Foreward by Charles A. Pasternak, PhD, MD
Today, zinc supplements are found on the health-food shelves of pharmacies and drug stores, alongside ginseng, yeast extract, and oil of wintergreen. But let us not forget that today's alternative or homeopathic medicine -- complementary is probably a better word -- is tomorrow's orthodox medicine. There are plenty of examples to illustrate this point: from the use of digitalis to prevent heart attack or quinine to prevent malaria, to the technique of vaccination to prevent infectious disease. The latter is a particularly striking example. Three centuries ago the practice of variolation (inhaling the pus from a small-pox victim to protect oneself against the onset of this disfiguring disease) was not so much an old wives' tale as a young mistress's tale: having been used for centuries earlier by the Chinese, it was prescribed for the Circassian maidens who inhabited the sultan's seraglio in the Ottoman Empire to protect their luscious skins. Today, following on from the success story of the small-pox vaccine, billions of dollars are being spent by the most respected research establishments of the world to develop vaccines against malaria, influenza, HIV, and a host of other infectious agents. If we had a vaccine against rhinoviruses, we might not need to fight the common cold with Zn2+ ions from zinc lozenges.
The trouble with zinc is that, like vitamin C, it is present in most of our diets in quantities sufficient to prevent major deficiency disease (rare enough, anyway, in the case of zinc). Why should we take more? The answer lies in the way in which vitamins and other essential nutrients such as iron, copper, zinc, or iodine work: with the possible exception of iodine, whose function seems to be confined to the thyroid gland, most other vitamins and nutrients play a role in practically every tissue of the body. For example, while the dietary intake of vitamin C or zinc by healthy people of the Western world may be sufficient to prevent scurvy or the skin disease of Acrodermatitis enteropathica, respectively, this does not mean that a little bit extra may not be beneficial in fighting a number of different infectious diseases. For not only do vitamin C and zinc function in many different tissues, but the natures of those functions are manifold. Zinc, for example, is required for dozens of quite different molecular interactions within cells: it is easy to envisage that at a particular dietary intake most of these work normally, but one or two are below par; this would place the individual at risk for the onset of disease. Moreover, the imposition of a particular stress such as a viral infection places additional demands on certain cells within the body, and no one should be surprised that a higher concentration than normal of a critical nutrient such as zinc turns out to be beneficial.
George Eby is a courageous man. He is neither scientist nor physician, yet he has battled with the medical establishment and pharmaceutical companies for a decade to persuade them to take seriously his proposal regarding throat lozenges releasing Zn2+ ions as an effective treatment for common colds. There is room in all walks of life for astute and intelligent men like George Eby: the challenge from inquiring and critical laymen is often immensely beneficial to scientists and physicians set in their ways. And who in the United States can doubt the contributions made by their most eminent layman -- President Thomas Jefferson? While George Eby's suggestion 15 years ago that his hospitalized leukemic daughter be given additional nutrients that included zinc may have not been as dramatic as the decision 250 years ago of Lady Mary Worley Montague -- wife of the British Envoy in Constantinople -- to administer a small dose of live small pox to her son to protect him against subsequent exposure, George Eby may nevertheless have stumbled onto more than one novel form of therapy using zinc. Read what follows and judge for yourself.
Charles A. Pasternak, Ph.D., D.Sc., Hon M.D.
Professor of Biochemistry
University of London at
St George's Hospital Medical School
London (UK)
and
Director of the Oxford International
Biomedical Centre
Foreword by David AJ Tyrrell, MD, Director
Some years ago George Eby noted that using zinc gluconate lozenges apparently benefited his daughter's colds, so he organized a clinical trial to test the idea. The results showed that such treatment improved the outcome. Although the trial did have some faults, we conducted a further test of his formulation in volunteers given experimental colds at the Common Cold Unit at Salisbury. The results of the test seemed to show benefit if the lozenges were given before or during the cold, yet similar studies at the excellent unit at the University of Virginia failed to confirm our findings.
Mr. Eby has taken expert advice and investigated the possibility that it isn't merely the presence of zinc in the lozenge which matters, but the amount and duration of the Zn2+ ions released that determines whether there is an effect or not. He has combined his own studies of the characteristics of the formulations used with the published results of trials in a type of meta-analysis. It is not possible to present the amount of benefit in formally the same terms, but the results do support his case that the differences might be due to the release characteristics of the Zn2+ ions.
Of course this doesn't settle the problem. It has been suggested that our trials failed to control adequately for the volunteers guessing whether they had active or placebo lozenges, and so produced a spurious positive result. There is also the problem that there is no evidence that Zn2+ ions actually reach the infected mucous membranes in the nose; however, in a sense that does not matter as there are many examples of active treatments being discovered when there was no evidence of how they worked.
It is therefore worthwhile keeping the debate open in spite of the negative results in some trials and other much less plausible claims for benefits from zinc. This book helps in that debate by bringing together summaries of the biology of zinc, the results of the trials in common colds and the results of the analyses of the formulations used. The texts of original papers are also there to help the careful reader.
I welcome this book. The best result of its publication would be at least one vigorous trial using zinc lozenges formulated with precisely the characteristics of those used and recommended by Mr. Eby, and with vigorous monitoring of the double-blind precautions and the clinical course of the patients.
David A. J. Tyrrell, M.D.,
retired Director Common Cold Unit
British Medical Research Council,
Salisbury (UK)
and currently with the:
British Medical Research Council
AIDS Directed Programme Public Health Laboratory Service
Centre for Applied Microbiology and Research
Porton Down, Salisbury, UK
Foreword by Widad Al-Nakib, MD
In 1994, there continues to be a debate as to the efficacy of zinc in the prevention and/or treatment of the common cold. The initial studies conducted by Eby et al (1984) did suggest some efficacy although the trials were not perhaps as vigorously controlled as they should have been. We conducted double blind placebo-controlled studies at the MRC Common Cold Unit in Salisbury and found some benefit if the lozenges were given just before or after the onset of colds. One of the main criticisms of our trials was that there was not a sufficient number of volunteers in the second phase of the study which was the treatment with zinc lozenges. Studies in the USA and Australia however, failed to confirm these findings. This book attempts to review the role of zinc lozenges in the prevention and treatment of the common cold and summarizes the biology of zinc. I, like David Tyrrell, therefore welcome this book and hope that it would continue to debate the subject further with the hope that it may encourage further controlled trials.
Widad Al-Nakib, MA FRCPath PhD
Principal Investigator, Common cold Unit
British Medical Research Council CCU
currently at Advanced Pathology Services
London UK
Preface
In an effort to provide a unifying hypothesis, this handbook analyzes all reports of zinc lozenge for common cold research reported since publication of my 1984 article in Antimicrobial Agents and Chemotherapy which documented a way of reducing the average duration of common colds by seven days using zinc gluconate lozenges. Common colds are mostly caused by rhinoviruses, and zinc gluconate is a good source of Zn2+ ions which are antirhinoviral.
The story has been told around the world of how in 1979 my leukemic 3-year old daughter, Karen, started a revolution. She had refused to swallow her 50-mg zinc supplement because she had a severe common cold. Instead, she allowed the zinc gluconate tablet to dissolve slowly in her mouth during an afternoon nap, resulting in the termination of her cold within several hours -- without further treatment or relapse. After this serendipitous discovery, I found similar results in other family members, friends, and co-workers.
Swallowed tablets, nasal ointments, nasal sprays, and nose drops were also tested. Nose drops were expected to work better than lozenges; however, no reduction in duration of common colds was observed. The dichotomy was difficult to understand, as colds are an infection of the nose, not the mouth. In retrospect, these findings are consistent with published literature dating from 1901 on zinc treatment of nasal catarrh via the nasal route as a short-lived nasal decongestant.
Why? A biologically closed electric circuit (BCEC) between the mouth and nose controls local movement of metallic ions. Of the many BCECs described in 1984 by Björn E. W. Nordenström, the mouth-nose BCEC is the most readily observable.
Over a two-year experimental period from 1979 to 1981, I formalized what I thought to be the best protocol for using zinc gluconate lozenges. William W. Halcomb (a general practice physician and allergist now in Mesa, Arizona), Donald R. Davis (a nutrition scientist who worked for National Academy of Science member Roger J. Williams [deceased] at the Clayton Biochemical Institute Foundation at the University of Texas at Austin), and I conducted the original double-blind study using slow-dissolving zinc gluconate tablets -- as lozenges -- in the fall of 1981 to treat wild common colds.
The results showed the expected efficacy. Zinc gluconate lozenges reduced the average duration of common colds by seven days, with exceptionally strong statistical significance from the first few hours, again without relapse of colds. Our article caused others to attempt to replicate our findings.
In 1984, the Medical-Scientific Director of RBS Pharma-Milan (now part of Rôhne-Poulenc Pharma, Italia, S. P. A.), Rinaldo Pellegrini sought my team's advice on how to compound zinc gluconate lozenges. By that time, my team had completed a no-effect zinc orotate (non-ionizable) lozenge for common colds study. On the basis of the conflicting zinc gluconate and zinc orotate results, we recommended avoidance of zinc chelators in lozenges. The pleasant-tasting, fructose-based RBS Pharma lozenges were tested on experimental colds by David A. J. Tyrrell and co-workers at the Great Britain Medical Research Council (MRC) Common Cold Unit. Analysis of the data from the MRC study showed nasal secretions essentially returned to normal in the zinc-treated group by day 4, while colds in the placebo-treated group continued. Analysis of mean clinical scores showed colds were essentially absent in six days with zinc treatment. Compared to the historic average of 10.8 days for untreated colds, a reduction of 4.8 days in common cold duration occurred. For the first time, an internationally recognized common cold research group verified a clinical treatment to shorten common cold symptoms. The positive results were discomfiting to the MRC scientists, because the operative mechanism remained elusive.
The issue became confounded when other studies came up with different findings from the Texas and MRC studies. Some zinc gluconate lozenges had objectionable taste and long-lasting aftertaste, seriously impairing patient compliance. Zinc gluconate developed a reputation for being bitter, and lozenges needed flavor-masking. Actually, bitterness results only when zinc gluconate is combined with dextrose. Zinc gluconate in fructose -- as in the MRC lozenges -- tastes pleasant when flavored and has a mild aftertaste. The wide disagreement between studies caused researchers to assume the positive findings to be faulty. In 1988, letters to the editor of Antimicrobial Agents and Chemotherapy suggested differences in stability constants as being responsible for failures. The letters produced both insightful, and misleading information.
In apparent defense of citric acid flavor-masked zinc gluconate lozenge work, one letter asserted zinc gluconate-citrate lozenges produced a salivary pH of 2.3 (stomach acid pH), contending one hundred percent of the zinc was released as Zn2+ ions.
Realizing the improbability of a salivary 2.3 pH from use of the zinc gluconate-citrate lozenges and the improbability of availability of Zn2+ ions at physiologic pH, Guy Berthon, Director of Research at INSERM Unit 305 in Toulouse, France, entered the fray. One responsibility of INSERM Unit 305 is to determine the bioavailability of drugs at physiological pH 7.4, the only relevant pH for antivirals and many other chemotherapeutic agents. Determination of bioavailability is a complex and difficult effort involving solution chemistry. After a close collaboration between Guy Berthon and myself from 1988 to 1993, a report was produced thoroughly examining bioavailability of Zn2+ ions from the conflicting zinc lozenge articles. The resulting report, -- The "Zinc Lozenge and Common Cold Story" -- is published separately by Marcel Dekker, Inc. in Handbook of Metal-Ligand Interactions in Biological Fluids, edited by Guy Berthon. We all owe Guy Berthon our gratitude. Had he not intervened, the work would have died, and I would have gone on to do something else, disillusioned and disappointed. Worse, an effective cure to the common cold would have been buried and probably never resurrected.
Presentation of comprehensive solution chemistry data is part of the analysis of the various conflicting reports in this handbook. Guy Berthon's research demonstrated Zn2+ ions were available at physiologic pH from efficacious zinc gluconate lozenges. More importantly, he clearly and convincingly demonstrated Zn2+ ions were not available at physiologic pH from non-efficacious lozenges.
Quantification of the amount of Zn2+ ions capable of penetrating oral mucous membranes through lozenge use relies upon Zn ion salivary concentration at pH 7.4 and time of contact, following Fick's laws of membrane diffusion. The zinc ion availability (ZIA) method of analysis discussed in Chapter 3 was developed in 1991 as an application of Fick's laws in a mouth-nose BCEC. ZIA values are determined by the availability of Zn2+ ions at pH 7.4 over time of absorption into oral mucosal membranes.
Electrical charge of zinc species is important as Zn2+ ions are absorbed into oral tissues and follow a readily measurable mouth-nose BCEC. Neutral and negatively charged species are unaffected or repelled, respectively, and have no known biologic activity in treating colds.
Comparing ZIA values of the zinc lozenges to the resultant changes in duration of colds yields a linear regression having a r (rho) value of 0.96, providing reconciliation of all previously divergent results and a sound statistical basis for a unifying hypothesis. For complete details, see Chapter 5 and examine Figure 19 entitled "Relationship of zinc ion availability (ZIA) values and reduction in duration of common colds." Lozenges having a positive ZIA released Zn2+ ions and were beneficial. Lozenges releasing no Zn2+ ions produced no results, and lozenges having negative ZIA values usually worsened colds.
The ZIA versus cold duration relationship also demonstrates a method to predict outcome of future studies with assurance of results in clinical trials. Linearity in ZIA -- versus -- cold duration data is the heart of this handbook and forms the foundation for future research.
Chapter 7 discusses zinc acetate lozenges as the successor to zinc gluconate for use in common cold treatment. Zinc acetate has essentially no taste in dextrose or fructose at efficacious ZIA values, and lozenges are flavor-stable when properly formulated. Zinc acetate lozenges release 100 percent of their zinc as Zn2+ ions at physiologic pH 7.4. Full ionization of zinc acetate is a significant improvement over zinc gluconate, as zinc gluconate releases only 30 percent Zn2+ ions possible at pH 7.4. Chapter 7 details findings relating ZIA-to-lozenge dissolution rates, compressive forces used in tablet manufacture, zinc dosage, lozenge weight, and many other variables. Chapter 7 also shows unexpected non-linearity in ZIA values as zinc acetate content is increased in lozenges.
Without comprehensive solution chemistry and ZIA analyses, understanding differences between the zinc lozenges for common cold studies is impossible, as was found by Y. J. Potter and L. L. Hart, who surveyed literature describing use of zinc lozenges for common colds in the May 1993, issue of The Annals of Pharmacotherapy. Potter and Hart were given an impossible task, as they only had an idea of the complexity of the chemistry involved and did not have sufficient information (particularly critical unpublished lozenge design materials from manufacturers) to arrive at a correct conclusion.
I believe governmental and pharmaceutical company officials, as well as the public, want an inexpensive and safe cure for common colds. Unfortunately, present society has been taught to equate common cold cures to the elusive fountains of youth sought centuries ago. Without this handbook, the literature seems to support that belief. I sincerely hope this handbook will stimulate medical researchers without vested interests in other common cold treatments to conduct clinical trials of ZIA 50 to 200 zinc acetate lozenges for common colds. Before the public can benefit, responsible public and private health officials must find the truth for themselves. Once the -- no cure for the common cold -- fable is universally revealed as false, perhaps governmental and pharmaceutical company officials will listen to my zinc lozenge story and the public will eventually benefit.
Engraved in glistening white marble above the entrance to the University of Texas Main Building in Austin, Texas, which houses comprehensive medical, life science and pharmaceutical libraries, are the encouraging Biblical words: "Ye shall know the truth and the truth shall make you free."
Perhaps the full truth about zinc lozenges and common colds established and preserved in this handbook will result in new, focused research and submission of a New Drug Application to the United States Food and Drug Administration for zinc acetate lozenges as cure for common colds. I have done all I can. I must place the future of zinc acetate lozenges as cure for common colds in the hands of others. Let's see what will be done.
Assuming availability of appropriate finances and cooperation by common cold authorities and regulatory agencies, we can rightfully expect zinc acetate lozenges to win approval of a Food and Drug Administration New Drug Application, resulting in placement of zinc acetate lozenges as the cure for the common cold on the market within the next five years.
Acknowledgments
I am deeply indebted to a large number of scientists, medical researchers, and others to whom I can only say thank you. The following are acknowledged for specific participation:
William W. Halcomb, now of Mesa, Arizona, conducted our 1984 clinical trial. Donald R. Davis and Mitchell E. Gidseg of Austin, Texas, helped in statistical analyses, writing the original 1984 text, and in many fruitful discussions.
Bruce D. Korant, of Du Pont Central Research in Wilmington, Delaware, worked with Zn2+ ions and rhinoviruses and provided helpful insight.
Rinaldo Pellegrini of Milan, Italy, Medical-Scientific Director of RBS Pharma-Milan, took the time to visit with us and listen to our warnings about metallic chelators and made the flavor-masked zinc gluconate lozenges successfully demonstrated by the British Medical Research Council Common Cold Unit in Salisbury, England (MRC).
David A. J. Tyrrell and co-workers at the MRC Common Cold Unit had the courage to publish the clinical truth, even though they could not determine the operative mechanism, and for his kind foreword remarks.
Guy Berthon, Director of Research at INSERM Unit 305 in Toulouse, France, went far out of his way to help, and single-handedly saved this line of research.
Charles A. Pasternak, at St. George's Hospital Medical School, University of London, took the time to visit with me and explain how Zn2+ ions could stabilize cell plasma membranes and perhaps be the means by which zinc lozenges shorten colds. I am also grateful for his kind foreword.
Bill Bannen of General Nutrition Products in Greenville, South Carolina, disclosed the McNeil formulation.
Claude. B. Goswick of Texas A&M University, College Station, Texas, revealed the actual dosages used in the McNeil clinical trial.
Jack M. Gwaltney Jr., of the University of Virginia at Charlottesville, Virginia, provided frank and helpful comments.
R. Bruce Martin, University of Virginia at Charlottesville, Virginia, provided the formula and zinc-citric acid speciation data applicable to the Bristol Myers lozenges.
R. J. E. Williams of Faulding LTD, Adelaide, South Australia, disclosed the formulation of the effervescent lozenges used by Robert M. Douglas. Robert M. Douglas, now at the Australian National University, National Centre for Epidemiology and Population Health in Canberra, has shown continued interest.
M. L. McCutcheon of the University of Minnesota at Duluth, sent me an unpublished account of their failed zinc aspartate study (0 ZIA), which helped show that nothing happens if there are no zinc ions. Ira Hill of Research Directions in Locust, New Jersey, lent support and technical assistance.
James W. McGinity, Salomon A. Stavchancsky, Roland A. Bodmeier, and others at the Drug Dynamics Institute, College of Pharmacy, University of Texas in Austin, gave much and varied assistance.
Paul T. Zeltzer, now at the Developmental Biology Group at UCLA in Los Angeles started me on this line of inquiry while he was my daughter's oncologist. Richard M. Holt of Children's Hospital of Austin, Texas provided pediatric services and particpated in many helpful conversations. Michael Castleman, author, of San Francisco, popularized zinc lozenges for colds and has given me endless support.
Allison E. Rowland of Texas A&M University, College Station, Texas, contributed much-needed editorial services.
Most of all, I very much appreciate the support provided to me by my family. Thelma Lloyd Eby, my mother (deceased), who financed the beginning of this research; Patsy Ann Eby, my beloved wife who gives and gives and gives without end; Karen Lynn Eby, my beloved daughter, and the child who prompted the insight as well as the need for this line of inquiry at the tender age of three; and Colin Martin Eby, my beloved son, for his support and understanding.
The Elephant - Adapted from a Famous Sufi Story
Once there was a poor Persian village where all were blind. One day a strange new creature called an elephant appeared at the village wall. Since no one in the village had ever heard of an elephant, the three wisest of the blind villagers went out to discover what the new creature was like. They all felt the creature. The first blind sage felt the tail and said, "This creature cannot be an elephant, this is a rope!" The second blind sage felt the leg and said, "No, this is a tree!" The third blind sage felt the side and said, "No, you fools, this is a wall!"
As the three sages argued amongst themselves, a lesser blind man, not knowing any better, mounted the elephant and rode away.
Adapted from a Famous Sufi Story
Chapter 1. Introduction
|
Executive summary: Chapter 1 introduces (a) the multibillion dollar annual magnitude of the common cold problem, (b) new evidence showing rhinoviruses as the cause of 60 to 70 percent of colds, (c) the immune system's response to viruses as cause of common cold symptoms, (d) the universal failure of existing commercial treatments to reduce common cold duration, (e) the beneficial effects of zinc gluconate lozenges containing 23 mg zinc used every two hours while awake in reducing symptom severity and the average duration of common colds by seven days, (f) applicable scientific and mathematical concepts, and (g) the solution chemistry determination of a 30 percent hydrated Zn2+ ion release from zinc gluconate at physiologic pH 7.4. |
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.
1. Goodwin JS, Goodwin JM. The tomato effect: rejection of highly efficacious therapies. Journal of the American Medical Association. 1984;251:2387-2390.
2. Acute Conditions, Incidence and Associated Disability, United States, July 1977-June 1978. National Health Survey publication (PHS) 79-1560. Washington DC: U.S. Department of Health, Education and Welfare;
1979:3.
3. Fox JP, Hall CE. Viruses in families. Littleton, Mass: PSG Publishing Co; 1980.
4. Murphy W. Coping with the Common Cold. Alexandria, Va:Time-Life Books. 1981.
5. Castleman M. Cold Cures. New York:Fawcett Columbine; 1987.
6. Johnston SL, Sanderson G, Pattemore PK, et al. Use of polymerase chain reaction for diagnosis of picornavirus infection in subjects with and without respiratory symptoms. Journal of Clinical Microbiology. 1993;31:111-117.
7. Eby GA, Davis DR, Halcomb WW. Reduction in duration of common colds by zinc gluconate lozenges in a double blind study. Antimicrobial Agents and Chemotherapy. 1984;25: 20-24.
8. Al-Nakib W, Higgins PG, Barrow I, et al. Prophylaxis and treatment of rhinovirus colds with zinc gluconate lozenges. Journal of Antimicrobial Chemotherapy. 1987;20: 893-901.
9. Merluzzi VJ, Cipriano D, McNeil D, et al. Evaluation of zinc complexes on the replication of rhinovirus 2 in vitro. Research Communications in Chemical Pathology and Pharmacology. 1989;66: 425-440.
10. Staunton DE, Merluzzi VJ, Rothlein R, et al. A cell adhesion molecule, ICAM-1, is the major surface receptor for rhinoviruses. Cell. 1989;56:849-853.
11. Martell AE, Smith RM. Critical Stability Constants. New York:Plenum Press; 1991;1-6.
12. Furia TE. Sequestrants in food. In Furia T.E. ed., CRC Handbook of Food Additives. 2nd ed. West Palm Beach,
Fl:CRC Press; 1972:271-294.
13. Alemdaroglu T, Berthon G. Trace metal requirements in total parenteral nutrition II. Potentiometric study of the metal-ion equilibria in the zinc-histidine, zinc-glycine,zinc-cysteine-histidine,zinc-glycine- histidine and zinc-glycine-cysteine systems under physiological conditions. Journal of Electroanalytical Chemistry and Interfacial
Electrochemistry. 1981;128:49-62.
14. Cannan RK, Kibrick A. Complex formation between carboxylic acids and divalent metal cations. Journal of the American Chemical Society. 1938; 60:2314-2320.
15. Adler S, Fraley DS. Acid-base regulation: cellular and whole body. In: AI Arieff, RA DeFronzo, eds., Fluid, Electrolyte, and Acid-Base Disorders. New York:Churchhill Livingstone; 1985;1:221-257.
16. Guyton AC. Regulation of acid-base balance. In: Textbook of Medical Physiology. New York:W. B. Saunders Company; 1986;37:438-451.
17. Hacht B, Berthon G. Metal Ion-FTS nonapeptide interactions. A quantitative study of zinc(II)-non-apeptide complexes (thymulin) under physiological conditions and assessment of their biological significance.
Inorganic Chimica Acta. 1987;136: 165-171.
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
Chapter 1. References
Chapter 2. - In Vitro Effects of Zn2+ ions
Executive summary Chapter 2 describes in vitro beneficial effects of Zn2+ ions in (a) virology, with special attention to rhinoviruses, (b) bacteriology, (c) astringency, and Zn2+ ion's beneficial effects in stabilizing and protecting secretory cell membranes, (d) prevention of release of histamine, perforin, other common cold biochemicals, mucus, and serous fluids, (e) stimulation of primary T-cell lymphocyte immunity, (f) induction of interferon release from T-cell lymphocytes, and (g) reduction of inflammation in nasal tissues. In each case, the beneficial effects of Zn2+ ions from zinc lozenges are at nontoxic concentrations achievable in human throat and nasal tissues. |
Although the exact mechanism by which zinc shortens common colds may never be determined, the Zn2+ ion has multiple, biochemical effects in vitro, almost certainly acting synergistically in common cold therapy. According to Charles A. Pasternak of the St. George's Hospital Medical School at the University of London, hydrated Zn2+ ion at 6 to more than 60 times normal zinc serum concentration has multiple beneficial effects, increasing as extracellular Zn2+ ion concentration increases.(1)
As discussed in detail below, the beneficial effects observed in treating colds with lozenges releasing Zn2+ ions are caused by 1) astringent drying action on all cell membranes including mucus-secreting goblet cells; 2) inhibition of rhinovirus replication above 0.05 mMol Zn2+ ion; 3) immediate protection and stabilization of cell membranes from all cytotoxic agents including cytolysin (perforin), with a strength equal to interferon; 4) induction of interferon-gamma within 24 hours; 5) immediate cell and capillary membrane pore closure and prevention of transcapillary serous leakage, a function which promotes long-distance closed-circuit transport of ions; and 6) immediate inhibition of release of histamine and other vasoactive biochemicals from mast cells and catabolism of histamine. Serum zinc concentration is 0.015 mMol.
Elevated extracellular Zn2+ ion is beneficial and elevated intracellular zinc is cytotoxic, although recently some authors have suggested that slightly elevated extracellular zinc is cytotoxic. In some cells, rounding and refractile changes occur at about 0.1 mMol Zn2+ ion and at much lower concentrations for most lipophilic and strongly chelated zinc complexes. These observations were interpreted as cytotoxicity and suggested a low 1:2 or 1:4 antirhinoviral therapeutic index for zinc.
Researchers highly familiar with the unique appearance of cell plasma membranes after the astringent action of Zn2+ ions, place the index at 10 to 100 times higher; as extracellular Zn2+ ion is a newly recognized host defense according to Pasternak.(1) Hydrated Zn2+ ions protect cell plasma membranes against damage induced by cytotoxic agents of environmental origin long enough for other defense mechanisms to be brought into play. Up to 1 mMol, Zn2+ ions protect cell plasma membranes in vitro.(1)
No evidence of toxicity from lozenges releasing Zn2+ ions exists. The only adverse effect -- if it can be called that -- is mild, transitory oral irritation on occasion, even though lozenges used by Eby et al.(2) in 1984 produced initial salivary Zn2+ ion concentrations of 7.4 mMol. The highest recorded initial salivary Zn2+ ion concentration from zinc acetate lozenges is 21 mMol. Rather than being toxic to oral tissues, Zn2+ ions are associated with accelerated patient recovery. Oral irritation and strong taste sensation from strong lozenges are much less apparent in patients with colds than without colds, perhaps because of increased oral membrane permeability in patients with untreated colds.
Positively charged Zn2+ ions from soluble, highly ionizable zinc compounds with very low stability constants were demonstrated to be highly effective antirhinoviral agents in vitro by Korant and others at Du Pont using HeLa cells (human epithelioid carcinoma of the cervix cells).(3) Many other metals were determined not to be antirhinoviral at nontoxic dosages. Korant and colleagues determined that Zn2+ ions inhibit cleavage of rhinovirus polypeptides. Addition of Zn2+ ions, at concentrations 0.1 mMol and above, at any time during rhinovirus replication immediately inhibited further formation of infective virions.(3) Antirhinoviral concentration is 6.67 times higher than normal zinc serum concentrations. Plaque-forming ability of rhinoviruses was reduced by 90 to 100 percent in eight of nine rhinoviruses tested.(3) Zinc ions rapidly inhibit virus production and lead to accumulation of rhinovirus precursor
polypeptides cleaved predominantly to stable virus polypeptides upon removal of Zn2+ ion.(4) Zn2+ ions complex with rhinovirus coat proteins and alters them to prevent their function as substrates for proteases or as reactants in the assembly of virus particles.(4) Zn2+ ions were not shown to de-activate mature rhinoviruses.(3) The Du Pont team conducted an exhaustive five-year study of antiviral effects of Zn2+ ions on rhinoviruses and other picornaviruses.(3 - 10)
A. S. Prasad, who is regarded as the father of human zinc nutrition research,
suggested two ways by which Zn2+ ions block
cleavage of rhinovirus proteins. One is by activation of one or more proteases. The
other is by binding to and altering substrate so it cannot be cleaved.(11) The latter
model is preferred because (a) Zn2+ ion almost
immediately blocks virus production, suggesting one of the components of the virion is
affected directly by Zn2+ ions; (b) Zn2+ ions interact directly with rhinovirus capsids; (c) sufficient
amounts of purified virus will produce crystals, but amorphous precipitates form in the
presence of a small amount of Zn2+; and (d)
results of cleavage inhibition indicate sensitive proteolytic reactions invariably involve
precursors containing capsid protein sequences.(11) No information on changes in
intracellular zinc concentration from zinc was presented by the Du Pont team, and none
is likely since elevated extracellular Zn2+ ions
strongly inhibit cellular Zn2+ absorption.(1)
Zn2+ ions render the cell plasma membrane non-permeable so the rhinoviruses cannot enter or exit, thus terminating viral replication.
In 1989, Merluzzi and others showed antirhinoviral effects of zinc to be directly
related to amount of Zn2+ available and unrelated
to the total amount of zinc complex available.(12) As zinc was complexed with ligands
of increasing binding strength, antirhinoviral activity proportionately fell. Maximum
antirhinoviral effectiveness was with zinc chloride (K1 = 0.0). Minor increases in
lipophilicity using crypate complexes drastically affected their toxicity to activity ratios,
with increases in toxicity associated with increases in lipophilicity, suggesting lipophilic
zinc complexes should not be used in throat lozenges to treat common colds.
Cell rounding and refractile changes occur at about 0.1 mMol Zn2+ and at much lower concentrations for most lipophilic and strongly
chelated zinc complexes.(12) These observations were interpreted as cytotoxicity by
Merluzzi and co-workers.(12) The effect of 0.05 mMol Zn2+ from zinc chloride (one-half the concentration used by Korant and
co-workers) was equal to human interferon-beta at its most effective concentrations of 100
to 1000 IU in its antirhinoviral activity and ability to protect infected cell monolayers.(12)
No significant antirhinoviral activity for several zinc compounds was reported by Geist
and associates (nor by Korant and others) at 0.03 mMol,(13) a Zn2+ ion concentration that does not produce cellular rounding and
refractile changes. Antirhinoviral effects were similarly observed by Geist and co-workers at 0.10 mMol.
Korant and his co-workers at Du Pont have found refractile changes and cell
rounding not to be an indication of zinc cytotoxicity. Korant and co-workers showed the
effects noted by Geist and associates, as well as by Merluzzi and associates could be
induced by many noncytotoxic agents, including slight changes in carbon dioxide
concentration and very minor changes to culture medium.(14)
Other common cold-causing viruses inhibited by Zn2+ ions include herpes simplex viruses, reviewed by Eby and
Halcomb,(15) and coxsackie(7) viruses. Zn2+
ions were shown by Merluzzi and co-workers not to have an antiviral effect on influenza-A.(12) Oxford and Perrin, and Cload and Hutchinson separately found Zn2+ ions to inhibit polymerase activity in influenza A and
B,(16,17) although its effect on infectivity was not demonstrated.
Zn2+ ions, but not zinc complexes, have
antiviral properties, and those properties are documented for a number of important
viruses unrelated to common colds. Avian myeloblastosis,(18,19) bacteriophages,(20)
calicivirus,(21) equine herpes,(22) herpes simplex I and II,(23-30) polio,(31,32)
encephalomyocarditis,(33,34) enterovirus,(35) foot-and-mouth disease,(36-38)
mengovirus,(39) Rous sarcoma,(40) Semliki Forest,(41) Sindbis,(42) SV40,(43) tobacco
mosaic viruses,(44) vaccina,(45,46) viroids and prions,(47) are all reported to have
features controlled by Zn2+ ion usually at
concentrations between 0.1 and 2.0 mMol without harm to cells.
DNA is about 5000 times less susceptible to damage by Zn2+ ion than is RNA, suggesting zinc plays a role in predominant
evolutionary selection of DNA, rather than RNA, as the bearer of the primary genetic
information.(48)
Inhibitors of viral protein cleavage are considered a possible method to control HIV
infection.(49-51) Zn2+ ions, inhibitors of viral
protein cleavage, have been found to have effects on Human Immunodeficiency Viruses
1 and 2 (HIV-1 and HIV-2).(49) Its nucleocapsid binds zinc and forms retroviral-type zinc
fingers, which may have significance in the development of vaccines.(52) HIV-1 and HIV-2 protease are easily inhibited by Zn2+ ions at
nearly normal zinc serum concentration(49) but without inhibition of virus infectivity.(14)
Several virologists, including Korant, suggest viral replication or inhibition of various
viral functions by Zn2+ ions may occur in many
other viruses.
Zinc also has antibacterial activity in the mouth regarding bacteria unrelated to
common colds. Zinc and other metal salts temporarily inhibited growth of Streptococci
and Actinomyces as well as other dental caries producing bacteria.(53) Zinc chloride
solutions of 20 mMol reduced plaque formation in heavy plaque formers(54) and reduced
acidogenicity of dental plaque for several hours but were associated with undesirable
taste and excessive oral drying.(55,56)
Other reported therapeutic activity of zinc complements the record. Growth of
Chlamydia trachomatis, a frequent cause of sexually transmitted diseases, was inhibited
at 0.01 - 0.1 mMol Zn2+ ion in vitro.(57) Antibiotic
activity of amniotic fluid is dependent upon zinc.(58) The list of zinc compounds used for
topical antiseptic, antifungal, or astringent purposes in human beings or animals in the
Merck Index includes zinc bacitracin, zinc acetate, zinc chloride, zinc carbonate, zinc
citrate, zinc iodate, zinc oxide, zinc permanganate, zinc peroxide, zinc p-phenolsulfonate, zinc propionate, zinc salicylate, zinc stearate, zinc sulfate and zinc
tannate.(59) Calamine lotion is mainly zinc oxide and has been used for many years as
a topical protectant and astringent.(60) Zinc pyrithione is an active ingredient found in
antibacterial, antifungal, and antiseborrheic shampoos.(61)
Zn2+ ions are best known for their
astringency. The basic effect of Zn2+ ions on
many cells, including the immune system cells, seems related to their effects on cell
plasma membranes, perhaps in a manner linked to and dependent upon astringency.
Hydrated Zn2+ ions from loosely bound zinc
complexes such as zinc chloride and zinc acetate (but not most tightly bound or
lipophilic zinc complexes) are astringent. Zinc oxide is topically astringent but releases
hardly any Zn2+ ions in a nonacidic medium. For
Zn2+ ions, but not for other more tightly bound
zinc compounds, cell rounding and refractile changes appear to result from its
astringent, protective action on cell membranes, not from cytotoxicity. These changes
often occur at about 0.1 mMol Zn2+ ions and at
much lower concentrations for most lipophilic and strongly chelated zinc complexes.(12)
These observations were interpreted as cytotoxicity for zinc and suggested a low 1:2 or
1:4 antirhinoviral therapeutic index for Zn2+
ions.(12,13)
Other researchers, including those much more familiar with the appearance of the
astringent action of Zn2+ ion on cell plasma
membranes, place the index 10 or more times higher in vitro. Extracellular
Zn2+ is a newly recognized host defense acting
to stabilize and protect cell membranes.(1,62-67) All astringents, including
Zn2+ ions, are locally applied protein precipitants
having such low cell penetrability that action is essentially limited to cell surfaces and
interstitial spaces (contraction, rounding, wrinkling and blanching in vitro). Permeability
of cell membranes is reduced by astringents including Zn2+, but cells remain viable. Astringents harden the cement substance
of capillary epithelium, inhibiting pathologic transcapillary movement of plasma protein
and reducing local edema, inflammation, and exudation. Additionally, astringents reduce
mucus and other secretions in tissues containing goblet cells and other secretory cells,
causing affected areas to become drier and heal faster.(62)
Many astringents, including Zn2+ ions, are
irritants or caustic in high concentrations.(62) Astringents are used therapeutically to
arrest hemorrhage by coagulating blood (styptic action) as well as to check diarrhea,
reduce inflammation of mucous membranes, promote healing, toughen skin, and
decrease sweating.(62) The astringent effects of zinc lozenges on immune system cells
and mucosal tissues are harmless, and normal cellular appearance and function returns
upon removal of Zn2+ ions. The astringent
effects of Zn2+ on immune system cells and
particularly its effects on mast cells as well as other immune cells and functions is
important in understanding how Zn2+ affects
common colds. Recommended concentrations of zinc acetate for use as a topical
astringent are 0.2 to 2.0 percent (9 to 90 mMol Zn2+),(62) suggesting concentrations from zinc lozenges to be
appropriate.
From these observations, hydrated Zn2+ ions
are observed not to enter or damage cells, and beneficial effects of Zn2+ ions occur exclusively at the cell membrane. By inference,
oral absorption of topical Zn2+ ions through the
oral mucosal membrane from zinc lozenges relies upon a non-lipophilic mechanism.
Perhaps the most consistently reported effect of Zn2+ ion on mammalian cells is membrane stabilization.(63) Zinc is
present in many mammalian cell membranes, and stabilizing actions of certain steroid
hormones on lysosomal membranes may be secondary to the effects of zinc.(63) The
exact mechanism by which zinc stabilizes cell membranes is not clear and may be
different for different membranes.(63) Hemolytic viruses, bacterial and animal toxins,
components of activated complement, cytolysin (perforin), cationic proteins, and
detergents have all been shown to induce a sequence of permeability changes at the
plasma membrane that are in every case beneficially sensitive to changes in
Zn2+ ion concentrations from normal levels up to
100 times normal serum concentration.(64-67) Membrane damage induced by a
wide variety of hemolytic agents can be prevented by zinc ions at normal to 100 times the normal concentration of zinc found
in human serum without harm to cells.(67) Within a range, as Zn2+ ion concentration is increased, the strength of protection also
increases.
The large dietary requirement for zinc cannot be explained by its known cellular and
enzyme requirements, but it can easily be explained by requirement for high plasma
membrane Zn2+ ions as protection against
damage induced by cytotoxic agents of environmental origin. Zinc, present in human
extracellular fluid at approximately 0.015 mMol, is likely to prevent damage only at
rather low concentrations of cytolytic agent, and a higher concentration is required for
protection against higher amounts of various cytolytic agents. Increasing concentration
of extracellular divalent zinc may be useful in augmenting host defenses against a wide
variety of cytotoxic agents and is considered by Pasternak to be a newly recognized
host defense.(1,67)
Similarly, calcium ions have been known since 1914 to
protect cell membranes in vitro, but calcium ions are not useful in vivo since
their concentration is under tight endocrine control. Elevated calcium ion
concentration leads to adverse effects in vivo in excitable cells like heart,
nerve, and muscle.(1) Concentrations of Zn2+ ions are not under endoctrine control, and their levels can be
raised in tissues in a beneficial manner protecting tissues from some viruses
and other cytotoxic agents. According to Pasternak, such action may well be
the responsible mechanism for ameliorating effects of common colds as
shown by Eby and others.(67)
Cytolysin (perforin) is a strong pore-forming agent released by natural
killer T-cell lymphocytes in response to virally injured cells.(65) The
molecular structure of cytolysin has been described.(68) Cytolysin is
released into virally infected tissues
where it can cause cell membrane damage or cell death. Some believe
cytolysin to be responsible for the increase in serous nasal drainage in
common colds. In some respects cytolysin is analogous to the C9
component of complement. Zn2+ ion prevents pore formation by cytolysin between
0.01 and 0.1 mMol Zn 2+ ion, and
blocks leakage from cells containing preformed cytolysin. The beneficial
response from Zn2+ ions occurs within
minutes. Removal of Zn2+ ions by
chelation with EDTA in the presence of cytolysin restores some cytolysin
pore-forming activity. The concentration of Zn2+ ions required to stop hemolysis of cells
containing preformed pores is somewhat higher than the concentration
required to prevent pore formation when all agents are introduced at the same
time.(65)
The C9 component of complement has cell membrane-damaging
properties capable of lysing or damaging cells. In the presence of 0.1 mMol
Zn2+ ions, red blood cells do not lyse
when complement C9 is added.
The inhibitory action of Zn2+ ions
appeared to be on the reaction or reactions occurring between the insertion of
C9 and the damage-producing step and is completely reversed upon
Zn2+ ion chelation.(69)
Mast cells and basophils are commonly known to be mediators of Type I
allergy and possibly also several symptoms collectively known as the
common cold. Mast cells are discussed because of their historic association
with common colds, because of their ubiquitous and mysterious nature,
because mast cells are the current subject of extensive zinc research, and
because mast cells are theorized by the present author to be potent antiviral
and T-cell function-modulating cells. Mast cells have been implicated
in allergy and common colds as causing tissue redness, inflammation, nasal
congestion, release of mucus from goblet cells, nose and throat pain, tickling
and itchiness, and, indirectly, coughing and sneezing.
Mast cell derived reactions result from release of histamine, heparin,
prostaglandins, SRS-A, and various powerful vasoactive amines from
granules on the surface of mast cells, possibly including kinins. Mucosal
mast cells are widely distributed in nasal, throat, and tracheal tissues and
are believed to respond to viral antigens by degranulation. However,
research shows histamine does not play a part in common colds.
One product of mast cell-induced inflammation in response to rhinoviral
attack is fever. One chemical mediator generated is endogenous pyrogen
which increases concentration of prostaglandins from the hypothalamus,
resetting the body's temperature to cause chills and fever.
Hydrated Zn2+ ions prevent
induced histamine release from mast cell granules(70) as well as release of
all mast cell granule contents as Zn2+
ions stabilize mast cell plasma membranes.(1,64,67,70 ) Several receptors at
plasma membranes might function as gates for transmitting information to
intracellular space. In the case of mast cells, histamine-releasing agents
appear to work through specific receptors at the cell
membrane or by calcium antagonism. Masking receptor sites by membrane-
impermeable zinc compounds could explain inhibition of release action,(70)
but at least four mechanisms could also be operational. The granules of both
basophils and mast cells
also contain Zn2+ ions stored
combined with histamine and heparin.(71) Concentrations are in the 4 to 20
mMol range for mast cell secretory granules,(72) which is 400 to 2000 times
greater than Zn2+ ion concentration in
human serum and identical to concentrations of Zn2+ ion in saliva from zinc gluconate or zinc acetate
lozenges. Both human and rat tissue mast cells contain high concentrations
(2.1 mg/million cells) of granule-associated zinc.(73) Perhaps some zinc
binds histamine
with heparin,(74) although research has shown this idea does not hold true in
mast cells of rats.(75)
Hydrated zinc ions stabilize cell plasma membranes and prevent induced
histamine and vasoactive amine release from tissue mast
cells.(1,64,67,72,76-78) Inhibition of histamine release begins at about 0.001
mMol concentration of Zn2+ ions in
human beings and is greatest (80 to 100 percent inhibitory) at 0.1 mMol
concentration.(76-79) This concentration of zinc is about 6.67 times higher
than normally found in human serum. When histamine is released from mast
cells, Zn2+ ions are also released in large amounts into
surrounding tissues, perhaps acting as a source of local antiviral activity and
T-cell immunostimulation. Zn2+ ions
from zinc gluconate act to inhibit 100 percent of rat mast cell histamine release at 0.1 to
1.0 mMol concentration in typical or connective tissue mast cells, while much
more is required for leukemic basophil cells.(80) Physiologic concentrations of Zn2+ ions inhibit release of histamine from human
basophils and lung mast cells presumably by blocking calcium uptake induced
by anti-IgE activation.(78) Zn2+ ions are a competitive antagonist of action of calcium ions in histamine secretion induced by anti-IgE. The zinc-
histamine stability constant is log K1= 5.0 for both
basophil and mast cell histamine,(78) but stability is sensitive to pH and is
reported for pH 7.4. Similarly, Martell reports log K1= 5.4 for zinc and histamine.(81)
Zn2+ ion has been proposed to be
involved in catabolism of histamine, as zinc has been proven to interfere with
pharmacologic effects of histamine leading to anaphylactic shock.(82-84)
Berthon and others showed the complexes of histamine formed with
Zn2+ ion and several naturally
occurring amino acids in plasma to be neutral and unlike histamine
itself. Histamine is inherently polar and exists mainly in a charged form
because of protonation under the prevailing physiologic 7.4 pH. These
neutral, mixed ligand complexes are thus thought to be capable of passively
diffusing through lipid membranes into tissue where histamine can be catabolized.
Dicarboxylic acid complexes of zinc, malate, malonate, tartarate, and
maleate (log K1 = 2.0 to 2.8), were shown to be effective in
catabolism of histamine,(83) but zinc aspartate and zinc glutamate (first
stability constants log K1= 5.9 and
5.45 respectively) were not.(84) Berthon and Germonneau found zinc
aspartate concentration in vitro needed to be raised 1000 times over normal
levels to be more efficient than Zn2+
ion alone to favor zinc-mediated histamine diffusion into tissues.(84)
Considering the stability constant of zinc and histamine is log K1 = 5.0, zinc complexes with stability constants
above 5.0 cannot readily react with histamine to catabolize it. Zinc
complexes with stability constants lower than 5.0 may reduce massive surges of histamine
suddenly released into plasma in response to antigens, a variety of local
stimuli, or general toxins. Mast cell Zn2+ ion complexation of
histamine might explain absence of histamine from nasal lavages in colds
(see below - Histamine or Kinins in Colds?).
Hydrated zinc ions (Zn2+ ions) in mast cell granules are chemically or physically protected
from strong zinc chelators, thus denying access to Zn
2+ ions by serum proteins and other zinc-complexing
agents.(73) Such a unique property allows zinc to be delivered as
Zn2+ ions or very lightly complexed zinc and not as
strongly bound complexes of serum proteins to local virally infected tissues
upon mast cell degranulation for use as a local, natural antiviral agent, an
interferon-inducing agent, and
a T-cell lymphocyte immunoactivator as well as a preventive of allergic
responses, when sufficiently present in mast cell granules.
Introduced nasally, zinc compounds including zinc chloride, sulfate,
sulfocarbolate, oxide, stearate, and borate have been used to treat nasal
catarrh for about 100 years.(85-91) Reports show intranasal zinc to be a mild,
short-term nasal decongestant.
Zinc electrically driven into nasal tissues provides beneficial relief from
nasal allergy for up to one year, although treatment is painful (without cocaine
pre-treatment) and may cause sloughing of nasal epithelium.(87-89)
Histamine appears active in common colds, considering the widespread
use of antihistamines to treat common cold symptoms, but such may not be
true. The British Medical Research Council Common Cold Unit first reported
histamine to be uninvolved in common colds in 1951, and antihistamines
were worthless in common cold treatment.(92) Even so, nasal secretions
from histamine-stimulated goblet cells in colds
and allergy have been poorly studied until fairly recently.
A wide-ranging amount of histamine (5 to 1,519 ng/ml, with a mean 91
ng/ml for non-allergic patients and 51/ng/ml
for allergic patients) is found in nasal secretions, with the histamine amount
being four times higher in men than women.(93) During symptomatic
rhinovirus infections, analysis of nasal lavages shows kinins to be
generated, vascular permeability increased, mast cells not participating, and
neutrophils entering nasal secretions.(94)
To test the hypothesis that viral respiratory infections cause symptoms
by activating nasal mucosal mast cells to release mediators active on
vasculature and mucosal glands, the presence of histamine in nasal
secretions was assessed during natural colds and in laboratory-induced
rhinoviral infections. Infection with rhinovirus and with influenza did not
change these concentrations significantly. Histamine tended to be lower
during viral infections.(95)
Increase in kinins, but not histamine, in nasal
lavages occurred in symptomatic common colds, suggesting mast cells and
basophil activation do not occur during rhinovirus colds.(96) Increases in
kinins correlated with increased vascular permeability, as monitored by increased concentrations of albumin in nasal lavages.(96) More information implicating kinins and not histamine in common cold symptomology has been obtained. (97-101) 2001 UPDATE: More on these important findings here.
Rhinoviral illness of the respiratory tract enhances airway reactivity and
predisposes allergic patients to develop late asthmatic reactions, which may
be an important factor in virus-induced bronchial hyper responsiveness.(102)
In infants with respiratory syncytial virus (RSV) infection, histamine and RSV-specific IgE
were far more common in wheezing infants than in non-wheezing infants and
adversely affected the outcome of RSV infections.(103)
B- and T-cell lymphocytes are the main warriors in the defense of the
nose. B-cells produce immunoglobins, antibodies that plug up cold-virus
receptor sites and prevent viruses from attaching to cells of the nose and
throat. Some cells become memory cells helping to prevent the recurrence of infection. T-cell lymphocytes, when
summoned to the site of infection, turn into "killer cells" (perhaps with help
from Zn2+ ions released by mast
cells) which release cytolysin (perforin), opening pores in cell membranes
and attacking and killing virus-infected cells. Other T-cells ("helper/inducer"
cells) stimulate B-cells to produce more antibody. Still other T-cells become
"suppressor" cells to shut off antibody production and killer-cell activity after
viruses have been defeated. T-cells also release several other substances
to help the body conquer infection, including macrophage activation factor,
macrophage
inhibition factor, interleukin 1 and 2, and interferon. Interferon prevents cell
death caused by viruses and prevents viral replication.(92)
In the common cold, Zn2+ ions
have effects on local T-cell function not yet completely elucidated, and which
are too complex for full discussion here. Emphasis here is on local mucosal tissue and cutaneous
effects, as zinc serum level does not rise with administration of zinc
lozenges in common colds. Zinc deficiency has been studied more than zinc
excesses. Zinc deficiency is universally accepted as being harmful to the T-cell lymphocyte system and is
potentially lethal in humans(63,104-107) because zinc transferrin is the
body's only T-cell lymphocyte mitogen.(108) Its necessity in thymic T-cell
lymphocyte function is well known.(109) Zinc is also necessary for transferrin synthesis(110) and a
deficiency in either transferrin or zinc can cause profound
T-cell immunosuppression. Zinc deficiency during prenatal life causes
persistence of immunodeficiency for three generations in
mice,(111) with predictably dire consequences for human beings. Golden and
associates 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.(112) Whether the
condition needing immunostimulation by zinc is malnutrition, HIV infection,
AIDs, acute lymphocytic leukemia (ALL) or any other T-cell lymphocyte zinc
immunodeficiency, daily dosage should be as described by Golden and associates for thymic
stimulation and regrowth in malnutrition. Both the young and the elderly
receive T-cell immunologic benefit with supplemental zinc in the 150 mg/day
range.(113,114)
At concentrations of 0.1 to 0.4 mMol zinc, a mitogenic response is
induced in normal T-cell lymphocytes but not in leukemic lymphocytes.(115)
This difference in response
has been used to stimulate normal T-cell function in leukemia.(116) Zinc
supplementation has been proposed to rectify T-cell anergy in pediatric
Hodgkin's disease.(117) As little as 15 mg zinc from zinc gluconate after
three weeks beneficially
changes the helper (OKT4) to suppressor (OKT8) ratio by normalizing the
suppressor population without increasing the absolute number of helper cells
in healthy people, with
no effect on leukemic T-cells.(115) One explanation for modulation of T-cell
subset ratios is histamine induction of suppressor T-cells,(118) and
Zn2+ ion inhibition of release of
histamine, and consequently its effect
on suppressor proliferation. As activation of T-cell lymphocytes requires 4 to
6 days for full effect (10 - 15 percent activated T-cells),(115) T-cell activity is a
delayed response and comes into play late in common colds.
T-cell activity is impaired after one month when healthy people take 300
mg zinc per day.(119) Large excesses of zinc are known to compete with
copper and manganese for intestinal binding sites adversely driving down
their absorption, resulting in sevAntiviral Effects of Zinc Ions
Antibacterial and Antifungal Activity
Astringency
Non-Specific Membrane Protection
Cytolysin
Complement
Mast Cells
Histamine or Kinins in Colds?
T-Cell Lymphocytes