`Treatment of Onychomycosis: 2delaleuca alternifolia
`(Tea Tree) Oil and Clotrimazole
`David S. Buck, MD, MPH; David M. Nidorf, MD; and John G. Addino, DPM
`Roch~er, 2Xrcw York, and Davis, California
`
`,,, . , i iii iiii
`
`.Background. The prevalence of onychomycosis, the
`nost frequent cause of nail disease, ranges from 2% to
`13%. Standard treatments include debrldement, topical
`medications, and systemic therapies. This study assesses
`the efficacy and to!erability of topical application of 1%
`dotfimazole solution compared with that of 100%
`]ffdaIeuca alternifblia (tea tree) oil for the treatment of
`toenait onychomycosis.
`
`2ffctho~. A double-b!knd, multicenter, randomized con-
`trolled trial was performed at two pri_maq¢ care health
`and residency, training centers and one pdvate podia-
`trlst’s once. The Partidpants included 1!7 patients
`with distal subungual onychomycosis proven by cul-
`ture. Padcnts received twice-daily application of either
`1% clotrimazo!= (CL) solution or 100% tea ~ (TT)
`oil for 6 months. Debridement and clinical assessment
`were performed at 0, 1, 3, and 6 months. Cultures
`were obtained at 0 and 6 months. Each patient’s sub-
`jcctive assessrr~nt was also obtained 3 months after the
`°~-onctusion of therapy.
`
`RmMt~. The b~tine characteristics of the treatment
`groups did not differ significantly. After 6 months of
`therapy, the two treatment groups were comparable
`based on culture cure (CL = 11%, TT = 18%) and
`clinical msessment documentirlg partial or flail resolu-
`tion (CL = 6!%, TT = 60%). Three months later,
`about one half of each group reported continued im-
`provement or resolution (CL = 55%; TT = 56%).
`
`Conclusions. All era-rent therapies have high recur~mce
`rates. Ora! therapy has the added disadvantages o£ high
`cost and potentially serious adverse effects. Topical
`therapy, including the two preparations presented in
`this paper, provide improvement in nail appearance
`and symptomato!ogy. The use of a topical preparation
`in conjunction with debridemem is an appropriate ini-
`treatment strategy.
`
`Kty words. Onychomycosis; mycoses; nails; nail dis-
`eases; clotrimazole; administration, topical. ,
`(J Ftvn Pruct 1994; 38:601.605)
`
`i i
`
`H.
`
`The prevalence of onychomycosis, the most frequent
`cause of nail disease, l-s ranges from 2% to 13%. Orq-
`chomycosis is caused by dermatophyte infections, the
`most common of which is Trixh0phyton rubrum; yeast
`(Ca.ndida spp); and occasionally molds, Three treatment
`modalities are available: debrldement to eliminate af-
`fected keratin, topical medications, and systemic therapy.
`Topical therapy may have limited effectiveness because of
`poor penetration of the medication into the nailA.s
`
`Oral therapies, begirmkng with griseofulvin in 1959,
`have been the "gold standard" treatment for derrnato-
`phyte onychomycosis.6 Unfortunately, cure rates with
`gr]seofi.dvin range from 3% to 38%, and although rares
`may be higher when combined with toenail avulsion or
`topical medication or both, no significant follow-up data
`exist for these combined modafities,r-9 Ketd~:onazole is
`attractive because it presumably treats yeast as wee as
`dermatophyte onychomycosis and shows a cure rate of
`50% to 93% at I year, S,*o,n which is much higher than
`that ofgriseofidvin. Although side effects are rare, they
`can include pruritus, idiosyncratic’ liver dysfimctlon,~
`and gynecomasda.~0 Furthermore, about 50% of toenail
`infections recur 4 years after the completion of treat-
`"mentA~ Itraconazote has cure rates ranging from 4% to
`92% with potentially fewer side effects, l~-~ ¯ but ~us far,
`
`i~94 Ap~k’~ & ~ge
`
`ISSN ~094-35~)
`
`The Journal o£ Family Practice, Vol. 38, No. 6Oun), 1994
`
`" 6o!
`
`ARGENTUM EX1036
`
`Page 1
`
`
`
`Treamaen~ of Onychomycosis
`
`Buck. Nidorr’, and Addino
`
`it has been evaluated only in small studies. Follow-up
`data beyond 1 year are unavailable. Fluconazole has been
`used by some physicians for both short- and long-term
`treatment, but no randomized controlled trials have been
`pertbrmed. Outside the United States, much recent re-
`search has focused on orat terbinafme (Lamisit), an active
`fungicidal agent. Cure rates range from 37% to 82% at
`6-month foUow-up, with a treatment period as short as 2
`weeks~v to 3 months.2°-24 Once again, long-term results
`and side effects are unknown. Only the topical form of
`terbinafine has been approved in the united States.
`In light of the varied cure rates, potential adverse
`effects, high cost, and significant recurrence rate of oral
`treatmen%2s effective topical therapy would be desirable
`as primary therapy or for augmentation of systemic ther-
`apies. Although the topical imidazole preparations are
`commonly used,t their efficacy has not been assessed in
`controlled trials. In a limited study, clotrimazole has been
`reported to be of mild benefit in :he treatment of onv-
`chomycosis.~6 Or~her imidazole preparations used in
`combination with nai! removal have resulted in one re-
`port of cure in 13 patients,s
`Nail tinctures and lacquers are also being tested with
`promising results.27 The tincture or lacquer is thought ro
`provide betzer nait penetration. Several recent studies
`have examined amorolfme 5% nail lacquer.28-30 One
`large study (N = 456) realized cure rares in the 50% to
`74% range.a0
`Tea tree oil comes from a shtublike tree in Australia
`known as lgelMeuca Mternifolia, It was named by Captain
`Cook, who observed the aborigines brewing these leaves
`for medicinal purposes. In World War I, it was used in
`first-aid kits for Australian troops to treat bums, bites,
`and infections. The active ingredient, Terpinen-4-oi, has
`both antibacterial and antifungaI properties.31.m Mmy
`brief studies have found this popular home remedy suc-
`cessfial in treating a variety, of ailments: tinea pedis and
`onychomycosis,33a4 trichomonal vaginitis,~s and ache36
`(the latter the subject of a randomized controlled trial).
`Tea tree oi! is available over the counter at most health
`food stores at a cost comparable to that of clotrimazole
`solution. We report a muldcenter, randomized, double-
`blind study to compare the efficacy of two topical prep-
`aratlons, tea tree oil and 1% elotrirnazoie solution, for
`the treatment of toenail onychomycosis.
`
`Methods
`
`Either I% clotrimazole solution or 100% tea tree oil was
`applied to the affected nail(s) twice daily for 6 months.
`
`Study Participant Crire,qa
`
`?dl patients presenting ro one of three sites between tune
`1991 and December 1991 with distal subungual toe
`onvchomvcosis proven by culture were enro!led. Patients
`were excluded if they had had immune-suppressant ther-
`apy within the previous 6 months, had used a topical
`agent: on the toenails in the previous 2 weeks, had a
`history, of psoriasis, or had known human immunodefi-
`ciency virus (HI’V) infection.
`
`Drag Treatment
`
`Patients were randomly assigned to receive I% clotrim-
`azole solution (Schering-Ptough Corp, Liberty Comer,
`NI) or 100% tea tree oil (Thursday Plantation Inc,
`Montecito, Calif). Solutions were received directly from
`the manufacturers. The Highland Hospital pharmacy.
`filled 60-cc standardized bordes with solutions ofctotri-
`mazote and of tea tree oil that appeared identical. The
`treatment groups were randomized by the phamiacy by
`means of a computerized random-number generator.
`The type of medicittion was blinded to both patient and
`provider. The patients were instructed on how to apply
`the medication top’fcally with a swab to all affected nails
`twice daitv. At the 1-, 3-~ and 6-month checkups, the
`patients’ nails were trimmed and debrided by the physi-
`cian, using straight-edged nail clippers. ,amy adverse re-
`actions were recorded. Compliance was encouraged by
`mailings and telephone calls, by recording the number of
`missed applications, and by reminding patients at each of
`their four visits of the importance oftavice-daity medicine
`application.
`
`There were three primary measures of outcome: culture,
`clinical assessment, and the patient’s subjective assess-
`ment (Table !). At the 6-month vi,siq repeat nail cutmres
`were performed. The de rmatophyte infection test me-
`dium was chosen because it achieves better than 97%
`diagnostic accuracy, and has a tow false-positive rate.w,38
`All three investigators standardized the method of nail
`debridement and use ofcutmre medium by organizing a
`protocol used by other investigators,aT-sg-~° The optimal
`technique for yielding an accurate mtture for distal sub-
`ungual om, chomvcosis is debriding to the healthy nail,
`scraping the debris with a curette (No. 15 blade) or small
`spatula, and inoculating the culture with the debris.<~,~i
`At the rime of the 6-month final culture, patients were
`requested to abstain from usin} the topical preparation
`for 48 hours before their visit to prevent false negatives.
`At the i-, 3-, and 6-month visits, the physician
`
`602
`
`The Journal of Family Practice, Vol. 38, No. 6(jun), t994
`
`2
`
`Page 2
`
`
`
`eatment of Onyc.homycosis
`
`Buck, Nidorf. and Addino
`
`bte t. Characteristics of Paticnu Treated Twice Daily with
`CIorAmazole Solution or. 10096 Tea Tree Oi! for Toenail
`kvchomycosls
`
`,ara~erisrdcs
`
`:sto@" of diabetes, %
`
`[story. oft~uma, %
`
`mil~ %
`
`.’e:’ag¢ age, y
`
`ill ~,.aL~ for more than I
`re;
`
`atrure r~ul~, %
`THehopbyr.~n rubrum
`Tr’~o~@ men:aSn~0/~
`
`Treated with
`Ctowimazole
`(n = 53)
`!9
`
`Treated with
`To Trc~ Oil
`(n = 64)
`t4
`
`8
`
`72
`
`59
`
`92
`
`77
`19
`
`6
`
`77
`
`61
`
`92
`
`83
`13
`
`:corded "full," "partial," or "no" resolution by appear-
`~ce of the index nail (the nail with the greatest fimgal
`urden at the time of entry into the study). In addition,
`[1 patients were telephoned 3 months after the conclu-
`on of the study. They were asked by a research assistant
`’hether their nail appearance and s)Tnptomatotogy (pru-
`"tis and p~) had resok, ed, improved, stayed the same,
`r worsened.
`
`:at ’e size calculations assumed a base cure rate of
`0~ ising c!or_Hmazole in order tO detect a cure rate
`vith tea tree oil of at least 30%, with alpha set at .05
`one-tailed) and beta set at °8.42 This calculation yielded
`¯ sample size of 52 per group, allowing for 10% loss to
`bilow-up.
`
` esults
`3he hundred seventeen patients (CL = 53; TT = 64)
`,vere randomly assigned to a treatment group. Stria
`"andom ass@lment was adhered to throughout the
`;rudy. The baseline characteristics of the treatment
`Uoups did not differ significandy (Table 2). Cultures
`.vere positive (excluding contaminants not considered
`?ositive) for predominantly ~vo species: THc..bophyron
`~ubrum (80%), T mentagrophytes (16%), and other (4%).
`Five (4%) of the 1!7 patients were dropped from
`:.he study because they had moved or their telephone had
`been disconnected (4 of 53 CL; I of 64 TT). Adverse
`reactions included erythema and irritation (most corn-
`
`Table 2. Results of 6 Months of Treao’nenr with I%
`Clotximazole and 100% Tea Tree Oil
`
`Re~uk
`
`Ctotrimazole
`Treamaent
`Group
`n (%)
`
`Cukur¢ nelctativ¢ at end of therapy
`
`4 (1 I)
`
`Tea Tree Oil
`Treamaent
`Group
`n (%)
`7 (18)
`
`Full or par’dal resolution at end of
`~e:apv
`
`22 (61)
`
`24 (60)
`
`FuiI or paixil! resolution 3 months
`2tier conclusion of ~heraW
`
`27 (55)
`
`33 (56)
`
`mon) and edema. Adverse reactions occurred in 7% (3 of
`53 CL; 5 of 64 TT), resulting in four (3%) of the
`origina! 1 I7 participants dropping out of the study.
`Chi-square statistica! anal}sis failed to reveal any
`significant differences bet’ween the two treatments for the
`culture being negative at 6 months, climcal assessment at
`6 months, or telephone follow-up 3 months after study
`completion (Table 1).
`
`Discussion
`
`This multicenter, double-blind, randomized dinlcal trial
`was designed to assess and compare the efficacy, and
`tolerabiliW of topical application of I% ctotrimazote
`solution vs 100% tea tree oil for the treatment of toenail
`onychomycosis. The two preparations were comparable
`in efficacy of cure, clinical assessment, and subjective
`improvement. Their cost is also comparable. One half to
`two thirds of the study patients showed improvement in
`both clinical assessment and subjective rating of nail
`appearance and symptomatolog’y.
`Our study yielded results similar to those of other
`studies.43 Cure rates in the 10% to i5% range have been
`found with a propylene glycol-urea-lactic acid solu-
`tion,** and with ciclopiroxotamine.4S-~ Even higher cure
`rates have been found with other treatments: 30% to :
`60% with urea*bifonazote solution47-~9; 42% with na~-"
`titine hydrodfloride gelSO; 64% to 84% with amorotf-
`i~e,s* and 50% to 74% with amoroitin¢ lacquer.~0
`The principal t~tation of the study was the 35%
`loss to culture follow-up. However, in a comparison of
`the partieipa~ts who either did or did not show up for
`the &month culture, no statistically s@nificant differ-
`ences were found at the 3-month posrtreatment tele-
`phone follow-up. Given the improvement reported at
`telephone follow-up in both groups (chose who did and
`those who did not attend their 6-month visit), the lack of
`follow-up does not appear to be related to outcome. A
`
`~’~e 1ournal of Fatuity Practice, Vol. 38, No. 6(Jun), 1994
`
`60:~
`
`Page 3
`
`
`
`Treawnent of Octychomycosis Buck. Nidorl~ and Add!no
`
`potential limitation of this s~dv was that no photo-
`graphs were taken of the nails, bu~ this is unlikely to have
`led to bias since this Jar=or affects each group equaUy.
`Some investigators have discouraged the use of the der-
`matophwce infection test medium for culture41,~ because
`of the potendai for contamination, bur in our study, this
`concern was resolved by using nail debris rather than nai!
`clippings,s7.~8
`Three additional interventions may have improved
`the outcome: simultaneous use of muldpte oral and top-
`ical agents, longer treatment ~mes, and a keratoivdc
`agent, such as DMSO, or other agems that improve nail
`penetration of the medication.
`One potential reason for the poor long-term benefits
`of any therapy is that it may be treating only a manifes-
`tation of underlying disease(s), such as generalized im-
`mune suppression’or peripheral micro- or macrovasealar
`disease. !n a study of 400 padents, Forckss looked at the
`"relationship between b!ood Circulation of the skin and
`the development of fi.mgus disease" and found a greater
`than 50% reduction in blood flow in patients with tinea
`pedis and onychomycosis as compared with patients
`wit.hour these ~orders. If onychomycosis is a s)nviptom
`of an underlying process, then treatment aimed at era&
`!cation of a pathogens4 may be unrealistic. A more ap-
`propriate goat may be the amelioration ofs)~ptoms and
`the improvement of nail appearance.
`Topical and oral therapies have high recurrence
`rates. Oral therapy has the added disadvantages of high
`cost and potentially adveme side effects. Topical thera-
`pies, including the ~vo preparations presented in this
`paper, provide significant improvement in nail appear-
`ance and symptomatology for over one haft of all sub-
`jeers. The use of a topical preparation in conjun~on
`with debridement is an appropriate inidal trean’nent
`strategy.
`
`Acknowledgments
`
`Scherlng-Hough Corp in Libe~(cid:128) Corner, Nc~v Jer~’, ~d Thursday
`Plantation tnc, in Momecko, California. provided technical
`finand~l support,
`We ~r¢ indebted aim to Dr Peter Frank* for ~¢¢hnleal advice, muldpl¢
`rcviovs, and ~sistanc¢ with svady dczign;, to Dr Peter Brod¢fiek and
`Dr Jay N.M.I. Hegde for ro-ivadng the manugripr: and to Silly.
`Ko~u, for her a~istance with data entry ~nd evaluation.
`
`Keferences
`
`1. Andre L Achtca G. Onychomycosis, Int I Dermztol" 1987; 26:
`481-90,
`2. Walshe MM, Engtish MP. Fungi in naiB. Br j" Dermatot 1966;
`78: I98-207.
`3. Roberts DT. Prcv£encc of dermamphy~c onychomycosis in the
`
`United Kingdom: rcsules of an omnibus survey. Br } Dermami
`t992; 126(suppl 39):23-7.
`4. Zaias N~ Onychomycosiso In: The nail in health and disease. New
`York: 8~xnsm Publications, t980:9t-1 i3.
`5. Hetfinger D. V£inskx/5I, Treatment of onychomycosis with nail
`avulsion and ~opieal kctoconazol¢, l Am Podiatr "deal Asso¢ 1991;
`81:28-32.
`6. Davies RK, Everail JD. Hamilton E. Mycologicai and clinical
`~,afuadon ofgriS¢othMn for chronic onychomycosis. BMJ I967;
`31464-8,
`7. Blank H, Ruth FJ Jr, Smith JG, ct aL The trc~lxncut of derma-
`tomycusis with orallv adminis~c~d gri~cofiaivi~. ,~MA Arch Der-
`matol i9591 79:259-6&
`8. Kordng HC, 5chafer-Cutting M. Is tinea un~ium still wideiy
`incurable? .~:h Dermaroi 1992; 128:243,-8,
`9. Hay Rl, Chymn YM, Moore MK. A comparison of do~onazole
`28% nail solution vet, us bay: as an adjunct to oral gdscothh-in in
`pafienu with onychomycosis. Clin Exp D¢craa~ol 1987:. f2:
`175--7.
`10. Hotub P, Hubbard E. Kctoconazoic in the treatment ofonycho-
`mvcosis~ J Am Poddatr Med .Ks~a~: I987; 77:331-9.
`1L H’anifin L Keroconazol¢ in the management of fungal di~a.~.
`B:dgowllah, Australia: Adis Pr~, 1983:156-9.
`12. Knight "I’, Shikuma C, Knight J. KctoconazoIe-induced fialmJnant
`hepatitis necessitating liver transplantation. J .Mat Acad DcrmaroI
`I991; 25:398-400.
`13. Torok I, Stehlich G. Long-term post treatment followup ofony-
`chomvcosis treated with ket~onazote, Mvkosen 1986; 29(8):
`372--7.
`t4. Ha), KJ, C|a~on YM, Moore MK, Midg!%’ G, ,~"; evaluation of
`itraconazole in the management ofonychomy¢osis, Br J Dermatol
`1988; 119:359-66.
`1S. Walsoc I, Strangerup M, Svejgaard E, ltraconazole in onychomy-
`cosis. Ac~a Deem Venereol (Stock.h) 1990; 70:137-40.
`16. Arenas K, Fernandez G, Domlngu~z L. Onychomycosis treated
`with kraconazoie or gris¢o~vin alone with and without a topical
`antim¢~:odc or keraroh’fi¢ a~ent~ tnt I Demaatot t991; 30:586-9.
`17. Piepponcu T, Blomqv’isr K.~Brandr H, et ft. Efficacy and safeq:" of
`irracon.xzolc in the longqerm treatment of on vchomycosis. J An-
`dmicrob Chemother 1~)2; 29:195-205,
`18. Degrcef H, Onychomycosis. Br J Clin Pract 1990; (suppl 71):
`91-7.
`1% Munro CS, Kecs IL, Shmter S. The un~p¢¢tcdly rapid respome
`of fi2rlg’aJ halt inf¢ctlon to short duration ~2aerapy, Acta Derm
`Venereot (Stockh) 1992; 72:131-3.
`20. Good~¢Id MID, KoweU NIL, Forstcr tL~ Evae, s EG, Kaven A.
`Trcatm~r of dermarophyte infection of the finger and tocnaits
`with terbinafine (SF 86-327, Lamisi!), an ora~y a~ve fimgiddat
`~gent. Br J Dermatol 1989; 121:753-7.
`21. Vaa dct Sc~ro¢ff JG, Cirkd PKS, ct al, A randomized treatment
`duration-finding srady ofterbinafine in onychomycosis. Br J Der-
`matot 1992; 126(suppt 39):36-9.
`22. Goodfidd MJ. Shorvduradon therapy with terbinaline for d~-
`matophvte onvchomvcosis: a multiccntre trial. Br I Dcrm~tot
`I9921 i’26(sul~pt 39)-33-5.
`2K Baudraz-P, os~lct F, Rakosi T, et al, Treatment of onychomycosis
`with terbinafine~ Br J Detmato! 19<)21 126 (suppl 39):ar0-6,
`24. GoodEeld MID, Andr~v L, Evans EGV~ Short term treatment of
`dermatoph.vte onychomycosis with tebinafine. BMI 199.2; 304:
`1151-4.
`25. Hay RJ. The current status of the andmycorics in the tream~¢n~ of
`[~J mycoses. Acta Detm Venercol (Stock, h) I986; 66(Suppt
`t21):103-8.
`26. Mahgoub ES. Clinical trials with ¢totdmazotc cream (Bay b 5097)
`in dermatophytosis ~d onychothycosis, Mycopathologia 19751
`56(3):149-52.
`27. Meyerson MS, Scher ~ Hochman LG~ et aL Olxn-labcl study of
`the safcw and the ¢fflcac’¢ of fungoid dncture in patients with distal
`s~abungua! onyehomvco’sis of the tc~, Cuds 1992:. 49:359-62.
`28. Pirtrof F, Gerhard~ j, Emi W, ct al. Loceryt naiI lacquer--reati~-
`
`604
`
`Tt~¢ Journal of Family Practice, VoL 38, No. 6(Jun), 1994
`
`4
`
`Page 4
`
`
`
`Treaunent of Om, chomv¢osis Buck, Nidorf, and Addino
`
`don of a new gaicnical aoproach ~o onvchomvcosis therapy. Clla
`Exp Dermatol 1992; 17(’suppl 1):26-8. "
`29. Mensing H, Polak-Wy~s .~ Splash:mann V, D¢:¢rmJnatioo oft.he
`subungud amiKmgat activie:, ofarnocolfin¢ ~a:~e* 1 month’s rrea:*
`ment in patients with onvchomycosis: comparison of two na:~
`lacquer formulations. Clin’Exp Dermatot 1992; t7(suppl t):29-
`32.
`30. Kcinel D. Topical treatment of" onychomycosis with ~oroL~r~c
`5% ndl lacquer: comparative eff~ca~, and tolerabiiiW of once ~’~d
`twice weekly use. Dermatology 1992; 184(suppl t):21-4.
`3 i. Ar.klnson N~ Antibiotics in Australian plants and funS. Med J Aust
`1949; h605-i0.
`32. Mamzzdh JC, Liguori L. The in ~itro andfim~ actMn" of
`esscnrhl oils. J Am Pharm Assoc 1958; 47:250-4.
`33. Walker M. A successful anfifimg~l regime, Curt Podiau’y 1962;
`8:i6-9.
`34. Waiker M. Ctinkal im.esdgadon of .australian ;~&/a!tuca a/rtrn~-
`!ia oil for a vafieW of common foot problems. Curt PodiauT 1972;
`2:7-15.
`35. Pena EF. Mda&uza a/romi~lia oil, ~.ses for trichomond va~tls
`and other vaginal infections. Obstet Gvnecot i962; 19:793-5,
`36. Bassert LB, Pannowitz DL, Bametson 1~C. Acomparatlvc study of
`tea-~ec oil versus benzoylperoxide in the ~’eamaent of ache. Med )’
`Aust 1990; 153:455-8.
`37. Pariscr DM. Super£cid fimgal infections. Postgrad Med 1990;
`87:205--14.
`38. TapL[n D, Zaias N, Kcbell G, Blank H. Isolation and recognition
`of derrmtophytea on a new medium (DTM)..~c~h Derma~ol
`1969; 96:203-,9.
`39. Pariser D, Caserio K, EagLs~e[n W. T~hniqu~ for diagnosing skin
`and hair disease. 2nd ed. New York: Thierac tnc, 1986:31-9.
`40, Suarez SM, Sih,ers DN. Scher KK, et :d. Histological evaluation of
`nail clippings for diagnosing onychomp:osis. Arch Dermatol
`1991; 127:t517-9.
`
`41. Dardd CK Iit, Lawson L. Tinca unguium. Cuds 1987; 40:326-7.
`42. Cohen J. Sta~sdcal power analysis for the behavioral sciences. New
`York: .academic Frem, 1992.
`43. Tulli A, Kuffdi MP, De.Simon: C_. The treamaent ofonychomycosis
`with a new form of do¢onazole. Chem]oterapla 1988; 7:160-3.
`44. Facrgcmann J, Swanbeck G. Treatment of onydnomycosi~ with a
`prowfene glycoburea-lacdc acid solution. Mycoses 1988; 32:
`536-40.
`45. Wu YC, Chuan MT, Lu YC. E~cacy. of cidopiroxolamlne 1%
`cream in onychomy¢osis and tinea pedis. Myco~ 1991; 34:93-5.
`46. Baodan Y, Guangj{ 7., Baoxi W, et al. A cllnical and laboratory.
`study of dctopiroxotamine (8% batr~qn) in the treatment of
`onychomvcosis. Chin Med Sci I 1991; 6:166-8~
`47. Hay KJ, koberts DT, Dohc~.’ VK, Kichardson MD, Midgley G.
`The topical treatment of onychomycosis ~mg a new combined
`urew%-aidazole preparation. Clin Exp Dermatol 1988; 13:164-7.
`48. Noltings S. Onychomycose~ and their successful therapy. Wien
`Med Wochenschr 1989; 139:854-5.
`49. Hardjoko FS, Widyanto S, Singgih ~ Susilo J. Treatment of
`onychorr~icosis with a bifonazolc-urea combination. Mycoses
`1990; 33:167-7L
`.50. Klaschka F. Treatment of on)~-~omy¢ods with na_¢titine ge!. My-
`cosen 1987; 30(suppl 1):i19-23.
`51. del Pahdo .K, Lopez-C.-omez S, Garda.Bravo M, ct aL E.xperienc~:
`with amoroffme ha the rream~ent of dermatomycoses. Dermatof
`ogy 1992; 184(suppl 1):25-9.
`52. Daniel CR ItL The diagnos~s of halt fimgal infeaions, Arch
`Dcrmatol 1991; !27:1566-7,
`53. Forck Go Rehdonship between the blood circuIadon of the skin
`and the devdopment of fungus disease. Zemat Bah Parasitkde
`1970; 212:544:-53.
`54. Roberts DT. Current therapy, for onychomycosis. J Detmatol
`Treatment 1990; t(suppt 2):49-50,
`
`The ]oumai of Family Practice, Vol. 38, No. 6(Iun), 1994
`
`605
`
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