nature. 1974; 248: 588-590.

13. Merluzzi VJ, Cipriano D, McNeil D, Fuchs V, Supeau C, Rosenthal AS, et al. Evaluation of zinc complexes on the replication of rhinovirus 2 in vitro. Research Communications in Chemical Pathology and Pharmacology. 1989;66:425-440.

14. Bashford CL, Alder GM, Menestrina G, MickLen KJ, Murphy JJ, Pasternak CA. Membrane damage by hemolytic viruses, toxins, complement, and other cytotoxic agents - a common mechanism blocked by divalent cations. The Journal of Biological Chemistry. 1986;261: 9300-9308.

15. Pasternak CA. A novel form of host defense: membrane protection by calcium and zinc ions. Bioscience Reports. 1987; 7:81-91.

16. Danscher G, Obel J, Thorlacius-Ussing O. Electron microscopic demonstration of metals in rat mast cells. A cytochemical study based on an improved sulfide silver method. Histochemistry. 1980; 66: 293-300.

17. Berthon G, Varsamidis A, Blaquiere C, Rigal D. Histamine as a ligand in blood plasma. Part 7. Malate, malonate, maleate and tartrate as adjuvants of zinc to flavor histamine tissue diffusion through mixed-ligand coordination. In vitro tests on lymphocyte proliferation. Agents and Actions. 1987;22:231-247.

18. Marone G, Columbo M, de Paulis A, Cirillo R, Giugliao R, Condorelli M. Physiological concentrations of zinc inhibit the release of histamine from human basophils and lung mast cells. Agents and Action. 1986;18:103-106.

19. Eggleston PA, Hendley JO, Gwaltney JM Jr. Mediators of immediate hypersensitivity in nasal secretions during natural colds and rhinoviral infection. Acta Oto Laryngologia Supplement. 1984;413:25-35.

20. Nordenström BE. Biologically Closed Electric Circuits: Clinical, Experimental and Theoretical Evidence for an Additional Circulatory System. Stockholm:Nordic Medical Publications. 1983; 112-172.

21. Briggs J, Finch P, Matulewicz MC, WeigaL H. Complexes of copper(II), calcium, and other metal ions with carbohydrates: Thin-layer ligand-exchange chromatography and determination of relative stabilities of complexes. Carbohydrate Research. 1981;97:181-188.

22. Eby GA. The zinc lozenge and common cold story. In: Berthon G, ed. Handbook of Metal-Ligand Interactions in Biological Fluids, 2: Bioinorganic Medicine, Volume 2. New York: Marcel Dekker, Inc., 1995; 1182-1190.

23. Eby GA. Linearity in dose-response from zinc lozenges in treatment of common colds. the Journal of Pharmacy Technology. 1995;11: 110-122.

24. Prasad AS. Zinc: the biology and therapeutics of an ion. Annals of Internal Medicine. 1996;125:142-144.

25. Select Committee On GRAS Substances. Evaluation of the health aspects of certain zinc salts as food ingredients. Federation of American Societies for Experimental Biology, Life Science Research Office - SCOGS-21. November, 1973.

26. Cannan RK, Kibrick A. Complex formation between carboxylic acids and divalent metal cations. Journal of the American Chemical Society. 1938; 60: 2314-2320.

27. Selye H. The Mast Cell. Washington DC: Butterworths Press; 1965;403-404.

28. Golden MHN, Jackson AA, Golden BE. Effect of zinc on thymus of recently malnourished children. Lancet. November 19, 1977;1057-1059.




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