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This activity is supported by an educational grant from ProPhase Labs, Inc.

Zinc and Zinc Preparations for Colds: An Update for Pharmacists

Nikhil Patel, PharmD, RPh
Medical Consultant
Hillsborough, New Jersey

 
Disclosures
The following contributors have no relevant financial relationships with commercial interests to disclose.
 
Faculty
Nikhil Patel, PharmD, RPh           

Pharmacy Times Office of Continuing Professional Education
Planning Staff—Judy V. Lum, MPA, and Steve Lin, PharmD
 
Pharmacy Times
Editorial Staff
Kirk McKay and David Allikas
 
An anonymous peer reviewer was part of the content validation and conflict resolution. The peer review­er has no relevant financial relation­ships with commercial interests to disclose.
 
Educational Objectives
Upon completion of this educational activity, participants should be able to:
1. Explain the impact of the common cold on adults and children and describe the potential role of zinc-based options for patients.
2. Discuss evidence in support of zinc and its hypothesized mechanism of action in fighting the rhinovirus.
3. Consider the evidence in support of different zinc formulations and be able to make appropriate recommendations to patients to help them manage their cold.
 
Target audience: Pharmacists
Type of activity: Knowledge
Release date: November 12, 2013
Expiration date: November 12, 2015
Estimated time to complete activity: 1 hour
 
Description: Description: harmacy Times/Ascend Media Office of Continuing Professional Education Pharmacy Times Office of Continuing Professional Education is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. This activity is approved for 1.0 contact hour (0.1 CEU) under the ACPE universal activity number 0290-0000-13-160-H01-P. The activity is available for CE credit through November  12, 2015.


Introduction
The common cold is one of the most frequent illnesses among humans, with an estimated prevalence of 1 billion cases occurring annually in the United States.1 The common cold usually has symptoms that last 1 to 2 weeks, but it is a leading cause of doctor visits and missed days from school and work in the United States.1,2 Because of this high prevalence of the common cold, it results in a high burden on the health care system. The common cold is responsible for 75 million physician visits per year and almost 150 million days lost from work.3 According to the National Center for Health Statistics, the common cold also results in 22 million school days lost annually in the United States.2 This high burden on the health care system has also been shown to exact a high economic burden—$17 billion in expenditures for physician visits.4 To reduce the burdens due to the common cold and improve patient outcomes, it is important to understand the pathophysiology of and treatment options to for the common cold.
 
Symptomatic Management of the Common Cold
The common cold occurs primarily because of the rhinovirus, which has been shown to be responsible for up to 80% of all upper respiratory infections in the colder seasons.4-6 The rhinovirus usually infects cells in the nasal membrane by binding to intracellular adhesion molecule-1 (ICAM-1).4,7,8 The binding of the rhinovirus protein to the ICAM-1 receptor sets into motion the inflammatory process, which is responsible for the symptoms related to the cold.4,9-11 Table 1 reviews some options for management of these symptoms.

Table 1. Symptomatic Treatment Options for the Common Cold12-16
Symptom Therapy Option
Rhinorrhea, sneezing Antihistamines (eg, chlorpheniramine, diphenhydramine), anticholinergics (ipratropium), humidification (Vicks [Procter & Gamble], inhalation therapy)
Congestion Decongestants (pseudoephedrine, phenylephrine, oxymetazoline), humidification
Fever, headache, myalgia, sore throat Analgesics (nonsteroidal anti-inflammatory drugs, acetaminophen), local anesthetics, dyclonine lozenges
Cough Expectorants (dextromethorphan, guaifenesin), antitussives (benzonatate, codeine)
General symptoms Alternative treatments: chicken soup, vitamin C, zinc, echinacea
 
The Use of Zinc for Treating the Common Cold
Zinc (Zn2+) ions are known to have astringent properties, which suggests that loosely bound complexes with hydrated zinc ions, such as zinc acetate, zinc chloride, and zin gluconate are astringent as well.4,8 In instances when these complexes are tightly bound or lipophilic, they do not have astringent properties.4,8 This is important because the astringent property of zinc is responsible for its beneficial effects in colds, which is usually exerted at the cell membrane.4,8 The zinc ions reduce the permeability of the cell membrane, and as an astringent, it alters the capillary epithelium, thus reducing local edema, inflammation, exudation, and mucus secretion.4,8
 
The exact mechanism of zinc in the common cold has not been identified yet, but it has been hypothesized that it is a competitive inhibitor of ICAM-1 in rhinovirus particles and the nasal epithelium.4,8,9 This action would prevent the rhinovirus from attaching to ICAM-1, entering the cell, and therefore replicating, and would also suppress inflammation.4,9
 
Considering this proposed mechanism of action of zinc in the common cold, the use of zinc has been explored by many and several preparations are currently used to manage the common cold (Table 2). However, the effectiveness of the different products for reducing the severity of the symptoms and duration of the common cold depends on the formulation and the route of administration (Table 3).4,8

Table 2: Top 3 Recommended Zinc Preparations17
Brand name Zinc Salt Dosage Form
Cold-EEZE (Cold-EEZE) Zinc gluconate glycine Lozenges (available in sugar free), Oral spray, and QuickMelts
Zicama (Matrixx Initiatives, Inc) Zinc acetate, zinc gluconium Intranasal gel, dissolvable tablets, chewables, oral mist, rapid melts, and swabs
Sucrets (INSIGHT Pharmaceuticals, LLC) Zinc gluconate (listed as inactive ingredient) Dyclonine lozenge containing zinc
aReceived recent FDA warning regarding permanent loss of smell associated with various products.
 
Table 3: Different Formulations of Zinc Lozenges
Lozenge Formulation Evidence Safety
Zinc gluconate
  1. Eby et al evaluated zinc gluconate tablets taken as a loading dose of 2 tablets, then 1 table every 2 waking hours, until the symptoms were resolved for at least 6 hours. The study showed that ionic zinc significantly shortened  the duration of a cold and reduced the severity of symptoms.20
  2. Combination of flavoring agents and sugars to zinc has been shown to cause the formation of highly bound complexes, resulting in the poor availability of ionic zinc and thus a lack of efficacy.4,21,22
  3. Godfrey et al evaluated zinc gluconate glycine and showed that this formulation resulted in resolution of symptoms after an additional 4.9 days from symptom onset compared with 6.1 days for placebo-treated patients.23
  4. Mossad et al showed that zinc gluconate lozenges resulted in significantly shorter (42%) duration of symptoms of the common cold (eg, nasal symptoms, cough, headache) compared with placebo.24
  1. Zinc lozenges used in the short term without magnesium have been shown to be harmless.25
  2. The most common side effect seen with the lozenges is taste disturbance. Other adverse events seen in less frequency include nausea, vomiting, diarrhea, and dyspepsia.28 
  3. On rare occasions, elderly patients have experienced noisome (offensive or disgusting odor) or bitter taste, which suggests an age-related zinc metabolism disorder.28
  4. Zinc gluconate lozenges have been shown to be safe in geriatric individuals, even those on multiple medications.29
  5. Large amounts of zinc ingested over several months can induce copper deficiency, which can result in immune suppression and possible neurologic disorders.29
    1. This occurs at long-term daily zinc intakes of >150 mg.30
    2. These levels increase the risk of cardiovascular disease by decreasing serum high-density lipoproteins and increasing low-density lipoproteins.30
Zinc acetate
  1. Trials evaluating zinc acetate lozenges showed that they also decrease the severity and duration of the cold and its symptoms.25,26
Zinc orotate
  1. Zinc orotate lozenges were investigated in patients with the common cold. The zinc lozenges were given in conjunction with a zinc gluconate nasal spray, which was given to keep the nasal tissues wet during wakeful hours. However, after 7 days of treatment, there was no significant difference between zinc-treated patients and placebo-treated patients in terms of duration and symptoms of cold.27
 
The ionic form of zinc is needed to allow zinc to reach and maintain contact with the ICAM-1 receptor. However, because zinc has an offensive metallic taste, manufacturers have tried to mask the taste by using chelating and flavoring agents, which if not selected correctly would reduce the concentration of ionic zinc and thus the efficacy of the product.4,9 Among the available products are lozenges, intranasal sprays, and intranasal gels, all of which have been evaluated in clinical trials to determine their effectiveness.4
 
The antiviral and antibacterial effects of zinc ions have been evaluated in clinical trials. Based on in vitro studies, it has been confirmed that the antirhinoviral activity of positively charged zinc ions occurs at concentrations of 0.1 mMol and above.12 At these concentrations, zinc ions inhibit cleavage of rhinovirus replication immediately and therefore inhibit further formation of infective virions.18 In addition, zinc also has been shown to have antibacterial activity in the mouth, albeit to bacteria unrelated to the common cold. Zinc and other metal salts have been shown to inhibit the growth of streptococci and Actinomyces spp as well as other dental caries–producing bacteria.19
 
Several trials have evaluated the effects of zinc lozenges and intranasal formulations on the duration and severity of the symptoms of the common cold.
 
Zinc Lozenges
Evidence from these trials illustrates that the type of zinc salt used and the use of additive ingredients in these lozenge formulations does make a difference in efficacy. When all the evidence is considered, zinc gluconate glycine lozenges have been shown to be the most effective for reducing the duration of symptoms of the common cold. This has been further supported by findings from 3 trials that showed the effectiveness of this formulation in school-aged children. In all 3 trials, treatment using zinc gluconate glycine significantly reduced the duration of the common cold.31,32 Zinc gluconate glycine was also shown to decrease the concomitant use of prophylactic antibiotic use as well as the median number of colds per year.31,32
 
Intranasal Sprays/Gels
Intranasal zinc formulations have also been studied. Nasal sprays and gels make sense from a common cold management perspective, especially because it is suggested that zinc competes for viral receptors in the nasal epithelium. However, the results from studies evaluating nasal sprays and gels have proven to be inconclusive because of the large heterogeneity in study design, dose, and results.33-36 Furthermore, intranasal zinc is no longer available, potential permanent anosmia is a concern when intranasal zinc preparations are used.37
 
Zinc Preparation Considerations
These studies have collectively shown that zinc products are fraught with an underlying problem: the lack of availability of zinc ions. The need for pleasant-tasting, candy-like, nonmetallic, nonastringent, and nondrying zinc lozenges and sprays has led to multiligand, nonionic compositions that do not have any effectiveness.28 However, some formulations have addressed zinc ion availability and have proven to be effective and safe.
 
Zinc Preparations with Herbals Remedies
Some herbal remedies (ie, echinacea, Rosa canina (rose hips), ginseng, vitamin C) have been shown to be helpful in managing symptoms of the common cold.38  Jawad and colleagues examined the safety and efficacy of Echinacea purpurea for preventing common cold episodes.39 The trial recruited 755 subjects who were randomized to receive either echinacea or placebo. Those receiving active treatment started with 0.9 mL 3 times a day and were instructed to increase their dose to 0.9 mL 5 times a day during acute stages of the cold, which totaled 4000 mg of extract a day.39  Over the 4-month period, echinacea was shown to reduce the total number of cold episodes and was even shown to inhibit virally confirmed colds.39 Overall, echinacea has been shown to have a positive risk-to-benefit ratio when used for treating the common cold.39,40
 
Rose hips, also known as Rosa Canina, have been used in some orally disintegrating tablets (QuickMelts) of zinc gluconate preparations to provide immune support due to its antioxidative properties. R canina has been shown to have high concentrations of certain antioxidants, such as natural vitamin C.41 The antioxidative effects of rose hips are said to be also due to polyphenolics, which have been shown to have strong anti-inflammatory effects.41,42
 
Considerations for Pharmacists
With the high prevalence of the common cold, pharmacists are very likely to frequently encounter patients with the infection. Pharmacists can play a significant role in helping patients obtain relief from the symptoms, and even reduce the duration, of the common cold. Understanding and being aware of the available therapeutic formulations that contain zinc, as well as knowing which have been shown to be effective, can help pharmacists direct their patients to choosing the most appropriate OTC remedy.
 
 
References
  1. David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc., and Linda J. Vorvick, MD. Common cold. Medline plus. www.nlm.nih.gov/medlineplus/ency/article/000678.htm. Accessed October 7, 2013.
  2. National Institute of Allergy and Infectious Diseases. Common cold: overview. www.niaid.nih.gov/topics/commonCold/Pages/overview.aspx. Accessed September 1, 2013.
  3. Garibaldi R. Epidemiology of community-acquired respiratory tract infections in adults. Am J Med. 1985;78(6):32-37.
  4. Hulisz D. Efficacy of zinc against the common cold viruses: an overview. J Am Pharm Assoc. 2004;44(5):594-603.
  5. Fendrick AM. Viral respiratory infections due to rhinoviruses: current knowledge, new developments. Am J Ther. 2003;10:193-2002.
  6. Heikkinen T, Jarvinen A. The common cold. Lancet. 2003;361:51-59.
  7. Arruda E, Boyle TR, Winther B, Pevear DC, Gwaltney Jr TR, Hayden FG. Localization of human rhinovirus replication in the upper respiratory tract by in situ hybridization. J Infect Dis. 1995;171:1329-1333.
  8. Novick SG, Godfrey JC, Godfrey NJ, et al. How does zinc modify the common cold? Clinical observations and implications regarding mechanisms of action. Med Hypotheses. 1996;46:295-302.
  9. Novick SG, Godfrey JC, Pollack RL, et al. Zinc-induced suppression of inflammation in the respiratory tract, caused by infection with human rhinovirus and other irritants. Med Hypotheses. 1997;49:347-357.
  10. Bella J, Kolatkar PR, Marlor CW, et al. The structure of the two aminoterminal domains of human ICAM-1 suggests how it functions as a  rhinovirus receptor and as an LFA-1 integrin ligand. Proc Natl Acad Sci USA. 1998;95:4140-4145.
  11. Gwaltney Jr JM, Ruckert RR. Rhinovirus. In: Richman DD, Whitley RJ, Hayden FG, eds. Clinical Virology. New York, NY: Churchill Livingstone; 1997:1025-1047.
  12. Turner RB. The common cold. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 7th ed. Philadelphia: Elsevier Churchill Livingstone; 2009:chap 53.
  13. Simasek M, Blandino DA. Treatment of the common cold. American Family Physician. 2007:75(4).
  14. Shah SA, Sander S, White CM, Rinaldi M, Coleman CI. Evaluation of echinacea for the prevention and treatment of the common cold: a meta-analysis. Lancet Infect Dis. 2007;7(7):473-480.
  15. Hemilä H, Chalker E, Douglas B. Vitamin C for preventing and treating the common cold. Cochrane Database of Systematic Reviews. 2007;3: article no CD000980.
  16. Singh M, Das RR. Zinc for the common cold. Cochrane Database of Systematic Reviews. 2011;2:article no CD001364.
  17. OTC Guide 2011. www.pharmacytimes.com/publications/otc/2011/OTCGuide. Accessed August 17, 2011.
  18. Gallagher IHC, Cutress TW. The effect of trace elements on the growth and fermentation by oral streptococci and ActinomycesArchives of Oral Biology. 1977;22:555-562.
  19. Korant BD, Kaurer JC, Butterworth BE. Zinc ions inhibit replication of rhinoviruses. Nature. 1974;248:588-590.
  20. Eby GA, Davis DR, Halcomb WW. Reduction in duration of common colds by zinc gluconate lozenges in a double-blind study. Antimicrob Agents Chemother. 1984;25:20-24.
  21. Douglas RM, Miles HB, Moore BW, et al. Failure of effervescent zinc acetate lozenges to alter the course of upper respiratory tract infections in Australian adults. Antimicrob Agents Chemother. 1987;31:1263-1265.
  22. Smith DS, Helzner EC, Nuttall CE Jr, et al. Failure of zinc gluconate in treatment of acute upper respiratory tract infections. Antimicrob Agents Chemother. 1989;33:646-648.
  23. Godfrey JC, Sloane BC, Smith DS, et al. Zinc gluconate and the common cold: a controlled clinical study. J Intern Med Res. 1992;20:234-246.
  24. Mossad SB, Macknin ML, Medendorp SV, et al. Zinc gluconate lozenges for treating the common cold. A randomized, double-blind, placebocontrolled study. Ann Intern Med. 1996;125:81-88.
  25. Petrus EJ, Lawson KA, Bucci LR, et al. Randomized, double-masked, placebo-controlled clinical study of the effectiveness of zinc acetate lozenges on common cold symptoms in allergy-tested subjects. Curr Ther Res. 1998;59:595-607.
  26. Prasad AS, Fitzgerald JT, Bao B, et al. Duration of symptoms and plasma cytokine levels in patients with the common cold treated with zinc acetate. Ann Intern Med. 2000;133:245-252.
  27. Eby GA, Halcomb WW. Ineffectiveness of zinc gluconate nasal spray and zinc orotate lozenges in common-cold treatment: a double-blind, placebo-controlled clinical trial. Altern Ther Health Med. 2006;12(1):34-38.
  28. Eby GA. Zinc lozenges as cure for the common cold: a review and hypothesis. Med Hypotheses. 2010;74:482-492.
  29. Silk R, LeFante C. Safety of zinc gluconate glycine (Cold-EEZE) in a geriatric population: a randomized placebo-controlled, double-blind trial. Am J Ther. 2005;12:612-617.
  30. The US Navy Seal Guide to Fitness and Nutrition. . In: Deuster PA, Singh A, Pelletier PA, eds. New York, NY: Skyhorse Publishing, Inc; 2007:496.
  31. McElroy BH, Miller SP. An open-label, single-center, phase IV clinical study of the effectiveness of zinc gluconate glycine lozenges in reducing the duration and symptoms of the common cold in school-aged subjects. Am J Ther. 2003;10(5):324-329.
  32. McElroy BH, Miller SP. Effectiveness of zinc gluconate glycine lozenges against the common cold in school-aged subjects: a retrospective chart review. Am J Ther. 2002;9(6):472-475.
  33. Belongia EA, Berg R, Liu K. A randomized trial of zinc nasal spray for the treatment of upper respiratory illness in adults. Am J Med. 2001;111:103-108.
  34. Turner RB. Ineffectiveness of intranasal zinc gluconate for prevention of experimental rhinovirus colds. Clin Infect Dis. 2001;33:1865-1870.
  35. Mossad SB. Effect of zincum gluconicum nasal gel on the duration and symptom severity of the common cold in otherwise healthy adults. QJM. 2003;96:35-43.
  36. Hirt M, Nobel S, Barron E. Zinc nasal gel for the treatment of common cold symptoms: a double-blind, placebo-controlled trial. Ear Nose Throat J. 2000;79:778-780,782.
  37. D’Cruze H, Arroll B, Kenealy T. Is intranasal zinc effective and safe for the common cold? A systematic review and metanalysis. J Prim Health Care. 2009;1(2):134-139.
  38. Mathes A, Bellanger R. Herbs and other dietary supplements: current regulations and recommendations for use to maintain health in the management of the common cold or other related infectious respiratory illnesses. J Pharm Pract. 2010;23(2):117-127.
  39. Jawad M, Schoop R, Suter A, Klein P, Eccles R. Safety and efficacy profile of Echinacea purpurea to prevent common cold episodes: a randomized, double-blind, placebo-controlled trial. Evid Based Complement Alternat Med. [Provide ] 2012:841315.
  40. Arroll B. Common cold. Clin Evid. 2011;03:1510.
  41. Daels-Rakotoarison DA, Gressier B, Trotin F, et al. Effects of Rosa canina fruit extract on neutrophil respiratory burst. Laboratoire de Pharmacologie et Pharmacie Clinique, Faculté des Sciences Pharmaceutiques et Biologiques. Philadelphia: John Wiley & Sons, Ltd; 2002.
  42. Lattanzio F, Greco E, Carretta D, Cervellati  CR, Speroni E. In vivo anti-inflammtory effect of Rosa canina L. extract. J Ethnopharmacol. 2011;137:880-885.
 

Zinc and Zinc Preparations for Colds: An Update for Pharmacists
Expires
11-12-2015
Credits
1.00
UAN
0290-0000-13-160-H01-P
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