| Introduction |
Handbook for Curing the Common Cold -- The Zinc Lozenge Story is provocatively titled. Some professionals may be inclined to reject this idea without reading past the first line. If so, consider that this handbook is a serious scientific writing on how to shorten the duration of common colds using zinc lozenges. This handbook shows zinc content alone is insufficient to determine efficacy; rather, the zinc compound used, the oral residence time, and other physical and chemical properties of lozenges determine lozenge efficacy.
Most people do not believe a cure for the common cold will be developed until well into the 21st century. If the reader is discomforted by what he reads, it is because the handbook disputes the "no cure for the common cold" conception. Scientists and physicians sometimes become defensive, and even apoplectic, at the thought of a lowly inorganic created near the beginning of time in a distant supernova having such novel effects. For laymen to learn a simple, readily manufactured common cold cure is available now, and to find major pharmaceutical companies have ignored it can be a source of considerable irritation as well. Perhaps those companies have turned away only because they have not understood the complex issues and solution chemistry involved.
A medical name for such rejection is the "tomato effect," according to Drs. James and Jean Goodwin writing in the Journal of the American Medical Association.(1) The Goodwins point out that many highly efficacious therapies, particularly very simple and inexpensive ones, are rejected if they are not completely understood. Often what gets lost in selecting a therapy are the only issues that really matter: Does it help? Is it toxic? How much does it cost?
This handbook opens a bold new world with its comprehensive instruction for further
exploration and maximization of understanding of the mechanisms of action, formula-
dependent efficacy, safety, and low cost of zinc acetate lozenges. As with many other
treatments, we may never be able to pinpoint the precise mechanism of action. With a
billion or more colds per year in the United States alone, a cure is desperately needed --
whether it is simple or complex -- so long as it is effective, safe, and inexpensive. A
simple solution for many colds is now available. It is not what classically trained
scientists wanted, but it is available to those sufficiently secure in their own training to
accept radical new concepts. The discovery of zinc lozenge for common colds must not,
therefore, become another "tomato effect."
Acute respiratory illness accounts for over one-half of all acute disabling conditions
annually according to national health survey data.(2) The common cold is the most
common of identifiable acute respiratory disorders and accounts for about 20 percent of
all conditions and ailments and about 40 percent of all respiratory conditions.(3) This
includes 110 million disabling colds per year, causing about 300 million days of
restricted activity, about 60 million lost days of school, and about 50 million lost days of
work.(4) When considering minor, nondisabling respiratory illnesses, common colds
represent a still higher proportion of respiratory diseases. They are estimated to occur
at rates of two to five colds per person per year. About 5 percent of the population have
a cold at any given time. Common cold symptoms usually last from a few days to two
weeks, and one-half are over in a week. Over one billion common colds occur in the
United States each year. Financial considerations of the common cold are staggering.
About $5.5 billion per year are spent on colds in the United States. About $3 billion are
spent on professional consultations with about $1.5 billion on remedies and about $1
billion on analgesics, much of that amount for treating common colds.(5) Many acute
respiratory disorders affect human beings, but this handbook considers only the
common cold, which is technically considered to be a viral, usually rhinoviral, infection
of the superficial columnar cells of the nasal turbinate epithelium and perhaps the
nasopharynx.
Michael Castleman's book "Cold Cures"(5) accurately condenses much of what is
currently known about the etiology of common colds. His book is cited in these sections
because of its essential authenticity and readability and because Handbook for Curing
the Common Cold is not about common colds per se, but their treatment with zinc
lozenges. Individuals interested in the virology, immunology, and physiology of
common colds should read the authoritative works of others.
Common colds are induced by over 200 types of viruses, with over 113 types of
human rhinoviruses causing the majority. Colds are also caused by corona viruses,
influenza viruses, herpes simplex viruses, respiratory syncytial viruses,
coxsackieviruses, parainfluenza viruses, adenoviruses, and echo viruses. Some colds
are caused either by unknown agents or viruses causing systemic viraemia. Echo
viruses, polio, measles, and some adenoviruses cause systemic viraemia as well as
common cold symptoms. Most other viruses do not, and they remain in nasal and
nasopharyngeal mucosa where they cause only common cold symptoms. Nasal
drainage and nasal congestion are primary symptoms of common colds. Malaise,
headache, fever, muscle pain, sore throat, scratchy throat, cough, and hoarseness are
frequently occurring secondary symptoms.(5)
Seasonal variations in cold-causing viruses have been noted with differences in host
susceptibility.(5) Rhinoviruses cause colds year-round, and have been implicated in
about 50 percent of all common colds occurring in the spring, summer, and fall, at least
until recently. The large number of rhinoviruses (over 100 distinct rhinoviruses) and
variants affecting children and adults make a vaccine essentially impossible.
Frequency of rhinovirus infection falls off with age. Parainfluenza viruses have been
implicated in 15 to 25 percent of fall, winter, and spring colds, affecting mostly infants
and children. This family of four viruses causes severe colds in infants with significant
potential for complications, but only mild colds in adults. Various strains of influenza A
and B are implicated in 10 to 20 percent of cold-like illnesses in late fall, winter, and
early spring. Influenza causes particularly severe symptoms as well as many more
cold-like illnesses during periodic worldwide epidemics.
Coronaviruses, a family of 13 viruses having a distinctive crowned appearance under
the electron microscope, cause 10 to 20 percent of upper respiratory infections and are
most active in winter and spring. Respiratory syncytial viruses (RSV) have been
implicated in about 10 percent of colds. These viruses are usually found in fall, winter,
and spring colds. They cause mild colds in adults, but are the leading cause of
pneumonia in infants. Ribavirin has been shown effective in RSV pneumonia. Three out
of more than 40 adenoviruses cause about 5 percent of winter colds. Military recruits
are at the greatest risk. Adenoviruses are most active in fall and winter. Strains of
echoviruses and coxsackieviruses, part of the enterovirus group, cause 5 to 10 percent
of colds. These enteroviruses are active from April through December with peak activity
in summer and fall. They affect mostly infants, children, and military recruits with typical
cold symptoms and possibly diarrhea. Other viruses cause up to 25 percent of colds
year-round. Herpes simplex viruses can cause colds of long duration. Rhinoviruses
cause colds year around, but they are most active from April through October, not during
the height of the annual cold and flu season.(5)
British researchers using new techniques have very recently suggested
rhinoviruses account for 60 to 70 percent of all common colds, not 30 to 50 percent as
previously reported. Sebastian Johnston, of the Department of Microbiology at the
University of Southampton in England, recently used polymerase chain reaction
techniques to develop ultrasensitive tests to better identify cold viruses in asthmatic
children. In 108 children, age 9 to 11 years with asthma, 290 respiratory complaints
(common colds and chest infections) were examined with the new research methods.
Seventy-eight percent of all complaints were virally related, and of them 60 to 70 percent
were caused by rhinoviruses.(6)
The nose is the body's first line of defense against airborne viruses.(5) The
temperature and moisture of the inner nose tend to inhibit growth of some viruses. The
nasal turbinates by their flap-like shape and copious blood supply assist in warming and
moistening air. The interior of the nose is lined with goblet cells that excrete sticky
mucus. The nasal interior also has cilia, tiny projecting hairs, that trap inhaled viruses,
pollen, medication, and dust particles. Cilia move them down the throat, preventing
contact with underlying cells in the nose and throat. The cells lining the respiratory tract
also secrete immunoglobulin A (IgA) helping to prevent infections by combining with the
surfaces of viruses and bacteria to change their shape into one not allowing attachment.
Recently, intercellular adhesion molecule 1 (ICAM-1) has been identified as the molecule
that attaches rhinoviruses to cells.(5)
During a cold, viruses have managed to penetrate nasal mucus and invade nasal
and perhaps nasopharyngeal tissues.(5) Viruses enter cells and within a few hours
seize control of cell genetics and force cells to make thousands of copies of invading
viruses. As cells become infected, they release chemicals initiating several responses
from the body's immune system, including responses from immune cells of the nasal
mucosa. Within an hour, prostaglandins are released producing inflammation and
attracting infection-fighting white blood cells called neutrophils. These cells attempt to
attack invading viruses without damaging infected cells. Neutrophil activity increases
inflammation, and the infected area becomes swollen and red. Onset of a common cold
is thus signaled with symptoms such as sore throat, itchy eyes, a headache, or a
generalized ill feeling. Tissues and capillaries dilate, and plasma, more neutrophils,
and other white blood cells flood the area. They cause increased mucus production, a
raised temperature, a runny nose, sneezing, and coughing. Release of kinins, perforin,
perhaps histamine, and other mast cell vasoactive ingredients increase capillary
permeability and cause increased mucus production by goblet cells.(5)
If raised nasal temperature and neutrophil engulfment are insufficient to stop viral
invasion, monocytes and lymphocytes pass though capillary walls and assist.(5) In the
presence of inflammation and other signs of infection, monocytes transform themselves
into macrophages eating as many as 100 viruses each. These cells release interleukin-
1 causing the body's temperature to rise and activate lymphocytes. Release of
interleukin-1 to reset temperature results in chills, which often precede a fever.
B- and T-cell lymphocytes are the main warriors in defense of the nose. B-cells
produce immunoglobulins. These antibodies plug cold-virus receptor sites and prevent
viruses from sticking to nasal and nasopharyngeal cells. Some of these cells become
memory cells helping to prevent recurrence of infection. T-cell lymphocytes when
summoned to the site of infection turn into "killer cells" that release cytolysin (perforin)
which opens pores in cells. Killer cells attack and kill virus-infected cells. Other
"helper/inducer" T-cells stimulate B-cells to produce additional antibody. Some T-cells
become "suppressor" T-cells terminating antibody production and killer-cell activities
after viruses have been controlled. T-cells also release several other infection-
managing chemicals, including macrophage activation factor, macrophage inhibition
factor, interleukin-1 and -2, and interferon. Interferon prevents cell death caused by
viruses and prevents viral replication. Complement proteins lyse cells and coat virus
particles making it easier for macrophages to recognize and digest them. Complement
aids killer cells in identifying infected cells, which must be destroyed. Common cold
symptoms are not produced by viruses, but by the immune system's many, perhaps
over reactive, responses to viral infection.(5)
Throughout recorded history, common colds have been refractory to attempts to
shorten their duration. Whether treated or not, the half-life of common colds remained
about 7 days with an average duration of about 10 to 11 days. Treatment and advice
include: Pliny the Younger's first century treatment of "kissing the hairy muzzle of a
mouse," avoiding dampness and exposure to cold temperatures, avoiding sneezes of
persons with colds, avoiding shaking hands, eating chicken soup, taking various herbs,
mentholated lozenges, eucalyptol lozenges, horehound lozenges, antihistamines, nasal
decongestants, analgesics, cough syrups, antitussives, inhaling warm moist air, taking
megadoses of Vitamin C, using interferon nasal sprays, "killer" tissues soaked in iodine,
gargles, anticholinergics, humidifiers, negative air ions, meditation, acupuncture,
electronic air filters, various antirhinoviral agents, antibiotics to prevent secondary
infection, and, most recently, the use of zinc gluconate throat lozenges.
In 1984, zinc gluconate lozenges containing 23 mg of zinc used every two hours
while awake (a lozenge about 9 times per day) were first reported by Eby and others at
the University of Texas at Austin to shorten the duration of common colds by an average
of 7 days when compared to placebo. Results of the study were carried by the
Associated Press and became headlines in newspapers world-wide. This study showed
the half-life of common colds treated with zinc to have been 2.7 days, compared to 7.5
days for placebo-treated patients. Statistical significance was high throughout the study
(P = 0.0005 on the seventh day of treatment). Lozenges were unflavored, over-the-
counter tablets having no soluble ingredients other than zinc gluconate. As a mildly
objectionable chalky taste and aftertaste were reported by about one-half of the patients
receiving zinc gluconate lozenges participating in the study, the statistics were also
evaluated excluding patients expressing comments about taste or aftertaste.
Results were found to remain the same, with high statistical significance.(7)
This 1984 report stimulated follow-up research both in vitro and in vivo. The new in
vivo work involved usage of chemically weaker and different lozenges, and controversy
ensued. Orally absorbed hydrated Zn2+ ions
transported mechanically and through preferential pathways in biologically closed
electric circuits between the oral and nasal cavities are believed to be responsible for
reduction in duration. Studies with positive findings demonstrate effects of lozenges
releasing adequate Zn2+ ions while negative
studies do not.
The first stability constant of zinc gluconate is log K1=1.70, which means zinc gluconate is highly ionizable and allows
ready release of Zn2+ ions into oral tissues for
localized absorption. A maximum of 60 percent of zinc from zinc gluconate will be
present in saliva as Zn2+ ions, but only a
maximum of 30 percent will be present at pH 7.4, the pH of oral tissues, blood, and
lymph. A percentage of Zn2+ ions is precipitated
by salivary proteins and hydroxide, while active amounts are absorbed into the oral and
oropharyngeal tissues. Having numerous pharmacologic properties, absorbed
Zn2+ ions provide a nearly perfect common cold
treatment.
Follow-up in vivo studies were marred by efforts to eliminate objectionable taste in
the zinc gluconate lozenges. No researcher attempted to replicate research using
lozenges identical to lozenges used by the Eby group. Most efforts by pharmaceutical
and nutritional supplement companies to prepare flavored, pleasant-tasting zinc
gluconate lozenges failed. Those efforts resulted in lozenges that were much weaker in
biologic activity. Also, those experimental lozenges usually tasted far more
objectionable than the unflavored lozenges used in the original 1984 study. Because no
other group attempted to replicate the original study with identical lozenges, it was not
clear whether the original study was faulty or the "improved" lozenges were impotent
because of Zn2+ ion unavailability or flavor-
masking difficulties.
Before the discovery of flavor-stable, pleasant-tasting zinc acetate lozenges,
elimination of objectionable taste was by strong chelation by zinc binders such as citric
acid, tartaric acid, sodium bicarbonate, glycine, aspartic acid, orotic acid, by addition of
anethole flavor-mask, or by use of low-dosages of zinc.
A good exception was the 1987 British Medical Research Council Common Cold Unit
zinc lozenge for common cold study.(8) Using lozenges chemically identical to the
original Eby group lozenges, the MRC Common Cold Unit study showed greater efficacy
in shortening colds than any previous study ever conducted by the Common Cold Unit.
Clinical failures of highly stable zinc complexes with excess chelator (essentially
negatively charged zinc species), highly stable zinc complexes (essentially neutrally
charged zinc complexes), and those lozenges containing very low zinc dosage have
caused loss of credibility for all zinc lozenge compositions as effective common cold
treatments, including those highly ionizable zinc compounds releasing large amounts of
active Zn2+ ions. Without means to flavor-mask
lozenges, it appeared Zn2+ ion might not become
a useful tool in the fight against common colds. Creation of flavor-stable, pleasant-
tasting zinc acetate lozenges as discussed in Chapter 7 herein, provides a new way to
study the effects of Zn2+ ion in shortening
common cold duration.
To study zinc and the common cold, one must realize Zn2+ ions in amounts sufficient to shorten common colds are available
only from a few highly soluble and highly ionizable zinc compounds. Some zinc
compounds are soluble at oral tissue pH but do not release Zn2+ ions as they have been strongly sequestered by the ligand; other
solubles release Zn2+ ions as they have been
only weakly sequestered. For sequestration of metallic ions to occur, two general
conditions must be met: (a) ligand must have proper stearic and electronic configuration
in relation to metal ions being complexed, and (b) the surrounding milieu (pH, ionic
strength, solubility, etc.) also must be conducive to complex formation. The capability of
a ligand to release metal ions under these varying conditions is found using solution
chemistry.
Positively charged, aqueous solution zinc ions (Zn2+ ions) from very weakly complexed zinc compounds are the only
form of zinc having anti-common cold properties including antiviral action, cell
membrane protection, antihistaminic effect, and interferon-inducing properties.
Zn2+ ions and several strongly chelated zinc
compounds have T-cell lymphocyte and astringency activity. Anti-common cold zinc
complexes and their relative antiviral strengths can be determined from the first stability
constant (formation constant, equilibrium constant, or reciprocal of dissociation constant)
of complexes of zinc and ligands. The theoretical importance of the availability of
Zn2+ ions in treating common colds was
demonstrated in 1989 by Merluzzi and co-workers at Boehringer Ingelheim
Pharmaceuticals while working on the ICAM-1 project.(9,10) These scientists
demonstrated the antirhinoviral effect of zinc to be directly related to the amount of
Zn2+ ions available and completely unrelated to
the total amount of zinc
complex.
Stability constants, a measure of sequestering power of ligands (chelators) for metal-
ions, are well defined and cataloged for zinc and other metals for many ligands.(11,12)
Electrical charges of zinc-ligand complexes in Martell's six-volume Critical Stability
Constants can be determined from the charges of metal ions and abbreviated ligand
formulas given in tables in well-defined systems.(11) In these systems, the relative
efficiency of metal-ion sequestrants can be compared by inspecting stability constants
for metals. In general terms, the stability constant of a metal complex can be calculated
as follows: K = [ML] / [M][L], where K is the stability constant and is usually expressed
as a logarithm; M is the amount of metal ion such as Zn2+ ion, and L is the amount of a ligand such as gluconate or
acetate.(11)
According to a leading solution chemist, Guy Berthon of INSERM U-305 in Toulouse,
France, the total concentration of metal CM can be computed with specialized
computation programs. The basic equation CM = [M] + [ML] with [ML] = K [M] [L]
becomes CM = [M] (1 + K [L]); hence [M] = CM / (1 + K [L]) shows that the concentration of
M, Zn2+ ion in this case, depends on the stability
constant of the complex and free concentration of the ligand which is dependent upon
corresponding pK and pH values.
For example, the above equation is used to compute the amount of Zn2+ ions positively charged zinc gluconate (ZnGl+), neutrally charged zinc gluconate hydroxide [ZnGl(OH)], and
several other zinc hydroxide species using equilibrium-based computer computations.
Figure 1 shows the various fractions of zinc species from zinc gluconate occurring at
each pH in aqueous solution. About 30 percent is present as Zn2+ ion at the pH of oral tissue (pH 7.4) although 30 percent is a
maximum value because some Zn2+ ions bind
with salivary proteins and hydroxides forming precipitates in saliva. Zn2+ ions are absorbed into oral and oropharyngeal tissues. Only
the orally absorbed Zn2+ ions have utility in
shortening the duration of common colds.
With increased first stability constant values in various other zinc compounds, more
zinc is complexed by the ligand, leaving less metal in cation form at each pH.
The first stability constant for zinc glycinate (log K1 = 4.8)(11,12,13) causes zinc as zinc glycinate to be more tightly
bound and much less available at each pH over 3 than would zinc as zinc gluconate (log
K1 = 1.70) or zinc chloride (log K1 = 0) or zinc acetate (log K1 = 1.03) because the latter compounds all have very have low
stability constants.(11,12,14) Zinc reacts rapidly with ligands and instantly complexes in solution. In the compilation
co-authored by Martell(11), the introductory remarks show only the most reliable data
were used resulting in the omission of data for mixed ligands. Furia(12) provides a
simplified table of first stability constants for metals and food ligands and provides a
brief discussion of stability constants.
Figure 1. Distribution of zinc ionic species in the Zn2+ and gluconic acid system. Curves were constructed from pK values
shown after the reactions: Zn2+ + L_ <=> ZnL+ (1.62) and
ZnL+ + OH_
<=> ZnL(OH)0 (8.14) at a concentration of 30 mMol
zinc. The pK values are courtesy of Gerritt Bekendam, Akzo Chemicals BV Research
Centre, Deventer, The Netherlands, 1989. The Zn2+ fraction over pH 6 is strongly affected by the second pK value.
Precipitates of hydroxides of zinc result in supersaturated solutions. Computer-
simulated distribution of zinc ionic species is courtesy of Guy Berthon, 1992. Stability constant values are valid only under well-defined laboratory conditions but
appear to be reasonable starting points for use with zinc lozenges because conditions
are similar. Body temperature is either slightly higher or identical, while salivary zinc
concentrations are slightly lower than concentrations usually tested in laboratories.
Published stability constants are vital for computation of amounts of Zn2+ ions and other zinc complexes at essential pH values.
The presence in zinc lozenges of non-aqueous additives, such as sugars, sugar
alcohols, food acids (strong chelators), bicarbonate (strong chelator), flavor oils, lake
colors (strong chelators), tablet lubricants, tablet binders (possibly strong chelators), and
other ingredients make analysis of net charge and concentration of Zn2+ ion much more uncertain, particularly where authors fail to
list the amount of each ingredient.
In two important cases (reviewed in Chapter 4 herein), metal-chelating additives
reversed net charge, resulting in complete loss of Zn2+ ions at pH 7.4 and adverse clinical results.
The only relevant pH in common cold therapy with zinc lozenges is the 7.35 to 7.4
range. All acids and other bases are quickly buffered to that pH range in blood, lymph,
and tissue.(15,16) Acid-base balance in body tissues and fluids is carefully regulated in
a state of good health and is always maintained within normal physiologic limits.
The 7.4 pH of blood and extracellular fluid is close to the natural 6.8 pH of 20 mMol
zinc acetate, suggesting good absorption potential as well as close approximation to
laboratory pH conditions. The physiologic pH is about one log unit higher than the
natural 6.2 pH of 20 mMol zinc gluconate.
When using zinc lozenges, salivary proteins complex with and precipitate some
Zn2+ ions at salivary pH, while some zinc is
swallowed, and some is absorbed into oral and oropharyngeal tissues and is held at pH
7.4. Once absorbed, some Zn2+ ions are chelated
by blood, lymph, and tissue while others remain in a hydrated ionic form. Whether or
not a given amount of a zinc compound can 1) provide sufficient Zn2+ ions to be antirhinoviral in nasal tissue, 2) induce local interferon
production, 3) provide local cell membrane stabilization, and 4) provide Zn2+ ions for the numerous other physiologic interactions at pH
7.4 is determined by the chemical stability of the zinc complex. Only absorbed
Zn2+ ions available at pH 7.4 migrating from oral
tissues into nasal and nasopharyngeal tissues are useful in shortening common colds.
High Zn2+ ion concentrations in common cold
lozenges at pH lower than 7.4 are irrelevant, misleading to the consumer, and useless in
practice.
Zinc compounds having very low stability constants such as zinc gluconate, zinc
chloride, and zinc acetate release useful amounts of Zn2+ ions at pH 7.4, while zinc compounds with higher stability constants
do not.
For example, at pH 7.4, 100 percent of the zinc from zinc acetate (log K1 = 1.03) remains as hydrated Zn2+ ions,(17) while only 30 percent of the zinc from zinc gluconate
remains as zinc ion (log K1 = 1.70).(11,12) Zn2+ ion
availability from zinc sulfate, lactate, malate, maleate, tartarate, and succinate (log
K1 = 1.8 to 2.8) ranges in effect from less than
desirable to useless for treating colds. Essentially no Zn2+ ions occur at pH 7.4 from zinc citrate, oxide, glutamate, carbonate,
glycinate, aspartate, orotate, amino acid chelates, EDTA, and other highly chelated zinc
compounds (log K1 = 4.5 to 16.5),(11,12) rendering
these compounds completely useless in treating colds. Examples of these effects are
shown in detail in Chapter 4.
Magnitude of Health Problem
Etiologic Agents
Seasonal Variation in Etiological Agents
New Evidence for Rhinoviruses as Principal Cause of Colds
Immune Response of the Nose
Overview of Common Cold Treatments
Introduction of Zinc Gluconate Lozenges
Stability Constants
Calculating Availability of Zn2+ Ions
Consideration of Body Acid-Base Balance