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Discussion
Discussion

By comparing daily ZIA values from lozenges having a non-negative ZIA (dose) and the duration of common colds (response) resultant from use of the lozenges in Figure 2, a well-defined relationship between them can be observed.

Linearity of Dose-Response as Central Finding

Linearity in the dose-response relationship between studies using lozenges having nonnegative ZIA values is the central finding of this report. Linearity disproves the conclusion by Potter and Hart that efficacy of zinc lozenges in treating common colds has yet to be proven.(3)

Linearity shows that seemingly divergent results are completely reconciled through consideration of ZIA values. The ZIA value -- but not total zinc -- is correlated directly with the reduction in duration of common colds, consistent with the in vitro findings of Merluzzi et al. for activity of Zn2+ ions against rhinovirus replication.(10)

Although the linear relationship between ZIA and clinical efficacy of trials is evident, much of the evidence for efficacy relies upon two trials -- that of Eby et al.(1) and Al-Nakib et al.(2) Negative results from trials using lozenges having low, zero and negative ZIA values show that Zn2+ ions are needed for efficacy, and these findings are not in conflict with positive findings. Indeed, they support the theory of in vivo Zn2+ ion antirhinoviral activity presented by Eby et al.(1)

Linearity in dose-response shows efficacy against common cold duration from clinically untested lozenges is predictable based on the basis of readily determined ZIA values of experimental lozenges.

Linearity in the dose-response relationship between studies using lozenges having nonnegative zinc ion availability values is the central finding of this report.

Importance of Availability of Zn2+ Ions at Physiologic pH

The linearity in dose-response shown in Figure 2 further supports the concept that Zn2+ ions are absorbed from zinc lozenges into oral and oropharyngeal tissues only at pH 7.4, consistent with findings by others concerning homeostatic regulation of acid-base balance.(26,27) If such were not the case, zinc gluconate-citrate lozenges, and other lozenges containing highly chelated zinc would have been effective in treating colds, as Zn2+ ions were generally available from them in moderately acidic solutions.

Facets of a Continuum

Each zinc lozenge for common colds trial showed only one facet of the continuum of possible results from lozenges having ZIA values varying from negative 55 to positive 100. Data for each of the zinc lozenge for common cold reports appears to have been correctly reported, although important data were frequently omitted and resultant data was misinterpreted which led to great confusion.

Tablet Bases

Sweet carbohydrates are usually acceptable as tablet bases in zinc lozenges intended to release Zn2+ ions. However, many zinc compounds, including zinc gluconate, mixed with sweet carbohydrates other than fructose result in exceedingly bitter complexes in solid state reactions after aging of compositions. Bitterness from zinc compounds is much more evident in hard-boiled sweets than in compressed tablets. Without strong zinc chelators added, boiled sweets containing zinc gluconate readily carbonize at all manufacturing temperatures. Had these circumstances not been the case, clinical success would have been higher because confounding variables (additive zinc chelators) would not have been needed or present.

Generally, carbohydrates are extremely weak zinc chelators. For example, dextrose has a first stability constant for zinc of log K1 = 0.01,(29) resulting in no competition as a zinc binding agent, compared with gluconic acid, which has a first stability constant for zinc of log K1=1.70.(45)

Excluding Metal Chelators

Strong metal chelators, also known as sequestrants or metal binding agents, tightly bind Zn2+ ions at neutral pH, but rarely at stomach acid pH. Strong zinc chelators having first stability constants over log K1 = 2.0 are incompatible with Zn2+ ion release; these include all amino acids, citric acid, ethylenediaminetetraacetic acid, salicylic acid, tartaric acid, most other food acids, acacia (gum arabic) and other vegetable gums, alkalis and their carbonates, oxalates, phosphates, sulfides, caustic lime, lake food colors, histamine, histadine, proteins, porphyrins, peptides, and other macromolecules.(46,47) All water-soluble anionic chemicals will bind zinc to some extent and should be excluded from lozenges. With increased first stability constants, more zinc is complexed leaving less zinc in cation form at each pH. Zinc compounds having a low first stability constant (zinc chloride log K1 = 0.00 or lower) react with carbohydrates forming brown spots on lozenges.

In clinical trials and use generally, food and drink (particularly highly processed or manufactured foods and drinks containing metal chelators as stabilizers) should be avoided for 30 minutes before and after zinc lozenge use. Sleep after zinc lozenge use has been associated with accelerated recovery, and may be resultant of immobilization of lymphatic removal of Zn2+ ions or non-use of foods and drink.

Validity of Negative Zinc Ion Availability Values

Negative ZIA values for 2 of the 3 zinc lozenges having excess strong zinc chelators were estimated by straight-line projection of the non-negative values in Figure 2. Lengthened colds were associated with several lozenge formulations having negative ZIA values -- that is, lozenges releasing negatively (and neutrally) charged zinc species at pH 7.4. One may question the validity of negative ZIA value estimates, but the fact remains that lozenges releasing negatively charged zinc species (ZnLN-) increased the duration of common colds in a dose-response manner relative to placebo.

Perhaps ZnLN- from zinc lozenges bound native Zn2+ ions present in oral and nasal tissues and fluids. In mast cell and basophil granules, Zn2+ ions are highly concentrated (4 to 20 mmol).(48) These Zn2+ ions are released during degranulation of these cells during inflammation.(49) If release of Zn2+ ions from these cells during inflammation has the function of inhibiting viral replication,(5-10) stimulating T-cells,(21-23) stabilizing cell membranes,(12-20) regulating mast cell homeostasis,(49) catabolizing histamine,(37,42) and stimulating interferon production(21-23) during common colds, as they do in vitro, then one could infer that common colds would be lengthened by neutralizing native Zn2+ ions with ZnLN- to render them biologically unavailable at physiologic pH.

The benefits of orally applied Zn2+ ions in reducing severity and duration of common colds have been demonstrated. Furnace analysis atomic absorption spectrophotometry demonstrated that zinc from zinc-laden saliva is not found in nasal mucus (personal communication, JM Gwaltney Jr, University of Virginia School of Medicine, January 25, 1984). Because the locus of infection is in the nose, logic suggests that Zn2+ ions should be applied using nose drops or nasal sprays, not orally by lozenges. However, highly ionizable to nonionizable zinc compounds have been used intranasally since the turn of the century as a mild, short-acting decongestant with no evidence of efficacy in shortening the duration of common colds. Zinc gluconate nasal spray used every 15 to 30 minutes in conjunction with zinc orotate lozenges were found to act as a mild decongestant, but had no effect upon common cold duration.(25) Frequent nasal application of Zn2+ ions (0.1% w/v zinc sulfate) showed no therapeutic effect in reducing the duration of common colds, but did show a mild decongestant effect (personal communication, D. Bryce-Smith, Professor, University of Reading, Berkshire, England, March 30, 1992). Thus, more than getting Zn2+ ions onto nasal tissue surfaces must be involved in reducing the duration of common colds using Zn2+ ions.

The mouth-nose BCEC selectively promotes movement of Zn2+ ions, but not neutrally or negatively charged species, from lozenges through the oral mucosal membranes to the infected superficial columnar cells of the nasal turbinate epithelium and nasopharynx, resulting in efficacy. Conversely, an outflow of electrons from the surface of nasal tissue (as well as outflow of nasal mucous and action of cilia) impairs topical penetration of nasally introduced Zn2+ ions, explaining inefficacy of nasal administration.

Exceedingly low mouth-nose BCEC resistances and differentials appear associated with chronic nasal drainage and allergies for which zinc dietary supplements and lozenge treatments may be beneficial. Low BCEC resistances and differentials suggest limited immunity to upper respiratory tract infections. Extremely high resistance and differentials appear associated with strong resistance to nasal infections and allergy. Nasal resistances and differentials of mouth-nose BCEC may be as important, or more important, than antibody titer in determining a patient's susceptibility to upper respiratory tract infections. Facial skin has a near infinite resistance as shown by an ohm meter.

Zinc Acetate as Successor to Zinc Gluconate

Of all zinc compounds tested by the present author in lozenges over the previous 10 years, zinc acetate dihydrate USP is the outstanding alternative to zinc gluconate as a source of Zn2+ ions. Zinc acetate also allows compressed tablets (compacts) to have pleasant tastes, even though the taste of zinc acetate crystals is vile.

The first stability constant of zinc acetate is log K1 = 1.0.(45) Hacht and Berthon demonstrated that zinc acetate releases 100% of its zinc as Zn2+ ion at any pH between 2.8 and 7.4 and far above,(41) yet it is sufficiently stable to be nonreactive with carbohydrates. Korant et al. demonstrated the antirhinoviral properties of zinc acetate.(5) Although hard-boiled sweets containing pharmaceutically active amounts of zinc acetate usually have an unpleasant metallic taste, are unpleasantly astringent, and often "set teeth on edge," otherwise identical compacts made at room temperature usually have excellent taste.

Zinc acetate compact ZIA values are nonlinear considering dosage, with higher than expected ZIA values resulting from use of high-dosage lozenges.(25) Astringency increases proportionately with ZIA values. Astringency reduces saliva generation, thus nonlinearly increasing mmol Zn2+ ion concentration and ZIA values. Astringency is far less noticeable in patients with colds than in healthy volunteers. Perhaps this difference is because oral, facial and nasal tissues in ill patients are more permeable than those in healthy volunteers, resulting in more rapid absorption and removal of Zn2+ ions from the oral mucosa. The edematous facial appearance of common cold patients is greatly reduced on use of zinc acetate lozenges, concurrent with rapid recovery, perhaps due to absorption of Zn2+ ions into facial tissues.

Unlike zinc gluconate lozenges, compacts of zinc acetate or several other highly ionizable zinc compounds having a crystalline fructose and dextrate tablet-base (30:70 to 50:50 ratios respectively) are flavor-stable and do not become bitter regardless of time or storage conditions.(50-52) Properly prepared ZIA 100 zinc acetate compacts have essentially no objectionable taste or aftertaste and do not produce adverse side effects.(25)

Compressive forces applied to compacts strongly influence zinc acetate lozenge ZIA values. Four-gram, crystalline fructose)- and dextrates-based, 3/4 inch diameter compacts containing 12 to 16 mg zinc (as zinc acetate) can have a ZIA value from 25 to 150 when used 9 times per day dependent mainly upon compressive forces used in tableting (1 to 7 tons) and consequent oral dissolution rates.(25) Peppermint oil on silica gel is a stable flavoring. Magnesium stearate is desirable as a tablet lubricant because its hydrophobic property slows lozenge dissolution. However, either compress softness or capping can occur with minor changes in compressive force if magnesium stearate as a sole lubricant is added too early during mixing. On the other hand, glyceryl monostearate increases tablet hardness and reduces capping but increases dissolution rate when used as a sole lubricant. A better lubricant is a mixture of magnesium stearate and glyceryl monostearate. Humidity control (< 55% relative humidity) is indispensable in lozenge manufacture.

Placebo Unblinding

Variations in clinical trial results previously have been attributed by others to placebo unblinding and faulty positive results. Because of the controversial nature of positive results in common cold research, the necessity of preventing placebo unblinding in trials cannot be overstated. Much common cold data collection is subjective and dependent upon statements of well-being made by patients. Therefore, patients receiving placebo lozenges and those receiving active lozenges must equally believe (statistically) they are receiving placebo or active. Provision for "don't know" should not be provided to taste testers. Complete details of placebo-matching efforts and results must be published along with positive clinical results for positive results to be convincing. Recommendations for clinical trial protocols are available from the present author.

Failure of Oral Administration

Orally administered (swallowed) zinc compounds have no effect upon the duration of common colds because non-toxic doses do not raise zinc serum concentration sufficiently high. Oral doses sufficiently large to raise serum zinc concentrations 10-fold to antiviral concentrations are emetic and toxic. Because of the drying effect of Zn2+ ions, parenterally administered (intravenous or aerosol) zinc acetate might be administered under hospital conditions to forestall life-threatening, inflammatory lower respiratory tract processes.



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