Preliminary and Short Report

TOLNAFTATE THERAPY OF MYCOTIC INFECTIONS

PRELIMINARY REPORT*

HARRY M. ROBINSON, JR., M.D.ANDJOAN RASKI N, M.D.

Prior to the introduction of the systemic use ofnaphthylthiocarbamate, was used in the treatment griseofulvin for the treatment of selected super-of 23 patients but study with this compound was ficial mycotic infections, there was no satisfactorydiscontinued because it proved to be only fungi- method of management available. Although greatstatic whereas tolnaftate is fungicidal. These com- claims had been made for some of the topicalpounds are soluble in organic solvents but are proprietary preparations, at best they were provedvirtually insoluble in water. The preparations as to be only palliative, the main virtue being thedispensed were odorless and colorless. keratolytic effect produced by them. In spite of The toxicity to man on topical application or on the fact that there is a low incidence of adverseoral administration is virtually negligible (1). reactions to griseofulvin, the problems of photo-Tolnaftate proved to be totally ineffective on oral sensitivity, gastrointestinal disturbances, head-and parenteral administration. In laboratory ani- ache, etc. are still encountered. Topically appliedmals the drug was found to have no pharmacologic griseofulvin, regardless of the excipient used, is ofaction on the cardiovascular apparatus, the questionable value. It is evident that an efficientcentral nervous system, or the respiratory ap- topical fungicidal or fungistatic agent with a lowparatus. The results of these studies by Japanese incidence of sensitivity reaction would be of in-investigators (1) have been confirmed in the estimable therapeutic value. United States by similar experiments (2). If per- During the past ten years, Japanese scientistscutaneous absorption of tolnaftate does occur, (1) have assayed more than 3000 topically appliedthe possibility of organic damage is negligible. compounds for toxicity and antifungal activity. Patient selection: Those included in this study In 1960 a group of agents with antifungal prop-were diagnosed and treated in the out-patient erties was derived from 0-2-naphthyl-N-inethyl-dermatology clinic of the University of Maryland thionocarbamates. The most promising compoundand the authors' private practice. The range in of this group proved to be 0-2-Naphthyl m, N-di-age was from 9 to 70 years. White and Negro pa- inethylthiocarbanilate. tients of both sexes were included. This drug, in two dilutions, one of its congeners, Treatment was initiated in 96 patients but of and a control were submitted under blind label forthis number, seventy five completed the prescribed clinical and laboratory investigation. This reportcourse. Direct microscopic examinations were contains the results of the preliminary study. positive for hyphae in all patients before medica- tions were prescribed. Cultures on Sabouraud's METnons AND MATERIALS medium were obtained from all of them at the The drugs: Supplies of four different prepara-time of the initial visit, except the six who had tions, in identical plastic containers, labelled A.tinea versicolor. Culture results from the other B, C, and D were delivered for study. The codesixty-nine patients who completed treatment were was contained in a sealed envelope which was notas follows: opened until a sufficient number of patients had Trichophyton rubruin 49 been treated to allow conclusions to be drawn. Candida albicans 3 The plastic squeeze bottles had narrow openings Epidermophyton floccosuni 2 to permit drop control of the medication. The Trichophyton mentagrophytes 2 control used was polyethylene glycol 400, the Microsporum audnuini 1 solvent used for the active agents. Each of the Conta,ninated cultures (organism not 12 preparations and the control were identical in identified) appearance and consistency. The twelve patients from whom the twelve The major portion of this study was performed contaminated cultures were obtained had clinical with tolnaftate (0-2-Naphthyl m, N-dimethyl-lesions of tinea corporis on the trunk. thiocarbanilate) using dilutions of 1.0% and Both local and disseminated lesions were pres- ent in the patients included in this series. The 0.5%. A congener, 0-2-naphthyl-N-methyl-1 -distribution of lesions and diagnoses were as shown in Table 1. Receivedfor publication September 27, 1963. Procedure: After the diagnosis of a mycotic in- *Fromthe Division of Dermatology of thefaction was established by direct microscopic cx- Department of Medicine, University of Marylandamination, a culture was made and the selected School of Medicine, Baltimore, Maryland. The drugs used in this study were furnished bymedication furnished to the patient with instruc- John A. Leer, Jr. M. D. of the Schering Corpora-tions to apply a thin fibn twice daily to the in- tion, Bloomfield, New Jersey. volved areas with a gentle rubbing motion. Solu- 185 186 THEJOURNAL OF INVESTIGATIVE DERMATOLOGY

TABLE 1 was used in the treatment of 3 of these patients and preparation "D" (0.5% tolnaftate solution) Number was administered to the other two. Relief of sub- of Location of Lesions Coltore Patients jective symptoms occurred in all 5 patients in from 24 to 72 hours and involution of lesions was complete in from 2 to 3 weeks. The "B" and "D" 14 groins Trichophyton rubrum solutions produced identical results. 2 Candida albicans Tinea versicolor: Four of these patients were 4 Contaminated culture treated with "B" solution and 2 with the "D" 4 one or both Trichophyton rubrum solution. After a period of 2 to 3 weeks, there was hands partial to complete disappearance of scale from 10 one or both Trichophyton rubrum the lesions but in all instances, in spite of clinical 3 feet Contaminated culture improvement, direct microscopic examination was positive for Malessezia forfur. 2 Trichophyton menta- Moniliel infections: One patient with candida grophytes albieans infection between the toes was treated 1 Candida albicans with solution "A" (the congener) and 2 patients 1 Epidermophyton with candida albicans infections of the groins fioccosum were treated with solution "B" (1% tolnaftate 11 body or extre-Trichophyton rubrum solution). There was no evidence of clinical im- 1 mities Epidermophyton provement in any of these 3 patients after 2 weeks floccosum of treatment. 2 Trichophyton rubrum infections: Sixteen pa- Contaminated culture tients with Trichophyton rubrum infections were 4 toenails or Trichophyton rubrum treated with solution "A" (the congener). Six of fingernails these had interdigital involvement of the feet, 1 scalp Microsporum audouini two had lesions on the trunk, three had tinea 5 bands and feetTrichophyton rubrum cruris and two involvement of the toenails. In 1 Contaminated culture four other patients who had lesions clinically 1 groins and Triehophyton rubrum characteristic of Trichophyton rnbrum infections, 2 feet Contaminated culture the initial culture was contaminated although the 6 tinea versi- No culture direct microscopic examinations were positive. color on These patients were also treated with solution "A". After one month of treatment no appreciable body change was observed in the toenail lesions and therefore treatment was discontinued. Relief from itching occurred in from 24 to 72 hours in all of tion "C", found by clinical trial to be the non-the other patients. The interdigital lesions showed medicated placebo, was given to five patients.improvement in one week and in all instances dis- When no improvement was noted with solutionappeared in 2 to 3 weeks. Lesions on the trunk, "C" after one week, solution "B" or "D" wasgroin and extremities showed marked improve- administered. Solution "A", later proved toment during the first week of treatment and be the fungistatic congener and subsequentlycomplete clearing in from 2 to 4 weeks. There was dropped from the study, was prescribed for 23clinical relapse of groin and trunk lesions in 3 patients. Three patients in this latter group hadpatients who subsequently responded to treat- recurrence of lesions and were subsequentlyment with solution "D". No evidence of irritation treated with the "D" solution (0.5% tolnaftate).or hypersensitivity developed from the use of this This solution was also given to 23 additional pa-solution. tients. The "B" solution (1.0% tolnaftate) was Solution "B" (1% tolnaftate) was used in the used in the treatment of 29 patients. Post-treat-treatment of 16 patients with Trichophyton robrunt ment direct microscopic examinations were per-infections. Six additional patients whose initial formed on the 6 patients who had tinea versicolor.culture was contaminated but who had clinical Post-treatment cultures were made from the sitelesions characteristic of Trichophyton rubrum in- of prior involvement of the other patients withfections were also treated with solution "B". Re- superficial mycotie infections. lief from itching was prompt in from 24 to 72 hours in all cases. All patients in this group showed some REsULTs degree of improvement within 7 days and in all Control stndy: Five patients with Trichophytoninstances involution of lesions was complete in rubrum infections of the groins were treated withfrom 2 to 4 weeks. After one month of treatment, the non-medicated placebo for one week. No re-no improvement was observed in the single ease lief of subjective symptoms or change in the ap-of onyehomyeosis and because of this treatment pearance of the cutaneous lesions was observedwas discontinued. No evidence of irritation or following the use of this preparation (solutionhypersensitivity developed from the use of this "C''). Preparation ''B'' (1% tolnaftate solution)solution. TOLNAFTATE THERAPY OF MYCOTIC INFECTIONS 187

Solution "D" (0.5% tolnaftate) was used innot observed in the nail infections of the four pa- the treatment of 17 patients who had positivetients treated with topical applications of tolnaf- cultures for trichophyton rubrum aud in 2 othertate. Rapid and complete clearing of interdigital patients who had lesions clinically characteristicfungus infections was noted in all cases treated. of Trichophyton rubrum infections but whoseIn these eases, tolnaftate produced involution of initial cultures were contaminated. Significantlesions, a result which could not be obtained with improvement was not observed in the one patientsystemically administered griseofulvin or kera- who had onychomycosis and therefore treatmenttolytie agents such as undecylenie acid or salicylie was discontinued. In all of the other patients thereacid. In all instances in which itching was a prom- was prompt relief from itching in from 24 to 72inent symptom, relief of subjective symptoms oc- hours. Clinical improvement was observed at thecurred in 24 to 72 hours. end of one week in all instances and complete in- This initial report indicates that tolnaftate is a volution of lesions was observed in 2 to 4 weeks.valuable and effective fungieidal agent with a low No evidence of irritation or hypersensitivity wasindex of sensitization. Obviously a more extensive noted. Positive cultures were obtained from 3study must be done with a larger series of patients. of these patients after all clinical evidence of in-It would be desirable to include in future studies fection had disappeared. eruptions due to as many of the dermatophytes as Epidermophyton fioccosum: Two patients withpossible. Further in vitro studies are indicated to Epidermophyton floccosum of the feet and trunkdetermine the spectrum of tolnaftate and its mode were studied. One of these was treated with solu-of action. tion "D" (0.5% tolnaftate) and the other with solution "B" (1.0% tolnaftate). In both iustances CONCLUSIONS there was relief from itching in from 24 to 72 hours. Partial involution of lesions occurred in one week 1. Tolnaftate (0.5% and 1.0% in polyethylene and in both instances complete involution ofglycol 400) is an effeetive agent in the treatment lesions had occurred in 3 weeks. No evidence ofof superficial mycotic infections due to Tricho- irritation or hypersensitivity occurred from thephyton rubrum, Trichophyton menteyrophytes, and medication. Epidermophyton fioccosum, and produces rapid Trichophyton mentegrophytes infections: Twoclearing of interdigital infections due to these patients with tinea pedis due to this organismfungi. were treated with solution "A". Relief from itch- 2. This drug is of no value in the treatment of ing occurred in from 24 to 72 hours and in bothCandida elbicens infections, in the management instances involution of lesions was completeof tinea eapitis, and of questionable value in tinea within 3 weeks. versicolor. 3. More intensive study and different technic COMMENT are required to determine its value in onyehomy- This preliminary study indicates that tolnaf-cosis. Satisfactory results were not obtained in the present study. tate, topically applied, is an effective agent for 4. No evidence of primary irritation or hyper- the treatment of superficial myeotic infectionssensitivity was observed. due to Trichophyton rubrum, Epidermophyton floccosum and Trichophyton menteyrophytes. The observations recorded reveal no incidence of REFERENCES primary irritation or acquired contact sensitivity. 1. Noow-em, T., KAJI, A., IGARASHI, Y., SmoE- Although the experience is slight, tolnaftate is MATSU, A. AND TANIGUCHI, K.: Naphthio- apparently of no value in the treatment of tinea mates: 2-Naphthyl Arylmethylthionoear- bamates, Novel Antitrichophyton Agents. capitis, or cutaneous lesions due to Candida Abstract 34, Second Interscience Conference elbicens. It is difficult to evaluate this drug in on Antimicrobal Agents and Chemotherapy, the management of onychomycosis because of the October 31, to Nov. 2, 1962, Chicago, Ill. prolonged observation time necessary. During the2. Sehering Corporation Laboratories: Unpub- time of this study, satisfactory improvement was lished data.