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The Use of Zinc Lozenges to Treat Acute Respiratory Tract Infection

For more than twenty years, clinicians have studied the efficacy of zinc lozenges in treating acute respiratory tract
infections (the common cold). Study results vary significantly, as the studies have used differing zinc compounds,
dosages and study designs. However, in well-designed clinical studies, the compound zinc gluconate glycine in a
corn-syrup lozenge form has shown consistent efficacy in reducing the duration and severity of the common cold.
antitussives, and combination products that offer two According to some estimates, Americans suffer from as many as one billion colds each year (NIAID Fact Sheet 2001). The National Center for Heath Statistics While traditional over-the-counter medications can estimates that in 1996, the common cold caused improve cold symptoms, these medications have not Americans to miss nearly 20 million days of work been shown to reduce the length or underlying and 22 million school days (Adams 1999). The severity of a cold. In addition, traditional over-the- common cold’s immense economic impact makes counter cold medications can pose risks, in particular prevention and treatment options of key importance. Each year, patients make more than 25 million office • Following an FDA warning regarding accidental visits seeking treatment options for colds (Gonzales overdose, several children’s cold medications 2001). Because prescription medications such as were voluntarily withdrawn from market in 2007. antibiotics are not effective in treating the common • Certain over-the-counter cold remedies can be cold (a virus), clinicians can only offer patients misused by teenagers seeking an easy and advice on using over-the-counter medications, nonpharmacological therapy, and/or homeopathic • Senior citizens are at a higher risk of side affects Acute Respiratory Tract Infections
Acute respiratory tract infections develop after exposure to infected secretions or to small- or large- Along with nonpharmacological therapy such as particle aerosols after an infected person sneezes or drinking water, room humidification, saline gargles, and so on, homeopathic cold remedies such as vitamin C, Echinacea, and zinc can be used. Once the cold virus enters the body, it moves to the throat and binds to the intercellular adhesion receptor The zinc gluconate glycine lozenge is a homeopathic molecule-1 (ICAM-1). The virus then reproduces in option that has been clinically shown to reduce the respiratory epithelial cells and spreads throughout the duration and severity of the common cold. These zinc nasopharynx area (Cauwenberge 2000, Winther lozenges have few side-affects and none of the risks associated with traditional over-the-counter cold The virus spreads quickly, and cold symptoms typically begin within 12 hours following infection. Zinc Lozenges
Patients typically experience cold symptoms for a Zinc lozenges marketed for treating acute respiratory week to ten days; some symptoms can linger for up tract infections contain as the active ingredient either Treatment Options
Traditional Over-the-Counter Medications Zinc gluconate glycine is a zinc compound that For patients who seek over-the-counter cold contains both zinc gluconate and the amino acid medications, a range of products area available for glycine. This formulation allows for an extended the reduction of cold symptoms. These include shelf life and a more palatable taste. In 1985, the zinc gluconate glycine compound was patented, and it is now marketed and distributed under the brand Cold- Each Cold-EEZE® zinc lozenge provides 13.3 mg of
ionic zinc per lozenge. Cold-EEZE® releases positive
zinc ions into the membranes in the mouth. Up to six lozenges may be taken per day. For adults and Zinc acetate is used in lozenges to treat the common children 12 years and older, this dosage can help cold, in dietary supplements, and as an astringent in strengthen the immune system, and is required for the ointments or lotions. Clinical studies have not shown development and activation of T-lymphocytes that zinc acetate to be as effective as zinc gluconate glycine for the reduction in length and severity of Study Results
A wide range of clinical studies have been conducted to analyze the effectiveness of zinc in treating the The use of zinc lozenges in treating the common cold common cold. (See table in Appendix for summary.) has gained significant support from the medical community as an intervention in rhinovirus colds. Independent, double-blind, clinical studies of zinc While zinc’s mechanism of action in treating the gluconate glycine lozenges, conducted by leading common cold is not entirely understood, there are infectious disease specialists at both the Cleveland Clinic and Dartmouth College, were published in the well-respected Annals of Internal Medicine (Mossad • Zinc lozenges may prevent the development of a 1996) and Journal of International Medicine protein that cold viruses need to reproduce. Once Research (Godfrey 1992). Both of these peer- virus reproduction ceases, cold symptoms begin reviewed, published studies support the effectiveness of Cold-EEZE® zinc gluconate glycine lozenges in
• Zinc may attach to the proteins of critical nerve reducing the symptoms of the common cold by endings and to proteins at the edge of a cold virus, interrupting nerve impulses and prohibiting the virus from entering the body’s cells. This In 1984, George Eby was the first to study zinc tablets that were dissolvable in the mouth. He created experienced by patients taking zinc lozenges. a formula that determines the strength of the zinc Zinc ions may be an important anti-inflammatory lozenge called “zinc ion availability.” The study concluded that ionic zinc notably shortened the • Zinc salts may act to protect and stabilize the duration of a cold and reduced the severity of its body’s cell linings, reducing the impact of a cold symptoms. The unflavored zinc gluconate was unpalatable, however, which caused a high patient dropout rate for the clinical studies (Eby 1984). The primary cited side-affects of zinc therapy for In 1987, after a tolerance study, double-blind placebo colds are dysgeusia (temporary dysfunction of the controlled trials were performed to determine the sense of taste) and stomach upset. Using zinc prophylactic effect of zinc gluconate lozenges on lozenges after a meal can help reduce these side- rhinovirus challenge. In the third study, the therapeutic efficacy of the lozenge was tested when it was given at the start of the cold. Patients were Cold-EEZE®-brand Zinc Lozenges
isolated for 48 hours, and then induced with a human Cold-EEZE®-brand zinc gluconate glycine lozenges rhinovirus. Daily examinations were given that have been shown in clinical studies to reduce the included grading of colds, weighing of nasal duration and severity of the symptoms of the secretions, counts of tissues used, blood samples for common cold by 42 percent. Cold symptoms include hematological values and 24-hour urine for zinc cough, stuffy nose, sore throat, sneezing, post-nasal content. As a result, it was concluded that zinc drip and hoarseness. Cold-EEZE® lozenges are most
effective when taken at the first sign of a cold. In 1992, patients showing cold symptoms within the In 2006, Kurugol et. al. studied a group of 200 previous two days were randomly chosen to have school-age children using zinc sulfate syrup over a placebo or zinc. The patients with zinc were given period of seven months. The study group received 15 23.7 mg of zinc gluconate lozenges every two hours mg of daily prophylactic, and 15 mg twice daily after for 10 days or until the symptoms stopped. Each day, the onset of a cold and until symptoms were resolved. the patients’ symptoms were monitored. As a result, Results of this study showed a reduction in the zinc helped reduce the symptom severity by 1.27 number of colds, and a reduction in the number of cold-related absences from school. There was also a shorter duration of cold symptoms in the zinc group In 1996, patients recruited from a health care center versus the placebo group (Kurugal, 2006). were admitted into the study if they showed at least 2 of 10 predetermined symptoms within 24 hours. The In 2004, in response to a critic’s assertion that zinc group was randomly divided into zinc and placebo. lozenges do not deposit zinc ions in the nasal 13.3 mg of zinc gluconate were given to the patients mucosa, a joint study (available for review but every two hours until the symptoms disappeared. As currently unpublished) was conducted by Retroscreen a result, the zinc group had a shorter duration than the Virology (University of London) and Synergy placebo group (4.4 days vs. 7.6 days). In addition, Research, Inc. Results of this phase II, single-center, nasal drainage, sore throat, cough, headache, and clinical trial indicate a statistically significant increase in zinc levels in the nasopharynx immediately after the oral administration of a Cold- In a review of cases from January 1998 to August EEZE® lozenge. This suggests that the oral
2001, 496 patient cases were analyzed regarding the administration of Cold-EEZE® results in increased use of zinc gluconate glycine lozenges in school-age zinc levels in the nasopharynx and is useful as a children. One lozenge (13.3 mg) was giving daily as therapeutic agent in the prevention of rhinovirus a prophylactic to 119 patients in the zinc group. Findings included a significant reduction in the Another recent clinical trial set out to determine if zinc median number of colds in the zinc group. can be detected in the nasopharynx after administration of zinc gluconate lozenges containing One study involving 48 adults found zinc acetate 13.3 mg of ionic zinc, using healthy human adult lozenges (12.8 mg zinc per lozenge) taken every two to three hours while the patient is awake reduced the duration of cold symptoms compared to placebo (4.5 • The mean change in zinc at the second sampling (using the time of administration of the lozenge as One placebo-controlled, seven-day study observed 65 baseline) was statistically significant (p=0.00210) individuals who took either a loading dose of 46 mg based on the Wilcoxon rank sum test of 32 zinc (two zinc gluconate lozenges) followed by 23 mg zinc (one lozenge) or placebo every wakeful hour until symptoms were absent for six hours. After • Twenty-five of thirty-two subjects (78%) showed seven days, 86% of the zinc group were symptom- an increase of zinc in their nasal mucosa at the free compared to 46% of the placebo group • The mean change in zinc at the second sampling In a seven month, phase IV trial, 134 school children time (using the time of administration of the were given 13.3 mg zinc (one zinc gluconate lozenge as Baseline) was statistically significant lozenge) daily as a preventative and 53.2 mg zinc (p=0.00333) based on the Wilcoxon rank sum test (four zinc gluconate lozenges) daily at cold onset until symptoms resolved. Previously collected data • After the oral administration of one lozenge, there was used as a control. Average cold duration days 9.0 was a statistically significant level of zinc in the +/- 3.5 days for the control group (McElroy 2004). • A statistical analysis was performed to determine common cold. This statement is unsupported, as the how long zinc persisted in the nasal mucosa. Fifty- authors of this report did not consider study factors six percent (56%) of subjects returned to their that have a significant impact on results, such as: baseline measurement, or below their baseline measurement, of zinc at the third and final nasal swab (performed on subjects between 10 and 180 • Variance in endpoints or severity scoring • Forty-four percent (44%) of patients continued to show an elevated level of zinc, represented by an increase over their baseline measurement, at the Furthermore, the authors defined a specific set of eleven criteria to select the published papers for their source material. This does not necessarily Studies with Inconclusive or Negative Results mean that one or more of their criteria were not While published studies exist that show inconclusive performed in the unselected studies. A review of or negative results regarding the use of zinc in protocols and study reports would have provided a treating the common cold, these studies each contain more accurate understanding, as the description of one or more of the following flaws in design: specific study methodology does not necessarily get reported in published papers. There was no review • Inadequate zinc dosing (4.5 mg, 10 mg) by these authors of per-protocol compliance. • Unavailable zinc ions due to chelating effect of pharmaceutical binders and sweeteners For example, the report by Caruso et. al. included a (sorbitol, manitol, citric acid, ascorbic acid) 1998 JAMA study by Macknin et. al. (referenced as • Tablets designed to dissolve quickly study 23 in the report) because it upheld the eleven (effervescent tablets) – limit dwell time in the criteria required for study inclusion. The Macknin et. al. study found zinc to have no effect on cold • Limited controls for etiology (rhinovirus, duration or severity. However, an independent per- protocol analysis of this study showed that it was a • The use of zinc sulfate, which is not used in poorly controlled study. Roughly 74 percent of the zinc lozenges and has not shown efficacy in study participants could not be evaluated due to a variety of issues, leaving only 64 subjects from the original 248 participant pool. While this study met Discussion
the inclusion criteria set by the report authors, its There is significant evidence that zinc gluconate results should not be used to evaluate the glycine lozenges reduce the severity and duration of effectiveness of zinc lozenges. (A per-protocol analysis is available from The Quigley Corporation A wide range of study on the subject has been conducted, yielding inconsistent results. The primary explanation for the inconsistencies between study • Dr Robert Lambkin-Williams, Director and results include differences in zinc preparations, General Manager Retroscreen Virology Ltd,
including form (zinc gluconate versus zinc acetate), University of London. Ph.D Avian Influenza, dosage (elemental zinc per lozenge; range from 5 – 23 mg), and composition of lozenge (Hulisz 2004, “The paper by Caruso et. al. reviewed a wide range of zinc / rhinovirus clinical trials and A recent report in Clinical Infectious Diseases concluded, based on their criteria, that only a zinc (Caruso 2007) reviewed 105 zinc studies. Of those, gel applied directly to the nasal passage was fourteen randomized controlled trials were selected effective. They also suggest that migration of to make a general conclusion that zinc gluconate zinc ions from the oral cavity to the nasal sinuses glycine lozenges are not effective against the has been challenged. Unknown to the authors, unpublished data from a controlled clinical trial has shown that zinc ions can be detected after a Finally, there was a recent report, that warned of volunteer dissolves a lozenge in their mouth, thus the use of the over the counter 'tussin' products supporting a mode of action of zinc lozenges. There is also published in-vitro data to support inappropriate use has resulted in some serious the mechanism of action of zinc ions against consequences. This has not been my experience The criteria that the authors used to review the • Larry Stephens, B. S. Pharmacy, Licensed papers were not unreasonable for a modern Pharmacist, Community Hospital Practice, clinical trial. The difficulty lies in reevaluating clinical studies that were conducted many years ago and to suitable standards at the time. In “Virtually every researcher has their opinion on addition, it would seem that only the papers were what makes a valid design, and the eleven criteria reviewed and it is possible that some of the selected by the authors of the Echinacea paper, criteria were included in the original design, but subsequently used in the Zn paper, are yet another example of this. I would like to hear from those who designed the studies with less than, or • Dr. Peter Lodewick, Endocrinologist, Clinician, other than, the eleven criteria to see what valid “I had a chance to review the article, Treatment There are problems with at least one of the of Naturally Acquired Common Colds with Zinc, criteria determined to be valid in the Zn study by by Caruso et. al., and I was quite surprised by Caruso, et. al. Validated case definition is their conclusions. As a clinician, both working as dependant on the skill of the practitioner making a diabetes specialist and an emergency physician the diagnosis. Most practitioners will freely over the years, my experience has been different. admit that differential diagnosis between early We know that most upper airway diseases of flu, allergy and cold symptoms is very difficult. acute onset are viral in origin. However, they can If the initial determination is incorrect, and provoke severe symptomatic illness, frequently someone with an allergy is entered into a study causing diabetes to go out of control, especially using Zn to treat common cold symptoms, we in patients with type I diabetes, maybe even the serious diabetic ketoacidosis, if patients and their family are not alerted as to preventive measures. I have seen various forms of zinc gluconate used It is imperative to be sure that the illness is not recommended by their physician, and self- bacterial in origin, so that an office visit to rule medication in others. The opinions on results out streptococal pharngitis or nonviral causes is vary, but most patients report benefit, especially definitely an important initial step. If it is viral in for sore throat symptoms. Others say it lessens origin, it has been my experience over the past 25 the time they are sick as compared to doing years to use zinc gluconate lozenges (my nothing and just ‘waiting it out’. Based on my preferred brand, Cold-eeze). My patients have experience and my opinion of relevant studies, I done well using zinc lozenges, frequently feel that zinc gluconate glycine (Cold-EEZE) has reporting that they feel better, especially if they value in the treatment of the common cold.” use them within 24 hours of onset, more quickly. It is also my opinion that the use of zinc lozenges It may also be of interest to scientists and clinicians may better in treating the common cold than to that early research indicates that ionic zinc may have use antibiotics, which may be called in over the antiviral effects on other viruses such as herpes phone, as the inappropriate use of antibiotics simplex 1 and 2 viruses and infections in animals and seems to be resulting in increasing resistance to humans. More research is needed in these, and other antibiotics, even streptococcus infections.
Clinicians and patients must balance the benefits and
risks of traditional over-the-counter cold remedies
Nonpharmacological treatments and homeopathic options such as use of zinc gluconate glycine lozenges offer important alternatives. The use of zinc gluconate glycine lozenges has shown significant clinical benefit to patients in the reduction of the severity and duration of the common cold. References
Gonzales R, Malone DC, Maselli JH, et. al. Excessive Adams PF, Hendershot GE, Marano MA. Current antibiotic use for acute respiratory infections in the United Estimates from the National Health Interview Survey, States. Clin Infect Dis. 2001;33:757-762. 1996. Hyattsville, Md: National Center for Health Statistics; 1999. Vital Health Statistics 10, No. 200.) Hulisz D. Efficacy of zinc against common cold viruses: an overview. J Am Pharm Assoc (Wash DV) 2004;44:594- Caruso TJ, Prober CG, and Gwaltney, Jr., JM September 1, 2007 Clinical Infectious Diseases Cauwenberge PBV, Kempen MJV, Bachert C. The common cold at the turn of the millennium. Am J Rhinol. McElroy GA. Zinc lozenges: cold cure or candy? Solution chemistry determinations. Biosci Rep 2004;24:23-39 Covington, TR, Henkin R, Miller S, et. al. Treating the Mossad SB, Machnin ML, Medendorp SV, Mason P. Zinc Gluconate lozenges for treating the common cold. Annals recommendation for Primary Care Clinicians; October of Internal Medicine 1996 Jul 15;126:81-87. Novick SG, Godfrey JC, Pollack RL, Wilder HR. Zinc- induced suppression of inflammation in the respiratory tract, caused by infection with human rhinovirus and other Eby GA. Zinc ion availability – the determinant of efficacy irritants. Med Hypotheses 1997 Oct;49(4):347-57 in zinc lozenge treatment of common colds. J Antimicrob Prasad AS, Fitzgerald JT, Pao B et al. Duration of symptoms and plasma cytokine levels in patients with the Eby GA. Zinc lozenges: cold cure or candy? Solution common cold treated with zinc acetate. A randomized, chemistry determinations. Biosci Rep 2004;24:23-39 double-blind, placebo-controlled trial. Ann Intern Med Godfrey JC, Conant Sloane B, Smith DS, Turco JH, Mercer N, Godfrey NJ, Journal of International Medical Winther B, Gwaltney JM, Mygind N, et al. Sites of rhinovirus recovery after point of inoculation of the upper airway. JAMA. 1986; 256(13):1763-1767.



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Interactive CardioVascular and Thoracic Surgery 15 (2012) 733–740What is the optimal anticoagulation in patients with a leftMichele Rossi*, Giuseppe Filiberto Serraino, Federica Jiritano and Attilio RenzulliDepartment of Cardiac Surgery, Magna Graecia University, Catanzaro, Italy* Corresponding author. Department of Cardiac surgery, Magna Graecia University, Viale Europa. Germaneto, 88100 Ca

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