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.

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.

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.

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)

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)

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.