Anosmia after Intranasal Zinc Gluconate Use Bruce W. Jafek, M.D., Miriam R. Linschoten, Ph.D., and Bruce W. Murrow, M.D., Ph.D. ABSTRACT Background: Zinc is an essential mineral. Beneficial zinc absorption takes place via enteral, parenteral, or cutaneous routes. However, direct application to the olfactory epithelium has been reported to cause loss of smell. Recently, intranasal zinc gluconate has been recommended as a treatment for the common cold. Severe posttreatment hyposmia and anosmia have been observed. Methods: The case report of a typical patient is presented and analyzed in detail, followed by a series of patients with severe hyposmia or anosmia after the use of intranasal zinc gluconate. Results: Although interindividual variation in drug response and drug effect is apparent, the severe hyposmia or anosmia appears to be long lasting or permanent in some cases. The mechanism of olfactory loss is thought to be the direct action of the divalent zinc ion on the olfactory receptor cell. Conclusions: Zinc ions are toxic to olfactory epithelium. Re- ports of severe hyposmia with parosmia or anosmia have occurred after intranasal use of zinc gluconate. (American Journal of Rhinology 18, 137–141, 2004) Z inc is an essential element found in almost every cell. It is involved in a number of areas of human physiol- ogy, including the activity of 100 enzymes, 1 the immune system, 2,3 wound healing, 4,5 the senses of taste and smell, 4,5 and DNA synthesis. 6 Zinc also supports normal growth and development during pregnancy, childhood, and adoles- cence. 7,8 The deleterious effects of both deficiency 2,5,6,9–11 and toxicity (acute and chronic) 2,12,13 are described. Beneficial zinc absorption takes place via enteral, paren- teral, or cutaneous routes. 5,13 However, direct application to the olfactory epithelium was known to be toxic over 60 years ago. 14–16 This toxicity is thought to be caused by the direct effects of the divalent zinc ion on the olfactory receptor cell. 17–19 Otherwise beneficial divalent ions (e.g., copper, cadmium, and barium) also have been shown to be toxic when applied directly to the olfactory epithelium. 17–19 Recently, intranasal zinc gluconate has been recommended as a treatment for the common cold. 20 We present a series of patients with severe hyposmia or anosmia after the use of intranasal zinc gluconate. METHODS/OBSERVATIONS Case Reports A 55-year-old man with previously normal taste and smell developed clear rhinorrhea and congestion and treated himself with over-the-counter (OTC) zinc glu- conate* for a self-diagnosed cold. He noted immediate burning in his nose and did not use the spray again. He noted immediate anosmia, which was persistent. He also noted a “slightly salty” taste, which was intermittent. He did not smoke. He had rheumatoid arthritis, for which he took Remicade (Imfliximab, CENTOCOR, Inc., Malvern, PA) and regular bursts of prednisone (which did not subse- quently improve his anosmia). He also took Arava (Lefluno- mide, Aventis Pharmaceuticals, Inc., Kansas City, MO) until 8 weeks before the incident and methotrexate (for the arthritis) until 10 weeks before the incident. His other med- ications included Prilosec (Omeprazole, AstraZeneca PLC, London, U.K.), Allegra, (Fexofenadine HCl, AstraZeneca PLC), and Flonase (Fluticasone Propionate, Glaxo Wel- come, Inc., Research Triangle Park, NC). He had some indications of lupus and his liver function tests were “bor- derline normal.” He was otherwise in excellent health. He was seen by an otolaryngologist, and the otolaryngo- From the Department of Otolaryngology—Head and Neck Surgery, University of Colorado School of Medicine, Denver, Colorado Address correspondence and reprint requests to Bruce W. Jafek, M.D., F.A.C.S., UCHSC (B-205) Otolaryngology, 4200 E. Ninth Ave., Denver, CO 80262 Copyright © 2004, OceanSide Publications, Inc., U.S.A. *Zicam, Mattrixx Initiatives, Phoenix, AZ American Journal of Rhinology 137
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Anosmia after Intranasal ZincGluconate Use
Bruce W Jafek MD Miriam R Linschoten PhD and Bruce W Murrow MD PhD
ABSTRACTBackground Zinc is an essential mineral Beneficial zincabsorption takes place via enteral parenteral or cutaneousroutes However direct application to the olfactory epitheliumhas been reported to cause loss of smell Recently intranasalzinc gluconate has been recommended as a treatment for thecommon cold Severe posttreatment hyposmia and anosmiahave been observed
Methods The case report of a typical patient is presented andanalyzed in detail followed by a series of patients with severehyposmia or anosmia after the use of intranasal zinc gluconate
Results Although interindividual variation in drug responseand drug effect is apparent the severe hyposmia or anosmiaappears to be long lasting or permanent in some cases Themechanism of olfactory loss is thought to be the direct actionof the divalent zinc ion on the olfactory receptor cell
Conclusions Zinc ions are toxic to olfactory epithelium Re-ports of severe hyposmia with parosmia or anosmia haveoccurred after intranasal use of zinc gluconate (AmericanJournal of Rhinology 18 137ndash141 2004)
Zinc is an essential element found in almost every cell Itis involved in a number of areas of human physiol-
ogy including the activity of 100 enzymes1 the immunesystem23 wound healing45 the senses of taste and smell45
and DNA synthesis6 Zinc also supports normal growth anddevelopment during pregnancy childhood and adoles-cence78 The deleterious effects of both deficiency2569ndash11
and toxicity (acute and chronic)21213 are described
Beneficial zinc absorption takes place via enteral paren-teral or cutaneous routes513 However direct application tothe olfactory epithelium was known to be toxic over 60years ago14ndash16 This toxicity is thought to be caused by thedirect effects of the divalent zinc ion on the olfactoryreceptor cell17ndash19 Otherwise beneficial divalent ions (egcopper cadmium and barium) also have been shown to betoxic when applied directly to the olfactory epithelium17ndash19
Recently intranasal zinc gluconate has been recommendedas a treatment for the common cold20 We present a series ofpatients with severe hyposmia or anosmia after the use ofintranasal zinc gluconate
METHODSOBSERVATIONS
Case Reports
A 55-year-old man with previously normal taste andsmell developed clear rhinorrhea and congestion and
treated himself with over-the-counter (OTC) zinc glu-conate for a self-diagnosed cold He noted immediateburning in his nose and did not use the spray again Henoted immediate anosmia which was persistent He alsonoted a ldquoslightly saltyrdquo taste which was intermittent He didnot smoke He had rheumatoid arthritis for which he tookRemicade (Imfliximab CENTOCOR Inc Malvern PA)and regular bursts of prednisone (which did not subse-quently improve his anosmia) He also took Arava (Lefluno-mide Aventis Pharmaceuticals Inc Kansas City MO)until 8 weeks before the incident and methotrexate (for thearthritis) until 10 weeks before the incident His other med-ications included Prilosec (Omeprazole AstraZeneca PLCLondon UK) Allegra (Fexofenadine HCl AstraZenecaPLC) and Flonase (Fluticasone Propionate Glaxo Wel-come Inc Research Triangle Park NC) He had someindications of lupus and his liver function tests were ldquobor-derline normalrdquo He was otherwise in excellent health
He was seen by an otolaryngologist and the otolaryngo-
From the Department of OtolaryngologymdashHead and NeckSurgery University of Colorado School of Medicine DenverColoradoAddress correspondence and reprint requests to Bruce WJafek MD FACS UCHSC (B-205) Otolaryngology 4200E Ninth Ave Denver CO 80262Copyright copy 2004 OceanSide Publications Inc USA
Zicam Mattrixx Initiatives Phoenix AZ
American Journal of Rhinology 137
logical examination was normal A magnetic resonanceimage with and without contrast was normal No evidenceof sinus disease was seen
Detailed chemosensory evaluation was done Absolutemonorhinal butanol sensitivity was determined with a two-alternative forced-choice method using a maximum-likeli-hood adaptive staircase procedure21 This procedure contin-uously estimates the sensory threshold while keeping trackof the pattern of responses as well as response bias Thethreshold results indicated severely limited detection abilitybilaterally Odor identification was absent on the right sideand severely limited on the left The composite score indi-cated severe hyposmia Using Vicks VapoRub (Proctor ampGamble Cincinnati OH) as a trigeminal stimulant bilateralnormal trigeminal activity was determined Taste testingwas normal except for the salty taste which was partiallyextinguished by 05 Diclone (Antra Astra PharmaceuticalProducts Inc Westborough MA) application The severehyposmia has persisted unchanged 10 months posttestingand 23 months postincident
Patient Series Data
Our taste and smell center (Department of Otolaryngol-ogy University of Colorado School of Medicine
Denver CO) receives numerous inquiries from patientswith chemosensory dysfunction By reviewing these anumber of patients with loss of smell after the use ofintranasal zinc gluconate have been identified
Seven men and three women aged 31ndash55 years com-prised the study series The distinguishing characteristicswere immediate severe burning of the nose (similar to thatreported previously in the zinc literature16) after the use ofintranasal zinc gluconate followed by severe hyposmiawith parosmia or anosmia in patients who reported previ-ously normal taste and smell and no other causative historyto account for the loss Through the use of the ColoradoChemosensory Questionnaire the possibility of othercauses of chemosensory loss (eg previous sinus surgery orchronic sinusitis nasal polyposis or other pathology or useof potentially toxic medications) was ruled out We assumethat additional patients did not contact us and that additionalcases still have not been diagnosed raising the apparentincidence of the smell loss
DISCUSSION
In 1934 investigations of the local effect of chemicals incontrolling viral disease (polio) in experimental animals
had shown the apparent beneficial effects of intranasal alumin preventing polio in exposed monkeys14 Intranasal picricacid then was tried with apparent greater success Schultzmethodically began testing a long list of chemicals in thehope of finding the ideal one that offered the most protec-tion and could be used safely on humans22 He found whathe thought was the ldquogolden chemicalrdquo zinc sulfate2223 Thetheory was that zinc ions ldquocoagulated natural proteins in theolfactory epithelium forming a protective coating around
the nerves which prevented them from absorbing the poliovirusrdquo14 At that time the hypothesis of the pathogenesis ofpolio was that the virus was inhaled into the olfactory cleftand then attacked the olfactory nerves to travel ldquoalong thesetiny nerves to the spinal cord where large motor bodies arelocatedrdquo14 Supporting this theory the virus had been re-covered from the nasal discharge of polio patients as well asfrom monkeys artificially infected with the disease Invari-ably the olfactory mucosa showed the marks of the virusand microscopic pathological changes were found along theolfactory nerves extending to the motor nerve cells of thespinal cord14 When the olfactory nerves were cut uptake ofthe virus in exposed monkeys appeared to be blocked whilethe disease occurred in control animals (monkeys withintact olfactory nerves) The watchword became ldquoprotectthe nose and prevent poliordquo24
Schultz initially tried the alum-picric acid on humans asan intranasal spray during the summer of 1936 when anepidemic of polio struck the southern states14 The results ofthe experiment in 4600 children and adults treated wereldquomost discouragingrdquo but the failure was attributed to thehaphazard manner in which the solution was administeredand the study was termed ldquounscientificrdquo and ldquoconfidence inchemically induced prevention of the dread disease wasunabatedrdquo14 Schultz argued that the Alabama experimenthad failed for two reasons the alum-picric acid solution wasintrinsically inferior to his own zinc sulfate compound andprotection could only be gained by erecting an impenetrablebarrier around the olfactory nerves The success of thetreatment would be judged by making the nerves ldquoinactivefor a period of timerdquo the criterion for success being ldquoloss ofthe sense of smellrdquo14 ldquoProtection against the virusrdquo couldnot be gained ldquounless the protective spray had temporarily(authorsrsquo emphasis) destroyed the sense of smellrdquo14 Severalauthors debated the proper technique and cautioned thatonly ldquotrained expertsrdquo could properly administer thezinc24ndash26 To accomplish proper application the zinc had tobe administered by experts in nose anatomy to reach thecritical area and had to be used often enough to produce thedesired anosmia which Schultz reiterated was only a tem-porary condition14
In 1937 therefore during an epidemic in Toronto Can-ada special clinics manned by ldquonose and throat specialistsrdquosprayed a population of 5000 children twice at intervals of10ndash12 days with a solution of 1 zinc sulfate and 05Pontocaine15 There were additional ldquooff protocolrdquo admin-istrations of the treatment as well estimated as over ldquoathousand more childrenrdquo as the public sought relief fromthe dreaded disease Most of the children suffered ldquosomediscomfortrdquo from the nasal spray However there were afew cases of severe nasal pain that ldquocontinued for manyhoursrdquo15 The most frequent complaints were headachesnausea or vomiting and some stiffness of the neck Some-times the child developed transient fever but overall ldquore-actions were singularly fewrdquo1415 ldquoIt was many months laterthat Schultz began receiving complaints from physicians
138 May-June 2004 Vol 18 No 3
that many of their patients had suffered a complete andpermanent loss of the sense of smellrdquo14 Using relativelyprimitive psychophysical testing employing oil of clovesand oil of spearmint 10ndash13 of children were thought to beanosmic apparently permanently14 Note that because oil ofcloves and oil of spearmint stimulate the trigeminal nerve apercentage of 10ndash13 is most likely a gross underestima-tion of the actual percentage of anosmics Unfortunately theprotective spraying with zinc sulfate did not alter the attackrate of the disease and a more critical examination of theolfactory tissues previously thought to be involved alongwith additional experimentation ruled out the olfactoryepithelium as the sole portal of entry of the polio virus intohumans15 But the toxic effect of zinc on human olfactoryepithelium was clearly shown Although interindividualvariation in drug response and drug toxicity is apparent theeffects appear to be dose related and long lasting or perma-nent in some cases Subsequently transient olfactory losshas been reported in some of the studies of experimentalanimals such as that of McBride27 The use of intranasalzinc was abandoned
In 1976 Matulionis observed distinct patterns of degen-eration and regeneration of the olfactory epithelium in micereceiving intranasal irrigation with 1 aqueous zinc sul-fate28 During the first 24 hours after treatment three pro-gressive manifestations of the degenerative process wereseen (1) a relatively mild condition which was character-ized by surface irregularities produced by cell protrusionshighly vacuolated cytoplasm presence of large lysosome-like bodies and prominent intercellular spaces (2) a moresevere condition in which large areas of the epithelium weredetached from the basement membrane and cellular debriswas present in the nasal chamber and (3) a condition oftotal or near-total denudation of the epithelium of olfactorymucosa The basal lamina was continuous and intact in mostregions and the integrity of the subadjacent connectivetissue mostly was well preserved The nerve bundles of thefila olfactoria were noted to be in varying degrees of de-generation during the course of the experiment with themost advanced neural degeneration from 24ndash72 hours aftertreatment
In 1978 Harding described immediate and total anosmiain mice irrigated with intranasal 017 M ZnSO417 Thisanosmia persisted for 6 weeks in at least 80 of the treatedanimals and 4 months in one-half of the treated animalsChanges were still apparent at 1 year the limit of theexperimental observation
By 1982 Cancalon attributed the ldquonecrotic effectrdquo ofvarious salt solutions to the divalent ldquozinc cationrdquo in irriga-tion experiments on the catfish olfactory mucosa usingconcentrations of 6ndash960 mM of zinc sulfate18 He noted thatZnSO4 and ZnCl were ldquoequally effective in destroying theolfactory epithelium offering proof that it was the zinccation that produces the toxic effects He reported that thedamage was very reproducible largely concentration inde-pendent and almost completely specific for the olfactory
receptor cells The nonsensory respiratory cells were unaf-fected The sustentacular cells surrounding the receptor cellswere affected mainly by a loss of microvilli The olfactorycells started to degenerate within a few hours and by day 4only 20 of the original receptor population remainedMucosal basal cell mitosis increased during days 3 and 4and by day 7 the receptor population had reached 80 of itsoriginal value On the other hand when the salt solution wasmaintained in contact with the olfactory epithelium forseveral days only very limited regeneration occurred asmost of the lamellae were irreversibly destroyed
In 1997 Mayer and Rosenblatt reported that the sprayapplication of ZnSO4 (174 in 09 saline) to the olfac-tory mucosa in rats produced severe nasal congestion thatcleared within 24 hours followed by in 48 hours anosmiain 80 of the treated animals29
From a more basic standpoint the transduction of odorsinto electrical signals takes place on the surface of theolfactory receptor cells and is necessary for olfactory func-tion In particular an odorant binds to a cyclic nucleotide-gated receptor that generates cyclic adenosine monophos-phate which in turn activates a nonspecific cation channelallowing Ca2 entry into the cell This Ca2 then activatesa calcium-activated chloride channel that results in depolar-ization of the cell The divalent cation Ba2 is suggested toblock the nonspecific cyclic nucleotide-gated channel inanimals30 This also appears to be the case in human olfac-tory receptor cells (Fig 1) Zinc a divalent cation also mayblock this channel and interfere with olfactory functionOngoing studies are evaluating both the short-term andlong-term effects of zinc on olfactory cell function
In 2000 Hirt et al recommended the intranasal use of anOTC zinc gluconate nasal gel formulation to bring themedication closer to the causative organism rhinovirus inalleviating the symptoms of the common cold decreasingthe duration of symptoms by 7520 Citing the antirhino-viral activity of ionized zinc31ndash33 they recommended thatthe ldquomixed benefitsrdquo of zinc gluconate lozenges dissolved inthe mouth affecting rhinovirus in the nose to prevent oralleviate the symptoms of the common cold could be im-proved by ldquodelivery of ionic zinc directly to the site ofinfectionrdquo203435 They noted that although 42 of ldquozinc-treated patientsrdquo and 37 of controls described a ldquoslighttingling or burning sensation on intranasal zinc applica-tionrdquo five other potential side effects (nausea bad tastereactions odor dizziness and drowsiness) were not foundIt is not apparent from their publication that they tested foror considered olfactory deficits in their study group
Other studies concluded that intranasal zinc was notnearly as helpful in the treatment of the common coldBelongia found ldquono effect on the duration of the commoncold but possibly mild and transient reduction in the sever-ity of nasal symptoms using 012 zinc sulfate nasal
Zicam Mattrixx Initiatives Phoenix AZ
American Journal of Rhinology 139
sprayrdquo36 Turner concluded that the commercially availablezinc gluconate gel was ldquolsquoineffectiversquo in preventing pro-gression of an experimentally induced rhinovirus infection33 mM of zinc gluconate in an emulsification of benzalko-nium chloride glycerine hydroxymethylcellulose sodiumchloride and sodium peroxide buffered to pH 72rdquo37
A single case report of anosmia due to inhalational zincsoon followed38
In 2003 Mossad concluded that ionic zinc (33 mmolL ofzincum gluconium) ldquoshortens the duration and reducessymptom severity of the common cold in healthy adultsrdquo39
Adverse effects were solicited by an open-ended telephonequestion the most commonly identified being ldquonasal sting-ing or burningrdquo Neither olfactory complaints nor evaluationwere mentioned
Because patients use the intranasal zinc when they ldquofeela cold coming onrdquo postviral anosmia should be considereda cause for the chemosensory loss Three factors argueagainst this conclusion First the admittedly modest studypopulation had a male preponderance of more than 21 asopposed to the 21 female ratio seen in postviral anosmiathe patients in the intranasal zinc group also were youngeron average than reported postviral patients40 Second post-viral anosmia typically occurs with ldquothe worst upper-respi-ratory infection (URI) Irsquove ever hadrdquo Our study populationtypically used the intranasal zinc early in the course of amild URI and most convincing was the immediate acuteldquoburningrdquo pain with the use of the zinc gluconate followedimmediately by persistent severe hyposmia or anosmiaOther explanations for the smell loss (eg post-traumaticetc) were ruled out by a negative history in each case AWeb site maintained by Dr Karl L Wuensch offers addi-tional discussion of the issue of loss of smell after the use ofintranasal zinc41
Recent advertisements have added a pediatric applicatorfor intranasal zinc This extension of the use of intranasalzinc gluconate to the pediatric age group is of concernbecause the use of intranasal zinc in this age group could beexpected to generate anosmia although this age group is lesslikely to describe the symptom resulting in repeated treat-ments rather than immediate discontinuation of the drug
It should be noted that only a single trademarked prepa-ration of zinc gluconate was available at the time of thisreport and was used by each of the patients cited immedi-ately before their loss of smell Subsequently this brandhas been extended by the manufacturer to several productsThis communication only concerns the product containingzinc gluconate
CONCLUSION
In conclusion the divalent zinc ion is reported to be toxicto olfactory epithelium the toxicity apparently being
related to both concentration and interindividual sensitivitybut not the source of the ion (eg salt source as shown byCancalon18 and others) The temporal association of the useof intranasal zinc gluconate with the development of severepartial or total loss of the sense of smell raises significantconcern regarding its safety for intranasal application inhumans Given the prevalence of viral URIs the strongdesire of patients for symptomatic relief and the widespreadavailability and marketing of OTC products for this pur-pose there is the potential for a very large number of peopleto be exposed to intranasal zinc gluconate Therefore evenif the frequency of loss of smell is low the number of
Zicam Mattrixx Initiatives Phoenix AZ
Figure 1 Human olfactory epithelium was isolated from freshcadavers and EOG recording techniques used to study olfactorytransduction40 (A) Cineole (100 M) applied to the olfactoryepithelium produced a response (B) that in the presence of 5 mMof Ba2 was blocked This effect was fully reversible after severalminutes of exposure to Ba2 The bars below each trace indicatethe application time of cineole and note that there was a delaybefore the start of the upward-going odorant response in panel ASaline control traces were subtracted from each trace and lowpass filtering was used
140 May-June 2004 Vol 18 No 3
people affected by this treatment could be alarmingly highThe public may assume that because intranasal zinc glu-conate is sold as an OTC ldquopatented homeopathicrdquo prepa-ration containing a ldquonaturalrdquo or even ldquoessentialrdquo elementthat it is safe This report raises important questions aboutthat generalization Because the effects appear to be some-what dose-related use of this drug in the pediatric age groupwould be expected to generate an even larger incidence ofanosmia in this population and is especially concerning
If history repeats itself and the unexpected always hap-pens how incapable must man be of learning from expe-rience
mdashGeorge Bernard Shaw (1856ndash1950)Irish dramatist
REFERENCES1 Sandstead HH and Alcock NW Zinc An essential and unher-
alded nutrient J Lab Clin Med 130116ndash118 19972 Solomons NW Mild human zinc deficiency produces an imbal-
ance between cell-mediated and humoral immunity Nutr Rev5627ndash28 1998
3 Prasad AS Zinc An overview Nutrition 1193ndash99 19954 Heyneman CA Zinc deficiency and taste disorders Ann Phar-
macother 30186ndash187 19965 Lansdown AB Metallothioneins Potential therapeutic aids for
wound healing in the skin Wound Repair Regen 10130ndash132 20026 Prasad AS Beck FW Grabowski SM et al Zinc deficiency
Changes in cytokine production and T-cell subpopulations inpatients with head and neck cancer and in noncancer subjectsProc Assoc Am Physicians 10968ndash77 1997
7 Simmer K and Thompson RP Zinc in the fetus and newbornActa Paediatr Scand Suppl 319158ndash163 1985
8 Fabris N and Mocchegiani E Zinc human diseases and agingAging (Milano) 777ndash93 1995
9 Prasad AS Zinc deficiency in women infants and childrenJ Am Coll Nutr 15113ndash120 1996
10 Hambidge KM Mild zinc deficiency in human subjects In Zincin Human Biology Mills CF (Ed) New York Springer-Verlag281ndash296 1989
11 King JC and Keen CL Zinc In Modern Nutrition in Health andDisease 9th ed Shils ME Olson JA Shike M et al (Eds) Chap11 Baltimore Williams amp Wilkins 223ndash239 1999
12 Hooper PL Visconti L Garry PJ et al Zinc lowers high-densitylipoprotein-cholesterol levels J Am Med Assoc 2441960ndash1961 1980
13 Shenkin A Trace elements and inflammatory response Implica-tions for nutritional support Nutrition 11(1 suppl)100ndash105 1995
14 Berg RH I can stop the virus In Polio and Its Problems Ch 5Berg RH (Ed) Philadelphia Lippincott 34ndash47 1948
15 Rutty CJ The middle-class plague Epidemic polio and the Cana-dian state 1ndash36-1937 Can Bull Med Hist 13277ndash314 1996
16 Tisdall FF Brown A and Defries RD Persistent anosmia fol-lowing zinc sulphate nasal spraying J Pediatr 1360ndash62 1938
17 Harding JW Getchell TV and Margolis FL Denervation of theprimary olfactory pathway in mice V Long-term effects ofintranasal ZnSO4 irrigation on behavior biochemistry and mor-phology Brain Res 140271ndash285 1978
18 Cancalon P Degeneration and regeneration of olfactory cellsinduced by ZnSO4 and other chemicals Tissue Cell 14717ndash7331982
19 Moran DT Rowley JC III Aiken GR and Jafek BW Ultrastruc-tural neurobiology of the olfactory mucosa of the brown troutSalmo trutta Microsc Res Tech 2328ndash48 1992
20 Hirt M Nobel S and Barron E Zinc nasal gel for the treatmentof common cold symptoms A double-blind placebo-controlledtrial Ear Nose Throat J 79778ndash780 782 2000
21 Linschoten M Harvey LO Jr Eller PM and Jafek B Fast andaccurate measurement of taste and smell thresholds using amaximum-likelihood adaptive staircase procedure Percept Psy-chophys 631330ndash1347 2001
22 Schultz EW Immunity and prophylaxis in poliomyelitis JAMA1072102ndash2104 1936
23 Schultz EW and Gebhardt LP Zinc sulfate prophylaxis in po-liomyelitis JAMA 1082182ndash2184 1937
24 Peet MM Echols DH and Richter HJ The chemical prophylaxisfor poliomyelitis The technique of applying zinc sulfate intra-nasally JAMA 1082184ndash2187 1937
25 Shahinian L Bacher JA McNaught RC and Newell RR Che-moprophylaxis in poliomyelitis JAMA 1101254ndash1257 1938
26 Ashley RE Chemoprophylaxis against impending poliomyelitisArch Otol 29104ndash114 1939
27 McBride K Slotnick B and Margolis FL Does intranasal applica-tion of zinc sulfate produce anosmia in the mouse An olfactometricand anatomical study Chem Senses 28659ndash670 2003
28 Matulionis DH Light and microscopic study of the degenerationand early regeneration of olfactory epithelium in the mouseAm J Anat 14579ndash99 1976
29 Mayer AD and Rosenblatt JS Peripheral olfactory deafferenta-tion of the primary olfactory system in rats using ZnSO4 nasalspray with special reference to maternal behavior Physiol Behav53587ndash592 1997
30 Miyamoto T Restrepo D and Teeter J Voltage-dependent andodorant-regulated currents in isolated oflactory receptor neuronsof the channel catfish J Gen Physiol 99505ndash529 1992
31 Korant BD Kauer JC and Butterworth BE Zinc ions inhibitreplication of rhinoviruses Nature 248588ndash590 1874
32 Korant BD and Butterworth BE Inhibition by zinc of rhinovirusprotein cleavage Interaction of zinc with capsid polypeptidesJ Virol 18298ndash306 1976
33 Kelly RW and Abel MH Copper and zinc inhibit the metabolism ofprostaglandin by the human uterus Biol Reprod 28883ndash889 1983
34 Novick SG Godfrey JC Godfrey NJ and Wilder HR How does zincmodify the common cold Clinical observation and implications re-garding mechanisms of action Med Hypotheses 46295ndash302 1996
35 Godfrey JC Godfrey NJ and Novick SG Zinc for treating thecommon cold Review of all clinical trials since 1984 AlternTher Health Med 263ndash72 1996
36 Belongia EA Berg R and Liu K A randomized trial of zincnasal spray for the treatment of upper respiratory illness inadults Am J Med 111103ndash108 2001
37 Turner RB Ineffectiveness of intranasal zinc gluconate for theprevention of experimental rhinovirus colds Clin Inf Dis 331865ndash1870 2001
38 DeCook CA and Hirsch AR Anosmia due to inhalational zincA case report Chem Senses 25659 2000 (Abs)
39 Mossad SB Effects of zincum gluconium nasal gel on theduration and symptom severity of the common cold in otherwisehealthy adults QJM 9635ndash43 2003
40 Duncan HJ Postviral olfactory loss In Taste and Smell Disor-ders Ch 6 Seiden AM (Ed) New York Thieme 72ndash78 1997
41 Murrow BW Jafek BW and Restrepo D The use of freshcadaveric human olfactory epithelium for physiologic studyAChemS Sarasota FL April 2001 e
American Journal of Rhinology 141
logical examination was normal A magnetic resonanceimage with and without contrast was normal No evidenceof sinus disease was seen
Detailed chemosensory evaluation was done Absolutemonorhinal butanol sensitivity was determined with a two-alternative forced-choice method using a maximum-likeli-hood adaptive staircase procedure21 This procedure contin-uously estimates the sensory threshold while keeping trackof the pattern of responses as well as response bias Thethreshold results indicated severely limited detection abilitybilaterally Odor identification was absent on the right sideand severely limited on the left The composite score indi-cated severe hyposmia Using Vicks VapoRub (Proctor ampGamble Cincinnati OH) as a trigeminal stimulant bilateralnormal trigeminal activity was determined Taste testingwas normal except for the salty taste which was partiallyextinguished by 05 Diclone (Antra Astra PharmaceuticalProducts Inc Westborough MA) application The severehyposmia has persisted unchanged 10 months posttestingand 23 months postincident
Patient Series Data
Our taste and smell center (Department of Otolaryngol-ogy University of Colorado School of Medicine
Denver CO) receives numerous inquiries from patientswith chemosensory dysfunction By reviewing these anumber of patients with loss of smell after the use ofintranasal zinc gluconate have been identified
Seven men and three women aged 31ndash55 years com-prised the study series The distinguishing characteristicswere immediate severe burning of the nose (similar to thatreported previously in the zinc literature16) after the use ofintranasal zinc gluconate followed by severe hyposmiawith parosmia or anosmia in patients who reported previ-ously normal taste and smell and no other causative historyto account for the loss Through the use of the ColoradoChemosensory Questionnaire the possibility of othercauses of chemosensory loss (eg previous sinus surgery orchronic sinusitis nasal polyposis or other pathology or useof potentially toxic medications) was ruled out We assumethat additional patients did not contact us and that additionalcases still have not been diagnosed raising the apparentincidence of the smell loss
DISCUSSION
In 1934 investigations of the local effect of chemicals incontrolling viral disease (polio) in experimental animals
had shown the apparent beneficial effects of intranasal alumin preventing polio in exposed monkeys14 Intranasal picricacid then was tried with apparent greater success Schultzmethodically began testing a long list of chemicals in thehope of finding the ideal one that offered the most protec-tion and could be used safely on humans22 He found whathe thought was the ldquogolden chemicalrdquo zinc sulfate2223 Thetheory was that zinc ions ldquocoagulated natural proteins in theolfactory epithelium forming a protective coating around
the nerves which prevented them from absorbing the poliovirusrdquo14 At that time the hypothesis of the pathogenesis ofpolio was that the virus was inhaled into the olfactory cleftand then attacked the olfactory nerves to travel ldquoalong thesetiny nerves to the spinal cord where large motor bodies arelocatedrdquo14 Supporting this theory the virus had been re-covered from the nasal discharge of polio patients as well asfrom monkeys artificially infected with the disease Invari-ably the olfactory mucosa showed the marks of the virusand microscopic pathological changes were found along theolfactory nerves extending to the motor nerve cells of thespinal cord14 When the olfactory nerves were cut uptake ofthe virus in exposed monkeys appeared to be blocked whilethe disease occurred in control animals (monkeys withintact olfactory nerves) The watchword became ldquoprotectthe nose and prevent poliordquo24
Schultz initially tried the alum-picric acid on humans asan intranasal spray during the summer of 1936 when anepidemic of polio struck the southern states14 The results ofthe experiment in 4600 children and adults treated wereldquomost discouragingrdquo but the failure was attributed to thehaphazard manner in which the solution was administeredand the study was termed ldquounscientificrdquo and ldquoconfidence inchemically induced prevention of the dread disease wasunabatedrdquo14 Schultz argued that the Alabama experimenthad failed for two reasons the alum-picric acid solution wasintrinsically inferior to his own zinc sulfate compound andprotection could only be gained by erecting an impenetrablebarrier around the olfactory nerves The success of thetreatment would be judged by making the nerves ldquoinactivefor a period of timerdquo the criterion for success being ldquoloss ofthe sense of smellrdquo14 ldquoProtection against the virusrdquo couldnot be gained ldquounless the protective spray had temporarily(authorsrsquo emphasis) destroyed the sense of smellrdquo14 Severalauthors debated the proper technique and cautioned thatonly ldquotrained expertsrdquo could properly administer thezinc24ndash26 To accomplish proper application the zinc had tobe administered by experts in nose anatomy to reach thecritical area and had to be used often enough to produce thedesired anosmia which Schultz reiterated was only a tem-porary condition14
In 1937 therefore during an epidemic in Toronto Can-ada special clinics manned by ldquonose and throat specialistsrdquosprayed a population of 5000 children twice at intervals of10ndash12 days with a solution of 1 zinc sulfate and 05Pontocaine15 There were additional ldquooff protocolrdquo admin-istrations of the treatment as well estimated as over ldquoathousand more childrenrdquo as the public sought relief fromthe dreaded disease Most of the children suffered ldquosomediscomfortrdquo from the nasal spray However there were afew cases of severe nasal pain that ldquocontinued for manyhoursrdquo15 The most frequent complaints were headachesnausea or vomiting and some stiffness of the neck Some-times the child developed transient fever but overall ldquore-actions were singularly fewrdquo1415 ldquoIt was many months laterthat Schultz began receiving complaints from physicians
138 May-June 2004 Vol 18 No 3
that many of their patients had suffered a complete andpermanent loss of the sense of smellrdquo14 Using relativelyprimitive psychophysical testing employing oil of clovesand oil of spearmint 10ndash13 of children were thought to beanosmic apparently permanently14 Note that because oil ofcloves and oil of spearmint stimulate the trigeminal nerve apercentage of 10ndash13 is most likely a gross underestima-tion of the actual percentage of anosmics Unfortunately theprotective spraying with zinc sulfate did not alter the attackrate of the disease and a more critical examination of theolfactory tissues previously thought to be involved alongwith additional experimentation ruled out the olfactoryepithelium as the sole portal of entry of the polio virus intohumans15 But the toxic effect of zinc on human olfactoryepithelium was clearly shown Although interindividualvariation in drug response and drug toxicity is apparent theeffects appear to be dose related and long lasting or perma-nent in some cases Subsequently transient olfactory losshas been reported in some of the studies of experimentalanimals such as that of McBride27 The use of intranasalzinc was abandoned
In 1976 Matulionis observed distinct patterns of degen-eration and regeneration of the olfactory epithelium in micereceiving intranasal irrigation with 1 aqueous zinc sul-fate28 During the first 24 hours after treatment three pro-gressive manifestations of the degenerative process wereseen (1) a relatively mild condition which was character-ized by surface irregularities produced by cell protrusionshighly vacuolated cytoplasm presence of large lysosome-like bodies and prominent intercellular spaces (2) a moresevere condition in which large areas of the epithelium weredetached from the basement membrane and cellular debriswas present in the nasal chamber and (3) a condition oftotal or near-total denudation of the epithelium of olfactorymucosa The basal lamina was continuous and intact in mostregions and the integrity of the subadjacent connectivetissue mostly was well preserved The nerve bundles of thefila olfactoria were noted to be in varying degrees of de-generation during the course of the experiment with themost advanced neural degeneration from 24ndash72 hours aftertreatment
In 1978 Harding described immediate and total anosmiain mice irrigated with intranasal 017 M ZnSO417 Thisanosmia persisted for 6 weeks in at least 80 of the treatedanimals and 4 months in one-half of the treated animalsChanges were still apparent at 1 year the limit of theexperimental observation
By 1982 Cancalon attributed the ldquonecrotic effectrdquo ofvarious salt solutions to the divalent ldquozinc cationrdquo in irriga-tion experiments on the catfish olfactory mucosa usingconcentrations of 6ndash960 mM of zinc sulfate18 He noted thatZnSO4 and ZnCl were ldquoequally effective in destroying theolfactory epithelium offering proof that it was the zinccation that produces the toxic effects He reported that thedamage was very reproducible largely concentration inde-pendent and almost completely specific for the olfactory
receptor cells The nonsensory respiratory cells were unaf-fected The sustentacular cells surrounding the receptor cellswere affected mainly by a loss of microvilli The olfactorycells started to degenerate within a few hours and by day 4only 20 of the original receptor population remainedMucosal basal cell mitosis increased during days 3 and 4and by day 7 the receptor population had reached 80 of itsoriginal value On the other hand when the salt solution wasmaintained in contact with the olfactory epithelium forseveral days only very limited regeneration occurred asmost of the lamellae were irreversibly destroyed
In 1997 Mayer and Rosenblatt reported that the sprayapplication of ZnSO4 (174 in 09 saline) to the olfac-tory mucosa in rats produced severe nasal congestion thatcleared within 24 hours followed by in 48 hours anosmiain 80 of the treated animals29
From a more basic standpoint the transduction of odorsinto electrical signals takes place on the surface of theolfactory receptor cells and is necessary for olfactory func-tion In particular an odorant binds to a cyclic nucleotide-gated receptor that generates cyclic adenosine monophos-phate which in turn activates a nonspecific cation channelallowing Ca2 entry into the cell This Ca2 then activatesa calcium-activated chloride channel that results in depolar-ization of the cell The divalent cation Ba2 is suggested toblock the nonspecific cyclic nucleotide-gated channel inanimals30 This also appears to be the case in human olfac-tory receptor cells (Fig 1) Zinc a divalent cation also mayblock this channel and interfere with olfactory functionOngoing studies are evaluating both the short-term andlong-term effects of zinc on olfactory cell function
In 2000 Hirt et al recommended the intranasal use of anOTC zinc gluconate nasal gel formulation to bring themedication closer to the causative organism rhinovirus inalleviating the symptoms of the common cold decreasingthe duration of symptoms by 7520 Citing the antirhino-viral activity of ionized zinc31ndash33 they recommended thatthe ldquomixed benefitsrdquo of zinc gluconate lozenges dissolved inthe mouth affecting rhinovirus in the nose to prevent oralleviate the symptoms of the common cold could be im-proved by ldquodelivery of ionic zinc directly to the site ofinfectionrdquo203435 They noted that although 42 of ldquozinc-treated patientsrdquo and 37 of controls described a ldquoslighttingling or burning sensation on intranasal zinc applica-tionrdquo five other potential side effects (nausea bad tastereactions odor dizziness and drowsiness) were not foundIt is not apparent from their publication that they tested foror considered olfactory deficits in their study group
Other studies concluded that intranasal zinc was notnearly as helpful in the treatment of the common coldBelongia found ldquono effect on the duration of the commoncold but possibly mild and transient reduction in the sever-ity of nasal symptoms using 012 zinc sulfate nasal
Zicam Mattrixx Initiatives Phoenix AZ
American Journal of Rhinology 139
sprayrdquo36 Turner concluded that the commercially availablezinc gluconate gel was ldquolsquoineffectiversquo in preventing pro-gression of an experimentally induced rhinovirus infection33 mM of zinc gluconate in an emulsification of benzalko-nium chloride glycerine hydroxymethylcellulose sodiumchloride and sodium peroxide buffered to pH 72rdquo37
A single case report of anosmia due to inhalational zincsoon followed38
In 2003 Mossad concluded that ionic zinc (33 mmolL ofzincum gluconium) ldquoshortens the duration and reducessymptom severity of the common cold in healthy adultsrdquo39
Adverse effects were solicited by an open-ended telephonequestion the most commonly identified being ldquonasal sting-ing or burningrdquo Neither olfactory complaints nor evaluationwere mentioned
Because patients use the intranasal zinc when they ldquofeela cold coming onrdquo postviral anosmia should be considereda cause for the chemosensory loss Three factors argueagainst this conclusion First the admittedly modest studypopulation had a male preponderance of more than 21 asopposed to the 21 female ratio seen in postviral anosmiathe patients in the intranasal zinc group also were youngeron average than reported postviral patients40 Second post-viral anosmia typically occurs with ldquothe worst upper-respi-ratory infection (URI) Irsquove ever hadrdquo Our study populationtypically used the intranasal zinc early in the course of amild URI and most convincing was the immediate acuteldquoburningrdquo pain with the use of the zinc gluconate followedimmediately by persistent severe hyposmia or anosmiaOther explanations for the smell loss (eg post-traumaticetc) were ruled out by a negative history in each case AWeb site maintained by Dr Karl L Wuensch offers addi-tional discussion of the issue of loss of smell after the use ofintranasal zinc41
Recent advertisements have added a pediatric applicatorfor intranasal zinc This extension of the use of intranasalzinc gluconate to the pediatric age group is of concernbecause the use of intranasal zinc in this age group could beexpected to generate anosmia although this age group is lesslikely to describe the symptom resulting in repeated treat-ments rather than immediate discontinuation of the drug
It should be noted that only a single trademarked prepa-ration of zinc gluconate was available at the time of thisreport and was used by each of the patients cited immedi-ately before their loss of smell Subsequently this brandhas been extended by the manufacturer to several productsThis communication only concerns the product containingzinc gluconate
CONCLUSION
In conclusion the divalent zinc ion is reported to be toxicto olfactory epithelium the toxicity apparently being
related to both concentration and interindividual sensitivitybut not the source of the ion (eg salt source as shown byCancalon18 and others) The temporal association of the useof intranasal zinc gluconate with the development of severepartial or total loss of the sense of smell raises significantconcern regarding its safety for intranasal application inhumans Given the prevalence of viral URIs the strongdesire of patients for symptomatic relief and the widespreadavailability and marketing of OTC products for this pur-pose there is the potential for a very large number of peopleto be exposed to intranasal zinc gluconate Therefore evenif the frequency of loss of smell is low the number of
Zicam Mattrixx Initiatives Phoenix AZ
Figure 1 Human olfactory epithelium was isolated from freshcadavers and EOG recording techniques used to study olfactorytransduction40 (A) Cineole (100 M) applied to the olfactoryepithelium produced a response (B) that in the presence of 5 mMof Ba2 was blocked This effect was fully reversible after severalminutes of exposure to Ba2 The bars below each trace indicatethe application time of cineole and note that there was a delaybefore the start of the upward-going odorant response in panel ASaline control traces were subtracted from each trace and lowpass filtering was used
140 May-June 2004 Vol 18 No 3
people affected by this treatment could be alarmingly highThe public may assume that because intranasal zinc glu-conate is sold as an OTC ldquopatented homeopathicrdquo prepa-ration containing a ldquonaturalrdquo or even ldquoessentialrdquo elementthat it is safe This report raises important questions aboutthat generalization Because the effects appear to be some-what dose-related use of this drug in the pediatric age groupwould be expected to generate an even larger incidence ofanosmia in this population and is especially concerning
If history repeats itself and the unexpected always hap-pens how incapable must man be of learning from expe-rience
mdashGeorge Bernard Shaw (1856ndash1950)Irish dramatist
REFERENCES1 Sandstead HH and Alcock NW Zinc An essential and unher-
alded nutrient J Lab Clin Med 130116ndash118 19972 Solomons NW Mild human zinc deficiency produces an imbal-
ance between cell-mediated and humoral immunity Nutr Rev5627ndash28 1998
3 Prasad AS Zinc An overview Nutrition 1193ndash99 19954 Heyneman CA Zinc deficiency and taste disorders Ann Phar-
macother 30186ndash187 19965 Lansdown AB Metallothioneins Potential therapeutic aids for
wound healing in the skin Wound Repair Regen 10130ndash132 20026 Prasad AS Beck FW Grabowski SM et al Zinc deficiency
Changes in cytokine production and T-cell subpopulations inpatients with head and neck cancer and in noncancer subjectsProc Assoc Am Physicians 10968ndash77 1997
7 Simmer K and Thompson RP Zinc in the fetus and newbornActa Paediatr Scand Suppl 319158ndash163 1985
8 Fabris N and Mocchegiani E Zinc human diseases and agingAging (Milano) 777ndash93 1995
9 Prasad AS Zinc deficiency in women infants and childrenJ Am Coll Nutr 15113ndash120 1996
10 Hambidge KM Mild zinc deficiency in human subjects In Zincin Human Biology Mills CF (Ed) New York Springer-Verlag281ndash296 1989
11 King JC and Keen CL Zinc In Modern Nutrition in Health andDisease 9th ed Shils ME Olson JA Shike M et al (Eds) Chap11 Baltimore Williams amp Wilkins 223ndash239 1999
12 Hooper PL Visconti L Garry PJ et al Zinc lowers high-densitylipoprotein-cholesterol levels J Am Med Assoc 2441960ndash1961 1980
13 Shenkin A Trace elements and inflammatory response Implica-tions for nutritional support Nutrition 11(1 suppl)100ndash105 1995
14 Berg RH I can stop the virus In Polio and Its Problems Ch 5Berg RH (Ed) Philadelphia Lippincott 34ndash47 1948
15 Rutty CJ The middle-class plague Epidemic polio and the Cana-dian state 1ndash36-1937 Can Bull Med Hist 13277ndash314 1996
16 Tisdall FF Brown A and Defries RD Persistent anosmia fol-lowing zinc sulphate nasal spraying J Pediatr 1360ndash62 1938
17 Harding JW Getchell TV and Margolis FL Denervation of theprimary olfactory pathway in mice V Long-term effects ofintranasal ZnSO4 irrigation on behavior biochemistry and mor-phology Brain Res 140271ndash285 1978
18 Cancalon P Degeneration and regeneration of olfactory cellsinduced by ZnSO4 and other chemicals Tissue Cell 14717ndash7331982
19 Moran DT Rowley JC III Aiken GR and Jafek BW Ultrastruc-tural neurobiology of the olfactory mucosa of the brown troutSalmo trutta Microsc Res Tech 2328ndash48 1992
20 Hirt M Nobel S and Barron E Zinc nasal gel for the treatmentof common cold symptoms A double-blind placebo-controlledtrial Ear Nose Throat J 79778ndash780 782 2000
21 Linschoten M Harvey LO Jr Eller PM and Jafek B Fast andaccurate measurement of taste and smell thresholds using amaximum-likelihood adaptive staircase procedure Percept Psy-chophys 631330ndash1347 2001
22 Schultz EW Immunity and prophylaxis in poliomyelitis JAMA1072102ndash2104 1936
23 Schultz EW and Gebhardt LP Zinc sulfate prophylaxis in po-liomyelitis JAMA 1082182ndash2184 1937
24 Peet MM Echols DH and Richter HJ The chemical prophylaxisfor poliomyelitis The technique of applying zinc sulfate intra-nasally JAMA 1082184ndash2187 1937
25 Shahinian L Bacher JA McNaught RC and Newell RR Che-moprophylaxis in poliomyelitis JAMA 1101254ndash1257 1938
26 Ashley RE Chemoprophylaxis against impending poliomyelitisArch Otol 29104ndash114 1939
27 McBride K Slotnick B and Margolis FL Does intranasal applica-tion of zinc sulfate produce anosmia in the mouse An olfactometricand anatomical study Chem Senses 28659ndash670 2003
28 Matulionis DH Light and microscopic study of the degenerationand early regeneration of olfactory epithelium in the mouseAm J Anat 14579ndash99 1976
29 Mayer AD and Rosenblatt JS Peripheral olfactory deafferenta-tion of the primary olfactory system in rats using ZnSO4 nasalspray with special reference to maternal behavior Physiol Behav53587ndash592 1997
30 Miyamoto T Restrepo D and Teeter J Voltage-dependent andodorant-regulated currents in isolated oflactory receptor neuronsof the channel catfish J Gen Physiol 99505ndash529 1992
31 Korant BD Kauer JC and Butterworth BE Zinc ions inhibitreplication of rhinoviruses Nature 248588ndash590 1874
32 Korant BD and Butterworth BE Inhibition by zinc of rhinovirusprotein cleavage Interaction of zinc with capsid polypeptidesJ Virol 18298ndash306 1976
33 Kelly RW and Abel MH Copper and zinc inhibit the metabolism ofprostaglandin by the human uterus Biol Reprod 28883ndash889 1983
34 Novick SG Godfrey JC Godfrey NJ and Wilder HR How does zincmodify the common cold Clinical observation and implications re-garding mechanisms of action Med Hypotheses 46295ndash302 1996
35 Godfrey JC Godfrey NJ and Novick SG Zinc for treating thecommon cold Review of all clinical trials since 1984 AlternTher Health Med 263ndash72 1996
36 Belongia EA Berg R and Liu K A randomized trial of zincnasal spray for the treatment of upper respiratory illness inadults Am J Med 111103ndash108 2001
37 Turner RB Ineffectiveness of intranasal zinc gluconate for theprevention of experimental rhinovirus colds Clin Inf Dis 331865ndash1870 2001
38 DeCook CA and Hirsch AR Anosmia due to inhalational zincA case report Chem Senses 25659 2000 (Abs)
39 Mossad SB Effects of zincum gluconium nasal gel on theduration and symptom severity of the common cold in otherwisehealthy adults QJM 9635ndash43 2003
40 Duncan HJ Postviral olfactory loss In Taste and Smell Disor-ders Ch 6 Seiden AM (Ed) New York Thieme 72ndash78 1997
41 Murrow BW Jafek BW and Restrepo D The use of freshcadaveric human olfactory epithelium for physiologic studyAChemS Sarasota FL April 2001 e
American Journal of Rhinology 141
that many of their patients had suffered a complete andpermanent loss of the sense of smellrdquo14 Using relativelyprimitive psychophysical testing employing oil of clovesand oil of spearmint 10ndash13 of children were thought to beanosmic apparently permanently14 Note that because oil ofcloves and oil of spearmint stimulate the trigeminal nerve apercentage of 10ndash13 is most likely a gross underestima-tion of the actual percentage of anosmics Unfortunately theprotective spraying with zinc sulfate did not alter the attackrate of the disease and a more critical examination of theolfactory tissues previously thought to be involved alongwith additional experimentation ruled out the olfactoryepithelium as the sole portal of entry of the polio virus intohumans15 But the toxic effect of zinc on human olfactoryepithelium was clearly shown Although interindividualvariation in drug response and drug toxicity is apparent theeffects appear to be dose related and long lasting or perma-nent in some cases Subsequently transient olfactory losshas been reported in some of the studies of experimentalanimals such as that of McBride27 The use of intranasalzinc was abandoned
In 1976 Matulionis observed distinct patterns of degen-eration and regeneration of the olfactory epithelium in micereceiving intranasal irrigation with 1 aqueous zinc sul-fate28 During the first 24 hours after treatment three pro-gressive manifestations of the degenerative process wereseen (1) a relatively mild condition which was character-ized by surface irregularities produced by cell protrusionshighly vacuolated cytoplasm presence of large lysosome-like bodies and prominent intercellular spaces (2) a moresevere condition in which large areas of the epithelium weredetached from the basement membrane and cellular debriswas present in the nasal chamber and (3) a condition oftotal or near-total denudation of the epithelium of olfactorymucosa The basal lamina was continuous and intact in mostregions and the integrity of the subadjacent connectivetissue mostly was well preserved The nerve bundles of thefila olfactoria were noted to be in varying degrees of de-generation during the course of the experiment with themost advanced neural degeneration from 24ndash72 hours aftertreatment
In 1978 Harding described immediate and total anosmiain mice irrigated with intranasal 017 M ZnSO417 Thisanosmia persisted for 6 weeks in at least 80 of the treatedanimals and 4 months in one-half of the treated animalsChanges were still apparent at 1 year the limit of theexperimental observation
By 1982 Cancalon attributed the ldquonecrotic effectrdquo ofvarious salt solutions to the divalent ldquozinc cationrdquo in irriga-tion experiments on the catfish olfactory mucosa usingconcentrations of 6ndash960 mM of zinc sulfate18 He noted thatZnSO4 and ZnCl were ldquoequally effective in destroying theolfactory epithelium offering proof that it was the zinccation that produces the toxic effects He reported that thedamage was very reproducible largely concentration inde-pendent and almost completely specific for the olfactory
receptor cells The nonsensory respiratory cells were unaf-fected The sustentacular cells surrounding the receptor cellswere affected mainly by a loss of microvilli The olfactorycells started to degenerate within a few hours and by day 4only 20 of the original receptor population remainedMucosal basal cell mitosis increased during days 3 and 4and by day 7 the receptor population had reached 80 of itsoriginal value On the other hand when the salt solution wasmaintained in contact with the olfactory epithelium forseveral days only very limited regeneration occurred asmost of the lamellae were irreversibly destroyed
In 1997 Mayer and Rosenblatt reported that the sprayapplication of ZnSO4 (174 in 09 saline) to the olfac-tory mucosa in rats produced severe nasal congestion thatcleared within 24 hours followed by in 48 hours anosmiain 80 of the treated animals29
From a more basic standpoint the transduction of odorsinto electrical signals takes place on the surface of theolfactory receptor cells and is necessary for olfactory func-tion In particular an odorant binds to a cyclic nucleotide-gated receptor that generates cyclic adenosine monophos-phate which in turn activates a nonspecific cation channelallowing Ca2 entry into the cell This Ca2 then activatesa calcium-activated chloride channel that results in depolar-ization of the cell The divalent cation Ba2 is suggested toblock the nonspecific cyclic nucleotide-gated channel inanimals30 This also appears to be the case in human olfac-tory receptor cells (Fig 1) Zinc a divalent cation also mayblock this channel and interfere with olfactory functionOngoing studies are evaluating both the short-term andlong-term effects of zinc on olfactory cell function
In 2000 Hirt et al recommended the intranasal use of anOTC zinc gluconate nasal gel formulation to bring themedication closer to the causative organism rhinovirus inalleviating the symptoms of the common cold decreasingthe duration of symptoms by 7520 Citing the antirhino-viral activity of ionized zinc31ndash33 they recommended thatthe ldquomixed benefitsrdquo of zinc gluconate lozenges dissolved inthe mouth affecting rhinovirus in the nose to prevent oralleviate the symptoms of the common cold could be im-proved by ldquodelivery of ionic zinc directly to the site ofinfectionrdquo203435 They noted that although 42 of ldquozinc-treated patientsrdquo and 37 of controls described a ldquoslighttingling or burning sensation on intranasal zinc applica-tionrdquo five other potential side effects (nausea bad tastereactions odor dizziness and drowsiness) were not foundIt is not apparent from their publication that they tested foror considered olfactory deficits in their study group
Other studies concluded that intranasal zinc was notnearly as helpful in the treatment of the common coldBelongia found ldquono effect on the duration of the commoncold but possibly mild and transient reduction in the sever-ity of nasal symptoms using 012 zinc sulfate nasal
Zicam Mattrixx Initiatives Phoenix AZ
American Journal of Rhinology 139
sprayrdquo36 Turner concluded that the commercially availablezinc gluconate gel was ldquolsquoineffectiversquo in preventing pro-gression of an experimentally induced rhinovirus infection33 mM of zinc gluconate in an emulsification of benzalko-nium chloride glycerine hydroxymethylcellulose sodiumchloride and sodium peroxide buffered to pH 72rdquo37
A single case report of anosmia due to inhalational zincsoon followed38
In 2003 Mossad concluded that ionic zinc (33 mmolL ofzincum gluconium) ldquoshortens the duration and reducessymptom severity of the common cold in healthy adultsrdquo39
Adverse effects were solicited by an open-ended telephonequestion the most commonly identified being ldquonasal sting-ing or burningrdquo Neither olfactory complaints nor evaluationwere mentioned
Because patients use the intranasal zinc when they ldquofeela cold coming onrdquo postviral anosmia should be considereda cause for the chemosensory loss Three factors argueagainst this conclusion First the admittedly modest studypopulation had a male preponderance of more than 21 asopposed to the 21 female ratio seen in postviral anosmiathe patients in the intranasal zinc group also were youngeron average than reported postviral patients40 Second post-viral anosmia typically occurs with ldquothe worst upper-respi-ratory infection (URI) Irsquove ever hadrdquo Our study populationtypically used the intranasal zinc early in the course of amild URI and most convincing was the immediate acuteldquoburningrdquo pain with the use of the zinc gluconate followedimmediately by persistent severe hyposmia or anosmiaOther explanations for the smell loss (eg post-traumaticetc) were ruled out by a negative history in each case AWeb site maintained by Dr Karl L Wuensch offers addi-tional discussion of the issue of loss of smell after the use ofintranasal zinc41
Recent advertisements have added a pediatric applicatorfor intranasal zinc This extension of the use of intranasalzinc gluconate to the pediatric age group is of concernbecause the use of intranasal zinc in this age group could beexpected to generate anosmia although this age group is lesslikely to describe the symptom resulting in repeated treat-ments rather than immediate discontinuation of the drug
It should be noted that only a single trademarked prepa-ration of zinc gluconate was available at the time of thisreport and was used by each of the patients cited immedi-ately before their loss of smell Subsequently this brandhas been extended by the manufacturer to several productsThis communication only concerns the product containingzinc gluconate
CONCLUSION
In conclusion the divalent zinc ion is reported to be toxicto olfactory epithelium the toxicity apparently being
related to both concentration and interindividual sensitivitybut not the source of the ion (eg salt source as shown byCancalon18 and others) The temporal association of the useof intranasal zinc gluconate with the development of severepartial or total loss of the sense of smell raises significantconcern regarding its safety for intranasal application inhumans Given the prevalence of viral URIs the strongdesire of patients for symptomatic relief and the widespreadavailability and marketing of OTC products for this pur-pose there is the potential for a very large number of peopleto be exposed to intranasal zinc gluconate Therefore evenif the frequency of loss of smell is low the number of
Zicam Mattrixx Initiatives Phoenix AZ
Figure 1 Human olfactory epithelium was isolated from freshcadavers and EOG recording techniques used to study olfactorytransduction40 (A) Cineole (100 M) applied to the olfactoryepithelium produced a response (B) that in the presence of 5 mMof Ba2 was blocked This effect was fully reversible after severalminutes of exposure to Ba2 The bars below each trace indicatethe application time of cineole and note that there was a delaybefore the start of the upward-going odorant response in panel ASaline control traces were subtracted from each trace and lowpass filtering was used
140 May-June 2004 Vol 18 No 3
people affected by this treatment could be alarmingly highThe public may assume that because intranasal zinc glu-conate is sold as an OTC ldquopatented homeopathicrdquo prepa-ration containing a ldquonaturalrdquo or even ldquoessentialrdquo elementthat it is safe This report raises important questions aboutthat generalization Because the effects appear to be some-what dose-related use of this drug in the pediatric age groupwould be expected to generate an even larger incidence ofanosmia in this population and is especially concerning
If history repeats itself and the unexpected always hap-pens how incapable must man be of learning from expe-rience
mdashGeorge Bernard Shaw (1856ndash1950)Irish dramatist
REFERENCES1 Sandstead HH and Alcock NW Zinc An essential and unher-
alded nutrient J Lab Clin Med 130116ndash118 19972 Solomons NW Mild human zinc deficiency produces an imbal-
ance between cell-mediated and humoral immunity Nutr Rev5627ndash28 1998
3 Prasad AS Zinc An overview Nutrition 1193ndash99 19954 Heyneman CA Zinc deficiency and taste disorders Ann Phar-
macother 30186ndash187 19965 Lansdown AB Metallothioneins Potential therapeutic aids for
wound healing in the skin Wound Repair Regen 10130ndash132 20026 Prasad AS Beck FW Grabowski SM et al Zinc deficiency
Changes in cytokine production and T-cell subpopulations inpatients with head and neck cancer and in noncancer subjectsProc Assoc Am Physicians 10968ndash77 1997
7 Simmer K and Thompson RP Zinc in the fetus and newbornActa Paediatr Scand Suppl 319158ndash163 1985
8 Fabris N and Mocchegiani E Zinc human diseases and agingAging (Milano) 777ndash93 1995
9 Prasad AS Zinc deficiency in women infants and childrenJ Am Coll Nutr 15113ndash120 1996
10 Hambidge KM Mild zinc deficiency in human subjects In Zincin Human Biology Mills CF (Ed) New York Springer-Verlag281ndash296 1989
11 King JC and Keen CL Zinc In Modern Nutrition in Health andDisease 9th ed Shils ME Olson JA Shike M et al (Eds) Chap11 Baltimore Williams amp Wilkins 223ndash239 1999
12 Hooper PL Visconti L Garry PJ et al Zinc lowers high-densitylipoprotein-cholesterol levels J Am Med Assoc 2441960ndash1961 1980
13 Shenkin A Trace elements and inflammatory response Implica-tions for nutritional support Nutrition 11(1 suppl)100ndash105 1995
14 Berg RH I can stop the virus In Polio and Its Problems Ch 5Berg RH (Ed) Philadelphia Lippincott 34ndash47 1948
15 Rutty CJ The middle-class plague Epidemic polio and the Cana-dian state 1ndash36-1937 Can Bull Med Hist 13277ndash314 1996
16 Tisdall FF Brown A and Defries RD Persistent anosmia fol-lowing zinc sulphate nasal spraying J Pediatr 1360ndash62 1938
17 Harding JW Getchell TV and Margolis FL Denervation of theprimary olfactory pathway in mice V Long-term effects ofintranasal ZnSO4 irrigation on behavior biochemistry and mor-phology Brain Res 140271ndash285 1978
18 Cancalon P Degeneration and regeneration of olfactory cellsinduced by ZnSO4 and other chemicals Tissue Cell 14717ndash7331982
19 Moran DT Rowley JC III Aiken GR and Jafek BW Ultrastruc-tural neurobiology of the olfactory mucosa of the brown troutSalmo trutta Microsc Res Tech 2328ndash48 1992
20 Hirt M Nobel S and Barron E Zinc nasal gel for the treatmentof common cold symptoms A double-blind placebo-controlledtrial Ear Nose Throat J 79778ndash780 782 2000
21 Linschoten M Harvey LO Jr Eller PM and Jafek B Fast andaccurate measurement of taste and smell thresholds using amaximum-likelihood adaptive staircase procedure Percept Psy-chophys 631330ndash1347 2001
22 Schultz EW Immunity and prophylaxis in poliomyelitis JAMA1072102ndash2104 1936
23 Schultz EW and Gebhardt LP Zinc sulfate prophylaxis in po-liomyelitis JAMA 1082182ndash2184 1937
24 Peet MM Echols DH and Richter HJ The chemical prophylaxisfor poliomyelitis The technique of applying zinc sulfate intra-nasally JAMA 1082184ndash2187 1937
25 Shahinian L Bacher JA McNaught RC and Newell RR Che-moprophylaxis in poliomyelitis JAMA 1101254ndash1257 1938
26 Ashley RE Chemoprophylaxis against impending poliomyelitisArch Otol 29104ndash114 1939
27 McBride K Slotnick B and Margolis FL Does intranasal applica-tion of zinc sulfate produce anosmia in the mouse An olfactometricand anatomical study Chem Senses 28659ndash670 2003
28 Matulionis DH Light and microscopic study of the degenerationand early regeneration of olfactory epithelium in the mouseAm J Anat 14579ndash99 1976
29 Mayer AD and Rosenblatt JS Peripheral olfactory deafferenta-tion of the primary olfactory system in rats using ZnSO4 nasalspray with special reference to maternal behavior Physiol Behav53587ndash592 1997
30 Miyamoto T Restrepo D and Teeter J Voltage-dependent andodorant-regulated currents in isolated oflactory receptor neuronsof the channel catfish J Gen Physiol 99505ndash529 1992
31 Korant BD Kauer JC and Butterworth BE Zinc ions inhibitreplication of rhinoviruses Nature 248588ndash590 1874
32 Korant BD and Butterworth BE Inhibition by zinc of rhinovirusprotein cleavage Interaction of zinc with capsid polypeptidesJ Virol 18298ndash306 1976
33 Kelly RW and Abel MH Copper and zinc inhibit the metabolism ofprostaglandin by the human uterus Biol Reprod 28883ndash889 1983
34 Novick SG Godfrey JC Godfrey NJ and Wilder HR How does zincmodify the common cold Clinical observation and implications re-garding mechanisms of action Med Hypotheses 46295ndash302 1996
35 Godfrey JC Godfrey NJ and Novick SG Zinc for treating thecommon cold Review of all clinical trials since 1984 AlternTher Health Med 263ndash72 1996
36 Belongia EA Berg R and Liu K A randomized trial of zincnasal spray for the treatment of upper respiratory illness inadults Am J Med 111103ndash108 2001
37 Turner RB Ineffectiveness of intranasal zinc gluconate for theprevention of experimental rhinovirus colds Clin Inf Dis 331865ndash1870 2001
38 DeCook CA and Hirsch AR Anosmia due to inhalational zincA case report Chem Senses 25659 2000 (Abs)
39 Mossad SB Effects of zincum gluconium nasal gel on theduration and symptom severity of the common cold in otherwisehealthy adults QJM 9635ndash43 2003
40 Duncan HJ Postviral olfactory loss In Taste and Smell Disor-ders Ch 6 Seiden AM (Ed) New York Thieme 72ndash78 1997
41 Murrow BW Jafek BW and Restrepo D The use of freshcadaveric human olfactory epithelium for physiologic studyAChemS Sarasota FL April 2001 e
American Journal of Rhinology 141
sprayrdquo36 Turner concluded that the commercially availablezinc gluconate gel was ldquolsquoineffectiversquo in preventing pro-gression of an experimentally induced rhinovirus infection33 mM of zinc gluconate in an emulsification of benzalko-nium chloride glycerine hydroxymethylcellulose sodiumchloride and sodium peroxide buffered to pH 72rdquo37
A single case report of anosmia due to inhalational zincsoon followed38
In 2003 Mossad concluded that ionic zinc (33 mmolL ofzincum gluconium) ldquoshortens the duration and reducessymptom severity of the common cold in healthy adultsrdquo39
Adverse effects were solicited by an open-ended telephonequestion the most commonly identified being ldquonasal sting-ing or burningrdquo Neither olfactory complaints nor evaluationwere mentioned
Because patients use the intranasal zinc when they ldquofeela cold coming onrdquo postviral anosmia should be considereda cause for the chemosensory loss Three factors argueagainst this conclusion First the admittedly modest studypopulation had a male preponderance of more than 21 asopposed to the 21 female ratio seen in postviral anosmiathe patients in the intranasal zinc group also were youngeron average than reported postviral patients40 Second post-viral anosmia typically occurs with ldquothe worst upper-respi-ratory infection (URI) Irsquove ever hadrdquo Our study populationtypically used the intranasal zinc early in the course of amild URI and most convincing was the immediate acuteldquoburningrdquo pain with the use of the zinc gluconate followedimmediately by persistent severe hyposmia or anosmiaOther explanations for the smell loss (eg post-traumaticetc) were ruled out by a negative history in each case AWeb site maintained by Dr Karl L Wuensch offers addi-tional discussion of the issue of loss of smell after the use ofintranasal zinc41
Recent advertisements have added a pediatric applicatorfor intranasal zinc This extension of the use of intranasalzinc gluconate to the pediatric age group is of concernbecause the use of intranasal zinc in this age group could beexpected to generate anosmia although this age group is lesslikely to describe the symptom resulting in repeated treat-ments rather than immediate discontinuation of the drug
It should be noted that only a single trademarked prepa-ration of zinc gluconate was available at the time of thisreport and was used by each of the patients cited immedi-ately before their loss of smell Subsequently this brandhas been extended by the manufacturer to several productsThis communication only concerns the product containingzinc gluconate
CONCLUSION
In conclusion the divalent zinc ion is reported to be toxicto olfactory epithelium the toxicity apparently being
related to both concentration and interindividual sensitivitybut not the source of the ion (eg salt source as shown byCancalon18 and others) The temporal association of the useof intranasal zinc gluconate with the development of severepartial or total loss of the sense of smell raises significantconcern regarding its safety for intranasal application inhumans Given the prevalence of viral URIs the strongdesire of patients for symptomatic relief and the widespreadavailability and marketing of OTC products for this pur-pose there is the potential for a very large number of peopleto be exposed to intranasal zinc gluconate Therefore evenif the frequency of loss of smell is low the number of
Zicam Mattrixx Initiatives Phoenix AZ
Figure 1 Human olfactory epithelium was isolated from freshcadavers and EOG recording techniques used to study olfactorytransduction40 (A) Cineole (100 M) applied to the olfactoryepithelium produced a response (B) that in the presence of 5 mMof Ba2 was blocked This effect was fully reversible after severalminutes of exposure to Ba2 The bars below each trace indicatethe application time of cineole and note that there was a delaybefore the start of the upward-going odorant response in panel ASaline control traces were subtracted from each trace and lowpass filtering was used
140 May-June 2004 Vol 18 No 3
people affected by this treatment could be alarmingly highThe public may assume that because intranasal zinc glu-conate is sold as an OTC ldquopatented homeopathicrdquo prepa-ration containing a ldquonaturalrdquo or even ldquoessentialrdquo elementthat it is safe This report raises important questions aboutthat generalization Because the effects appear to be some-what dose-related use of this drug in the pediatric age groupwould be expected to generate an even larger incidence ofanosmia in this population and is especially concerning
If history repeats itself and the unexpected always hap-pens how incapable must man be of learning from expe-rience
mdashGeorge Bernard Shaw (1856ndash1950)Irish dramatist
REFERENCES1 Sandstead HH and Alcock NW Zinc An essential and unher-
alded nutrient J Lab Clin Med 130116ndash118 19972 Solomons NW Mild human zinc deficiency produces an imbal-
ance between cell-mediated and humoral immunity Nutr Rev5627ndash28 1998
3 Prasad AS Zinc An overview Nutrition 1193ndash99 19954 Heyneman CA Zinc deficiency and taste disorders Ann Phar-
macother 30186ndash187 19965 Lansdown AB Metallothioneins Potential therapeutic aids for
wound healing in the skin Wound Repair Regen 10130ndash132 20026 Prasad AS Beck FW Grabowski SM et al Zinc deficiency
Changes in cytokine production and T-cell subpopulations inpatients with head and neck cancer and in noncancer subjectsProc Assoc Am Physicians 10968ndash77 1997
7 Simmer K and Thompson RP Zinc in the fetus and newbornActa Paediatr Scand Suppl 319158ndash163 1985
8 Fabris N and Mocchegiani E Zinc human diseases and agingAging (Milano) 777ndash93 1995
9 Prasad AS Zinc deficiency in women infants and childrenJ Am Coll Nutr 15113ndash120 1996
10 Hambidge KM Mild zinc deficiency in human subjects In Zincin Human Biology Mills CF (Ed) New York Springer-Verlag281ndash296 1989
11 King JC and Keen CL Zinc In Modern Nutrition in Health andDisease 9th ed Shils ME Olson JA Shike M et al (Eds) Chap11 Baltimore Williams amp Wilkins 223ndash239 1999
12 Hooper PL Visconti L Garry PJ et al Zinc lowers high-densitylipoprotein-cholesterol levels J Am Med Assoc 2441960ndash1961 1980
13 Shenkin A Trace elements and inflammatory response Implica-tions for nutritional support Nutrition 11(1 suppl)100ndash105 1995
14 Berg RH I can stop the virus In Polio and Its Problems Ch 5Berg RH (Ed) Philadelphia Lippincott 34ndash47 1948
15 Rutty CJ The middle-class plague Epidemic polio and the Cana-dian state 1ndash36-1937 Can Bull Med Hist 13277ndash314 1996
16 Tisdall FF Brown A and Defries RD Persistent anosmia fol-lowing zinc sulphate nasal spraying J Pediatr 1360ndash62 1938
17 Harding JW Getchell TV and Margolis FL Denervation of theprimary olfactory pathway in mice V Long-term effects ofintranasal ZnSO4 irrigation on behavior biochemistry and mor-phology Brain Res 140271ndash285 1978
18 Cancalon P Degeneration and regeneration of olfactory cellsinduced by ZnSO4 and other chemicals Tissue Cell 14717ndash7331982
19 Moran DT Rowley JC III Aiken GR and Jafek BW Ultrastruc-tural neurobiology of the olfactory mucosa of the brown troutSalmo trutta Microsc Res Tech 2328ndash48 1992
20 Hirt M Nobel S and Barron E Zinc nasal gel for the treatmentof common cold symptoms A double-blind placebo-controlledtrial Ear Nose Throat J 79778ndash780 782 2000
21 Linschoten M Harvey LO Jr Eller PM and Jafek B Fast andaccurate measurement of taste and smell thresholds using amaximum-likelihood adaptive staircase procedure Percept Psy-chophys 631330ndash1347 2001
22 Schultz EW Immunity and prophylaxis in poliomyelitis JAMA1072102ndash2104 1936
23 Schultz EW and Gebhardt LP Zinc sulfate prophylaxis in po-liomyelitis JAMA 1082182ndash2184 1937
24 Peet MM Echols DH and Richter HJ The chemical prophylaxisfor poliomyelitis The technique of applying zinc sulfate intra-nasally JAMA 1082184ndash2187 1937
25 Shahinian L Bacher JA McNaught RC and Newell RR Che-moprophylaxis in poliomyelitis JAMA 1101254ndash1257 1938
26 Ashley RE Chemoprophylaxis against impending poliomyelitisArch Otol 29104ndash114 1939
27 McBride K Slotnick B and Margolis FL Does intranasal applica-tion of zinc sulfate produce anosmia in the mouse An olfactometricand anatomical study Chem Senses 28659ndash670 2003
28 Matulionis DH Light and microscopic study of the degenerationand early regeneration of olfactory epithelium in the mouseAm J Anat 14579ndash99 1976
29 Mayer AD and Rosenblatt JS Peripheral olfactory deafferenta-tion of the primary olfactory system in rats using ZnSO4 nasalspray with special reference to maternal behavior Physiol Behav53587ndash592 1997
30 Miyamoto T Restrepo D and Teeter J Voltage-dependent andodorant-regulated currents in isolated oflactory receptor neuronsof the channel catfish J Gen Physiol 99505ndash529 1992
31 Korant BD Kauer JC and Butterworth BE Zinc ions inhibitreplication of rhinoviruses Nature 248588ndash590 1874
32 Korant BD and Butterworth BE Inhibition by zinc of rhinovirusprotein cleavage Interaction of zinc with capsid polypeptidesJ Virol 18298ndash306 1976
33 Kelly RW and Abel MH Copper and zinc inhibit the metabolism ofprostaglandin by the human uterus Biol Reprod 28883ndash889 1983
34 Novick SG Godfrey JC Godfrey NJ and Wilder HR How does zincmodify the common cold Clinical observation and implications re-garding mechanisms of action Med Hypotheses 46295ndash302 1996
35 Godfrey JC Godfrey NJ and Novick SG Zinc for treating thecommon cold Review of all clinical trials since 1984 AlternTher Health Med 263ndash72 1996
36 Belongia EA Berg R and Liu K A randomized trial of zincnasal spray for the treatment of upper respiratory illness inadults Am J Med 111103ndash108 2001
37 Turner RB Ineffectiveness of intranasal zinc gluconate for theprevention of experimental rhinovirus colds Clin Inf Dis 331865ndash1870 2001
38 DeCook CA and Hirsch AR Anosmia due to inhalational zincA case report Chem Senses 25659 2000 (Abs)
39 Mossad SB Effects of zincum gluconium nasal gel on theduration and symptom severity of the common cold in otherwisehealthy adults QJM 9635ndash43 2003
40 Duncan HJ Postviral olfactory loss In Taste and Smell Disor-ders Ch 6 Seiden AM (Ed) New York Thieme 72ndash78 1997
41 Murrow BW Jafek BW and Restrepo D The use of freshcadaveric human olfactory epithelium for physiologic studyAChemS Sarasota FL April 2001 e
American Journal of Rhinology 141
people affected by this treatment could be alarmingly highThe public may assume that because intranasal zinc glu-conate is sold as an OTC ldquopatented homeopathicrdquo prepa-ration containing a ldquonaturalrdquo or even ldquoessentialrdquo elementthat it is safe This report raises important questions aboutthat generalization Because the effects appear to be some-what dose-related use of this drug in the pediatric age groupwould be expected to generate an even larger incidence ofanosmia in this population and is especially concerning
If history repeats itself and the unexpected always hap-pens how incapable must man be of learning from expe-rience
mdashGeorge Bernard Shaw (1856ndash1950)Irish dramatist
REFERENCES1 Sandstead HH and Alcock NW Zinc An essential and unher-
alded nutrient J Lab Clin Med 130116ndash118 19972 Solomons NW Mild human zinc deficiency produces an imbal-
ance between cell-mediated and humoral immunity Nutr Rev5627ndash28 1998
3 Prasad AS Zinc An overview Nutrition 1193ndash99 19954 Heyneman CA Zinc deficiency and taste disorders Ann Phar-
macother 30186ndash187 19965 Lansdown AB Metallothioneins Potential therapeutic aids for
wound healing in the skin Wound Repair Regen 10130ndash132 20026 Prasad AS Beck FW Grabowski SM et al Zinc deficiency
Changes in cytokine production and T-cell subpopulations inpatients with head and neck cancer and in noncancer subjectsProc Assoc Am Physicians 10968ndash77 1997
7 Simmer K and Thompson RP Zinc in the fetus and newbornActa Paediatr Scand Suppl 319158ndash163 1985
8 Fabris N and Mocchegiani E Zinc human diseases and agingAging (Milano) 777ndash93 1995
9 Prasad AS Zinc deficiency in women infants and childrenJ Am Coll Nutr 15113ndash120 1996
10 Hambidge KM Mild zinc deficiency in human subjects In Zincin Human Biology Mills CF (Ed) New York Springer-Verlag281ndash296 1989
11 King JC and Keen CL Zinc In Modern Nutrition in Health andDisease 9th ed Shils ME Olson JA Shike M et al (Eds) Chap11 Baltimore Williams amp Wilkins 223ndash239 1999
12 Hooper PL Visconti L Garry PJ et al Zinc lowers high-densitylipoprotein-cholesterol levels J Am Med Assoc 2441960ndash1961 1980
13 Shenkin A Trace elements and inflammatory response Implica-tions for nutritional support Nutrition 11(1 suppl)100ndash105 1995
14 Berg RH I can stop the virus In Polio and Its Problems Ch 5Berg RH (Ed) Philadelphia Lippincott 34ndash47 1948
15 Rutty CJ The middle-class plague Epidemic polio and the Cana-dian state 1ndash36-1937 Can Bull Med Hist 13277ndash314 1996
16 Tisdall FF Brown A and Defries RD Persistent anosmia fol-lowing zinc sulphate nasal spraying J Pediatr 1360ndash62 1938
17 Harding JW Getchell TV and Margolis FL Denervation of theprimary olfactory pathway in mice V Long-term effects ofintranasal ZnSO4 irrigation on behavior biochemistry and mor-phology Brain Res 140271ndash285 1978
18 Cancalon P Degeneration and regeneration of olfactory cellsinduced by ZnSO4 and other chemicals Tissue Cell 14717ndash7331982
19 Moran DT Rowley JC III Aiken GR and Jafek BW Ultrastruc-tural neurobiology of the olfactory mucosa of the brown troutSalmo trutta Microsc Res Tech 2328ndash48 1992
20 Hirt M Nobel S and Barron E Zinc nasal gel for the treatmentof common cold symptoms A double-blind placebo-controlledtrial Ear Nose Throat J 79778ndash780 782 2000
21 Linschoten M Harvey LO Jr Eller PM and Jafek B Fast andaccurate measurement of taste and smell thresholds using amaximum-likelihood adaptive staircase procedure Percept Psy-chophys 631330ndash1347 2001
22 Schultz EW Immunity and prophylaxis in poliomyelitis JAMA1072102ndash2104 1936
23 Schultz EW and Gebhardt LP Zinc sulfate prophylaxis in po-liomyelitis JAMA 1082182ndash2184 1937
24 Peet MM Echols DH and Richter HJ The chemical prophylaxisfor poliomyelitis The technique of applying zinc sulfate intra-nasally JAMA 1082184ndash2187 1937
25 Shahinian L Bacher JA McNaught RC and Newell RR Che-moprophylaxis in poliomyelitis JAMA 1101254ndash1257 1938
26 Ashley RE Chemoprophylaxis against impending poliomyelitisArch Otol 29104ndash114 1939
27 McBride K Slotnick B and Margolis FL Does intranasal applica-tion of zinc sulfate produce anosmia in the mouse An olfactometricand anatomical study Chem Senses 28659ndash670 2003
28 Matulionis DH Light and microscopic study of the degenerationand early regeneration of olfactory epithelium in the mouseAm J Anat 14579ndash99 1976
29 Mayer AD and Rosenblatt JS Peripheral olfactory deafferenta-tion of the primary olfactory system in rats using ZnSO4 nasalspray with special reference to maternal behavior Physiol Behav53587ndash592 1997
30 Miyamoto T Restrepo D and Teeter J Voltage-dependent andodorant-regulated currents in isolated oflactory receptor neuronsof the channel catfish J Gen Physiol 99505ndash529 1992
31 Korant BD Kauer JC and Butterworth BE Zinc ions inhibitreplication of rhinoviruses Nature 248588ndash590 1874
32 Korant BD and Butterworth BE Inhibition by zinc of rhinovirusprotein cleavage Interaction of zinc with capsid polypeptidesJ Virol 18298ndash306 1976
33 Kelly RW and Abel MH Copper and zinc inhibit the metabolism ofprostaglandin by the human uterus Biol Reprod 28883ndash889 1983
34 Novick SG Godfrey JC Godfrey NJ and Wilder HR How does zincmodify the common cold Clinical observation and implications re-garding mechanisms of action Med Hypotheses 46295ndash302 1996
35 Godfrey JC Godfrey NJ and Novick SG Zinc for treating thecommon cold Review of all clinical trials since 1984 AlternTher Health Med 263ndash72 1996
36 Belongia EA Berg R and Liu K A randomized trial of zincnasal spray for the treatment of upper respiratory illness inadults Am J Med 111103ndash108 2001
37 Turner RB Ineffectiveness of intranasal zinc gluconate for theprevention of experimental rhinovirus colds Clin Inf Dis 331865ndash1870 2001
38 DeCook CA and Hirsch AR Anosmia due to inhalational zincA case report Chem Senses 25659 2000 (Abs)
39 Mossad SB Effects of zincum gluconium nasal gel on theduration and symptom severity of the common cold in otherwisehealthy adults QJM 9635ndash43 2003
40 Duncan HJ Postviral olfactory loss In Taste and Smell Disor-ders Ch 6 Seiden AM (Ed) New York Thieme 72ndash78 1997
41 Murrow BW Jafek BW and Restrepo D The use of freshcadaveric human olfactory epithelium for physiologic studyAChemS Sarasota FL April 2001 e
American Journal of Rhinology 141
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