Zinc Lozenge Method of Treating Colds
Chapter 3. - Zinc Lozenge Method of Treating Colds

Chapter Executive Summary

Zn2+ ions are highly antirhinoviral both directly and through stimulation of interferon production. Zn2+ ions protect cell membranes in vitro as effectively as interferon. If a way to introduce and keep Zn2+ ions in the vicinity of superficial columnar cells of the nasal turbinate epithelium (the cells thought to be infected by rhinoviruses in common colds) could be found, then Zn2+ ions could inhibit rhinoviral replication and protect cells from rhinoviral attack in vivo. It may seem less direct or implausible to apply zinc to oral tissues and not nasal tissues, but administration to the nose is known not to reduce the duration of common colds. Zn2+ ions applied to the oral and oropharyngeal mucous membranes appear to be readily absorbed into the oral membranes where Zn2+ ions migrate into nasal tissues by diffusion, osmosis, and electrophoretic force. Saliva is well known to be continually absorbed into oral and oropharyngeal tissues.

Nasal Administration and Systemic Absorption

Foreign substances introduced intranasally are rapidly cleared by mucous secretions and require frequent administration (every 10 to 15 minutes)(1) to keep substances in the nose on top of nasal mucus, cilia and mucous membranes, but not within nasal tissues. Nasal mucus is constantly being excreted, flowing outward from tissues and carrying viruses, antigens, dust, and medications into the throat by action of the cilia. Zn2+ ion diffusion into these infected tissues by nasal administration against the flow of mucus and mouth-nose electrical circuit is difficult if not impossible. Zinc nasal spray does not result in clinical reduction in duration of common colds, even when 10 mMol zinc gluconate nasal spray is administered every 15 to 30 minutes, although zinc does provide a temporary decongestant effect.(2) Similarly, zinc sulfate nasal sprays have been shown by Derek Bryce-Smith at the University of Reading in Great Britain to have a mild nasal decongestant effect with no effect on the duration of common colds.(3) Considerable evidence (discussed in Chapter 2) from before 1900 to about 1960 shows that zinc compounds applied to the nostrils were weak nasal decongestants unassociated with reduction in common cold duration.

Additionally, oral doses of zinc do not produce sufficiently high concentration in the nasal tissues to affect common cold duration, unless the oral doses are extremely large (several grams), and these large doses may be somewhat toxic to blood-forming tissues and other organs.

Oral Cavity Absorption

A much more effective method of introducing Zn2+ ions into nasal tissues has been developed using zinc throat lozenges. This use results from a serendipitous observation in 1979 of a near-instantaneous relief from a cold after use of a 50-mg zinc as zinc gluconate lozenge in a leukemic 3-year-old child.(4) The oral cavity -- and oropharyngeal tissues generally -- being part of the digestive system absorb, rather than repel, nutrients and other soluble substances remaining in contact with them. Absorption through these mucous membranes has been likened to absorption by other digestive system tissues and particularly to intestinal tissues, while nasal tissues appear to be more akin to ciliated, involuted skin. General absorption of drugs kept in the mouth consists of a process of dissolution, followed by transport of dissolved drug and other soluble ingredients across mucosal membranes into tissues and usually into general circulation.(5)

Drugs must traverse several biologic membranes before reaching the site of action. In the oral cavity there are two regions, buccal and sublingual, where the membranes are very thin and have a copious blood supply.(6) Sublingual administration of Zn2+ ion entails the placement of the lozenge under the tongue for its ultimate absorption into the systemic circulation and is not really practical because of the large size of the lozenges. Buccal administration of Zn2+ ion is ordinarily accomplished by placing the lozenge between the cheek and gums. Drugs, including Zn2+ ions given by sublingual and buccal administration enter the circulation directly and are carried to oral, facial, nasal, and body tissues before passage through the liver6 where Zn2+ ions may be sequestered by leukocyte endogeneous mediator (LEM) action.(7,8) Venous drainage from the oral cavity goes directly to the heart.(6) Estimates of in vivo availability of charged species from static in vitro observations, such as 11 percent Zn2+ ions in saliva(9 and 2 to 8 percent Zn2+ ions in serum,(10) may or may not be applicable in vivo because of numerous factors including pH, temperature, and electromotive forces acting on charged particles. In common cold therapy with zinc lozenges, oral-nasal potential difference accelerates absorption of Zn2+ ions from saliva, ionization of Zn2+, and motility of Zn2+ ions.

With highly soluble substances such as ionizable zinc compounds, the rate of permeation across biologic membranes, not dissolution, is the rate-determining step. The rate of permeation is dependent upon size, relative aqueous and lipid solubilities, and ionic strength.(5,6) Like most biologic membranes, oral mucosal membranes are largely lipoidal in character. Hence, good lipid solubility of a drug is an important factor in assessment of its absorption potential. Many drugs are either weakly acid or weakly alkaline compounds, and in solution, depending on pH value, exist as ionized or un-ionized species. Un-ionized neutral species are more lipid-soluble and hence more readily absorbed in the absence of an electromotive force (EMF). Charged species depend almost totally upon concentration applied, time applied, and charges of membranes and ionized solute and are absorbed through passive transfer aided or repelled by electromotive forces.(5,11,12) Endothelial cells themselves are permeable for lipophilic substances but not for hydrophilic substances.(5,11)

A published Zn2+ ion oil/water partition coefficient has not been found but is expected to be extremely low or zero. Salivary glycoproteins coating oral mucosa are known to carry negative charges and are an important binding site for cationic substances, such as Zn2+, in the mouth.(5) The latter, including Zn2+ ions, pass through capillary walls through interepithelial spaces, called stomata, pores or leaky junctions and are attracted to electronegative oral mucous membranes.(11) Once Zn2+ ions enter the oral mucous membrane, they appear to follow preferential pathways in biologically closed electric circuits leading to the nose where they exert beneficial effects, and/or Zn2+ ions may be mechanically transported. Therefore, the main factors in determining the amount of Zn2+ ions transferring through oral mucosal membranes are salivary concentration of Zn2+ ions, and the time oral and oropharyngeal mucosal membranes are exposed to Zn2+ ions, as well as electrical effects, which are presumably about the same in all people.

The fate, route, movement, binding, and concentration of soluble zinc, including Zn2+ ions, once absorbed into oral and nasal tissues using this method have not been determined. With topical treatment by zinc gluconate or acetate lozenges, an increase in Zn2+ ion serum concentration in oral, throat, and nasal tissues appears both possible and probable. Capillary membrane pores are known to be sealed by Zn2+ ions aiding in the transport of Zn2+ ions over long distances.(11) However, Zn2+ ions from zinc gluconate throat lozenges do not appear in nasal mucus after use of one lozenge in amounts different from placebo during the first few hours after administration in well, non-allergic patients as determined through use of furnace analysis atomic absorption spectrophotometry.(13) Such results are not unexpected, as no evidence exists of goblet cells selectively taking up Zn2+ ions to mirror lymph or plasma zinc content so quickly.

Anecdotal observation of weak local tissue sensations while using zinc gluconate lozenges suggests a way to track movement of zinc into tissues. Some patients say the zinc seems to migrate: upward into the nose, eyes, and ears where drying actions on tissues can be observed; then into facial tissues, and temples where it can be felt; then downward into the throat, pharynx, esophagus, and stomach. A drying effect of Zn2+ ions in the throat and on vocal cords of singers having respiratory allergies who use zinc gluconate lozenges results in improved ability to sing, showing movement of zinc or its drying effects into the larynx and trachea.

Although the means by which zinc moves into these tissues remains obscure (perhaps diffusion, osmosis, and electrophoresis), lymphatic circulation more than venous circulation of Zn2+ ions out of these tissues is deduced. For example, if zinc lozenges are used throughout the day and at bedtime, then zinc concentration in nasal and nasopharyngeal tissues may become high, and movement of zinc out of these tissues stops when lymph movement stops. Consequently, Zn2+ ions remain in contact with virally infected tissues overnight without lymphatic drainage. Colds are most often observed to disappear during nighttime sleep, which is a time when lymphatic circulation is arrested. Upon arising, the mouth and nose are often unusually dry. Oral drying follows the use of highly ionizable zinc compounds (not tightly bound zinc) and may be explained by antirhinoviral, antihistaminic effects, cell membrane stabilization, anti-cytolysin (perforin) effects, astringency, and other anti-inflammatory properties associated with Zn2+ ions.

Because the content of zinc in plasma (mostly tightly complexed with albumin, transferrin, and other blood proteins) is about 1 mg/ml and in most tissues it ranges from 11 to 150 mg/g, obviously an active or facilitated uptake exists, but little is known of the nature of the uptake mechanisms of various cells.(14)

Mouth-Nose Electric circuit

According to B. E. Nordenström of the Karolinska Institute in Stockholm, ample evidence exists for circulatory circuits with the ability to move electrically charged metallic ions long distances.(11) Using a digital voltmeter, the present author has measured a 90 to 120 millivolt potential difference between the oral cavity and the interior of the nose, with the mouth acting anodic. A mouth-nose current may also be inferred using an ohm-meter. Reversing mouth and nose leads changes readings usually by about 10,000 ohms (10,000 ohms one way and 20,000 ohms the other way). Resistance fluctuates by 100 to 300 ohms with the respiratory rhythm. Similar measurements while dissolving zinc acetate lozenges and at various times up to an hour after dissolution showed the same results. If confirmed by others, these observations may be the most readily observable examples of biologically closed electric circuits (BCEC) in human beings.

A surplus of negative charge always characterizes the surface of cells as well as most viruses, although some tissues have greater electronegativity than others. The source of electrons in the mouth may be from loss of protons from mucoproteins passed from oral tissues into saliva or the potential-inducing, battery-like, action of the tongue. Nordenström has shown muscles, such as the tongue, and injured or infected tissues to generate potentials of the magnitude noted by Eby in the mouth-nose circuit.(11)

Positively charged Zn2+ ions appear to migrate along preferential pathways between the mouth and nasal tissues as well as into other non-oral local tissues and venous and lymphatic drainage pathways. Perhaps some fraction of Zn2+ ions migrates the long distance (aided by Zn2+ ion-induced capillary membrane pore closure) from the oral cavity into nasal tissues via preferential pathways in BCEC, and some migrates by mechanical transport. Intranasal Zn2+ ions should provide an antirhinoviral effect, induce interferon production, and dry nasal tissues. These findings suggest passive absorption (mechanical transport, diffusion, filtration, and osmosis) of Zn2+ ions from mouth into the nose to be aided by electrophoresis.

Along with the strong repelling effects of nasal mucus and cilia on foreign substances introduced to the nose as noted by Aoki1 and many others, the voltage differential repels intranasally introduced Zn2+ ions from mucosal surfaces, further explaining inefficacy from 10 mMol zinc gluconate nasal sprays (see Chapter 4.B.1.).

Fick's First Law

Linearity in pharmaceutical dose-responsiveness is usually attributed to passive diffusion of neutrally charged lipophilic substances across biologic membranes according to Fick's first law and to mechanical transport by the arterial, venous, and lymphatic systems. Toxicity from intracellular accumulation of zinc from lipophilic or strongly bound complexes of neutrally charged zinc(15,16) may be quite real, suggesting only non-toxic, astringent, 100 percent hydrated Zn2+ ions should be provided from zinc lozenges.

Passive diffusion happens when drug molecules exist in high concentration on one side of a membrane and lower concentration on the other side. Diffusion occurs in an effort to equalize drug concentration on both sides of the membrane in those cases where the rate of transport is proportional to the concentration gradient across the membrane. When the volume of fluids is fixed, the movement of drug across a membrane can be described in terms of Fick's laws.

Fick's first law states the rate of diffusion or transport across a membrane is directly proportional to the surface area of the membrane and to the concentration gradient and is inversely proportional to the thickness of the membrane.(6) The general expression for Fick's first law of diffusion is dm/dt = -DAdc/dx where m is the quantity of drug or solute diffusing in time t, dm/dt is the rate of diffusion, D is the diffusion constant, A is the cross-sectional area of the membrane, dc is the change in concentration, and dx is the thickness of the membrane.(6) A change in any of these variables will alter the rate of transport of drug into the blood over a given time.

Drugs are rapidly absorbed through thin membranes such as the oral mucosa. In the assessment of absorption potential of drugs, various experiments using biologic membranes have been conducted to demonstrate Fick's first law. Experiments are carried out at different mucosal concentrations of drugs to determine the response to treatment.

Constancy of amount transferred per unit time per unit concentration over a wide range of mucosal solution concentrations indicates passive transfer of drug and compliance with Fick's first law.(5,6) Passive transfer refers to a free diffusion across a membrane composed of channels of various sizes without biologic activity or electrochemical processes being involved.(5,6)

As the concentration gradient across the barrier is increased, the flux across the barrier increases in direct proportion.(5,6) By varying the amount of drug given in vivo in a given time drug concentration can be varied. Drug absorption is ascertained by blood and urinary analysis or by response to treatment.(5,6)

A linear relationship between different amounts of drug given in a given period and the degree of improvement suggests absorption under Fick's first law applies in vivo.

In common cold therapy with Zn2+ ions, ectrophoretic effects alter Zn2+ ion motility and absorption under Fick's laws, which increases absorption over uncharged substances. Fick's laws include electromotive forces acting on electrically charged particles.(11,12) Hydrated Zn2+ ions move across membranes and through living tissues under Fick's first and second laws.(11) Hydrophilic substances, including Zn2+ ions, pass between cells through interepithelial spaces called stomata, pores or leaky junctions; in the case of metallic ions, they also follow preferential pathways in BCEC.(11)

Positively charged metallic ions are transported in charged clusters reacting with electronegative cell membranes at short distances or at long distances when capillary cell membranes are closed by high concentrations of Zn2+ ions.(11) Negatively charged complexes are repelled from cell surfaces and viruses which are always electronegative.(11) In contrast, neutrally charged complexes are not aided or repelled by electric fields and their movement depends only upon diffusion and mechanical transport.(11)

Ionic Diffusion

Starting with the authoritative works of Lehninger,(17) Bockris and Drazic,(18) Newman,(19) Nobel(20) and others, in the field of energy exchanges in chemical reactions, Nordenström developed the concept of biochemical reactions in BCEC to include ionic diffusion. Ionic diffusion in BCEC occurs according to Fick's first law which can also be written as -Q = D (dc/dx) in which Q, in mole per m2t, is the quantity of ions traversing a unit area of solvent per unit time. The factor D is the diffusion coefficient, which expresses (in 1/ m2t units) the proportional ability of an ion to diffuse a distance dx in a solvent at a concentration difference dc. In a non-steady state this concept can often be expressed as x = constant times the square root of Dt, where D = diffusion constant (in 1/m2t) and t = time (seconds).(11)

In Nordenström's eloquent words, in the following equation representing a nonstatic condition, the amount of material Q passing a unit area A per second over distance dx leads to QA - (Q + dQ/dx x dx) A = dc/dt x Adx showing the inflow of material Q through the area A, minus the rate of Q though the area A over the distance dx, equals the concentration change per unit time though the distance dx through the same area A. This equation can be simplified to the continuity equation -dQ/dx = dc/dt. Substituting Fick's first law into the continuity equation results in Fick's second law dc/dx = D(d2c / dx2), which in a three-dimensional distribution, gives dc/dt = D(d2c / dx2 + d2c / dy2 + d2c / z2). This equation describes the function of local administration of an ionic drug, such as Zn2+ ions, during application of experimental direct current or within a BCEC in living tissue.(11)

In common cold treatment with zinc lozenges, ionic motility and total diffusion calculations can be used in theory. However, for practical use in comparing the efficacy of different zinc lozenge formulations against the duration of common colds, Fick's laws can be greatly simplified by assuming constancy between patients for the cross-sectional area of the oral mucosal membrane, its thickness, facial three-dimensional geometry, BCEC configuration, mouth-nose EMF (and direction), as well as many other variables excluding all but the number of doses, the lozenge dissolution time, the electronic charge of the zinc species and the initial zinc concentration. Perhaps the largest error introduced by these assumptions results from the differing characteristics of small children and adults. By introducing time, rates are converted into totals.

Zinc Ion Availability (ZIA) Values

The notion of zinc ion availability (ZIA) used here is derived from Fick's first and second laws of diffusion, but ZIA does not measure the amount of Zn2+ ion absorbed across biologic membranes. By calculating ZIA values for the various studies, the finding of linearity in response to treatment (see Figure 19 in Chapter 5) suggests ZIA to be a relative determinant of the amount absorbed in compliance with Fick's laws of membrane diffusion. Therefore, ZIA is defined as the potential for daily absorption of Zn2+ ions into oral and oropharyngeal mucosal membranes at pH 7.4 between lozenges having several different characteristics, or ZIA = KZiT, where K = 0.7697, and Zi = initial concentration of Zn2+ ions, and T = time.

For calculation of daily ZIA for comparative purposes between lozenge formulations, the daily ZIA value equals the constant 0.7697, times lozenge zinc dosage (mg), times fraction as Zn2+ ion at pH 7.4 (initial fraction before precipitation of Zn2+ ions by salivary proteins and absorption into oral mucosal membranes), times oral dissolution time (minutes) of lozenges, times lozenges used per day, divided by volume (ml) of saliva generated (numerically equal to total saliva generated minus lozenge weight in grams corrected for lozenge specific gravity) during each oral dissolution. Some of the facts can be determined only by studying the intra-oral dissolution/expectorations of zinc-laden saliva, or zinc-laden saliva. Linear, or at least uniform, lozenge dissolution rates occur in all lozenges tested (see Chapter 7).

To further illustrate, the ZIA value of the original 1984 Eby lozenges is 100. The 660 mg lozenges containing 23 mg zinc gluconate initially released 30 percent Zn2+ ion at pH 7.4 (see Figure 1 in Chapter 1). The constant K is 0.7697. Lozenges dissolved in 30 minutes. Lozenges were used 9 times a day. Lozenges generated 15 ml zinc-laden saliva per application. When multiplied together, they equal +129.92K. To set the ZIA to 100 for the Eby lozenges as a standard; K, therefore, equals 0.7697 ml / minutes x mg x doses/day.

The ZIA formula and concept are used throughout the remainder of this handbook to compare critical performance criteria of different zinc lozenge formulations. Lozenges with equal ZIA values, within a reasonable range centered on the above example, theoretically will have equal efficacy against colds, although initial Zn2+ ion concentrations should be more than 5 mMol.

In the event more strong zinc chelator is present than needed to bind all Zn2+ ions and to otherwise produce a ZIA value of zero, the ZIA value is considered to be negative.

Mathematics of Common Cold Duration

Review of common cold studies shows results to have been expressed in various terms, with most of them showing the effect of treatment on symptom severity. Techniques include mean clinical scores, symptom clinical scores, total nasal mucus weights, total number of facial tissues used, and other subjective measures of wellness.

More recently, half-lives of common colds and weighted average durations of common colds were shown to be appropriate means of common cold analysis when the rate of decay is exponential.(4) According to Gwaltney, one-half of untreated rhinovirus colds are over in one week, three-fourths are over in two weeks, while seven-eighths last three weeks or less, and so forth.(21) Therefore, the half-life (H) of untreated colds is 7 days. With each passing week, one-half of remaining colds disappear.

Figure 2.  Effect of different half lives on colds Figure 2. Effect of different half-lives on percent of patients with symptoms on various days, showing weighted average durations (arrows).

The effect of a hypothetical zinc and placebo treatment having different half-lives on percentage of patients during first week of treatment and projected values beyond the week of treatment are shown in Figure 2. Consider the situation where 50 percent of patients are well by day 2.2 with zinc treatment and by day 7 with placebo; 75 percent are well by day 4.4 with zinc treatment, and by day 14 with placebo; 86.5 percent are well by day 6.6 with zinc treatment, and by day 21 with placebo. Using half-life theory, the expected number of patients recovered can be projected beyond duration of studies. Estimates after the week of treatment are predicated upon half-life of colds continuing to decay at same rate as during the week of treatment.

Related to the half-life of common colds is the average duration. Although average duration is not the same as half-life, they are frequently confused with each other. The average duration is equal to the number of days colds persist, where the sum of days is taken over the collection of patients, divided by total number of patients. The average duration is mathematically related to half-life (H) of common colds. For common colds decaying at a set exponential rate, average duration of common colds is provided by the mathematical expression where N is initial number of patients, and H is half-life of colds observed in study group.

Average duration of colds by half-lifes

The expression simplifies to H/ln 2, and ln 2 equals 0.6931. Therefore, once the half life (H) is determined and the decay rate is found to be exponential, the average duration can be directly determined. For example, zinc-treated colds having a half life of 2.2 days have an average duration of 3.2 days, and placebo-treated colds with a half-life of 7 days have an average duration of 10 days. Arrows in Figure 2 show weighted average duration. Differences in weighted average duration between treated and untreated colds directly follow. This method is not reliable for colds not decaying at an exponential rate.

Other methods of determining average duration must be used for non-exponentially decaying colds, which would involve observing the duration of each cold, an arduous task for placebo-treated colds. In the case of nonexponentially decaying colds, half-life analysis and comparison of decay rates (plotted as the number of colds remaining on each day of the study) are probably sufficient.

The above method of determining half-life and estimating average durations for exponentially decaying common colds should be adopted as the favored means to measure effects of zinc lozenges on shortening the duration of common colds. Half-life and average duration analyses may be used to supplement all other methods of measuring effects of treatments including mean clinical scores, total nasal mucus weights, and number of facial tissues used. Each of the reports in Chapter 4 have been re-analyzed using published facts and factual details from lozenge manufacturers, and half-life and average reductions (or increases) in duration have been calculated using all the available information.

Chapter 3 References

Chapter 4