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Do Zinc Lozenges cure the common cold?

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 equimolar zinc gluconate-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 are not remains unknown. However, I believe zinc gluconate-hydroxide is the source of oral irritation, objectionable taste and aftertaste, and lozenge bitterness.(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-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 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:

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Annals of Pharmacotheraphy 1996;30:1336-1338, www.coldcure.com.