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provided by Elsevier - Publisher Connector THE JOURNAL OF INVESTIGATIVE DERMATOLOGY Vol. 47, No. 2 Copyright 1566 by The Williams & Wilkins Co. Printed in U.S.A. Preliminary and Short Report

THE ANTI-SEBORRHEIC QUALITIES OF (ZINC -2--1-OXIDE) IN A CREAM VEHICLE

I. A PRELIMINARY REPORT* EARLE W. BEAUER, M.D., DONALD L. OPDYKE, PH.D. AND CLYDE M. BURNETT

Keratolytic or desquamating agents have beenZPT discolors and decomposes in the presence of employed as anti-seborrheic medicaments. Someultraviolet light, the degraded product does not are among the agents cited (1) as possessingdiffer in cutaneous irritation or acute oral toxicity keratin reducing abilities. A totally new compound, from the original material. whose possible use in pharmaceutical preparations (2) was suggested in 1957, was investigated to Antimicrobiol Activity determine its possible effectiveness as an anti- In vitro tests in our laboratories against &ophy- seborrheic remedy. lococcus oureus and albus and Pityrosporum ovole, revealed ZPT to be several hundred times more GE5CRIPTION OF ACTIVE AGENT effective than resorcinol, salicylic acid, sulfur and Zinc pyrithione (ZPT), also known as zinc pyri-related compounds. dine-2-thiol-1-oxide has the empirical formula CHIIIN2O2SIZn and the structural formula: Humon Potch Tests Repeated insult closed-patch-tests with the 0.5% concentration of ZPT in the cream vehicle on 100 human volunteers over a consecutive 20 week period was followed by a final challenge after a 2 O>KS week rest interval. There was no evidence of ad- zinc pyridine-2-thiol-1-oxide verse reaction.

Its possible use in pharmaceutical preparations Clinicol Experience was suggested as early as 1957 (2). The Cream vehicle containing 0.5% ZPT was TOXICOLOGY utilized as a hairdressing for daily gentle massage Toxicologic data on this active agent becameto the scalp in patients with seborrheic dermatitis available in 1958; and an extensive review has re-(pityriasis capitis). Subjects from 11—80 years of cently been published (3) evaluating the safety ofage with eruption of various degrees of severity the compound in a 2% concentration in a shampoocomprised the study carried out in two phases: vehicle. I—a simple clinical evaluation for effectiveness; Similarly, toxicologic data is presented with aand Il—a double-blind evaluation against a posi- ZPT concentration of 0.5% in a cream vehicle totive controlt in patients from the private prac- be used for repeated application to the scalptices of 5 dermatologists in several geographic (Table I). areas. In all cases, the subjects were observed for at Zinc pyrithione has demonstrable toxicity on re-least 2 weeks, while using mild , before peated ingestion, but apparently insufficientthe treatment program was instituted. amounts, if any, penetrate intact or abraded skin Clinical response was gradual, with pronounced to produce any manifestations of toxicity. An acute improvement in signs and symptoms in a majority dermal toxicity with the 50% suspension as ob- t The control product consisted of the same tained from the suppliert failed to elicit any re-cream vehicle as the test product; however the sponse at doses of 20 gm/kg of body weight oractive agents dehydroacetate salt, para-chloro- 10 gms of pure ZPT. meta-xylenol and allantoin were substituted for the While, like several other antibacterial agents,ZPT. The control product, with established anti- seborrheic qualities, has been marketed for 8 years. Received for publication July 22, 1966. § We are indebted to the following dermatolo- 'Fromthe Revlon Research Center, Inc., 945gists for their cooperation in this clinical study: Zerega Avenue, Bronx, New York 10473. Leonard D. Grayson, M.D., Quincy, Illinois; A. A. t Olin, Inc., Organics Division, Speciality Chem- Cuiducci, M.D., Warren, Ohio; D. E. Rackbarth, ical Products, 100 McKee Road, P.O. Box 206,M.D., Milwaukee, Wisconsin; C. Conrad Smith, Rochester, N. Y. MD,. Augusta, Georgia. 174 PRELIMINARY REPORT ON ZINC PYRITHIONE 175

TABLE I Summary of toxicology of ZPT 0.5% in a cream vehicle

Test Level Animal Where performed Result

LD5° 0.5% Fasted albino rat Revlon Research>30 g/kg Center Eye irritation 0.5% Albino rabbit Revlon ResearchPasses Draize Center test 20 day percutaneouslx, lOx use levelAlbino rabbit Food and Drug*Negative on abraded skin Research Labs 90 day percutaneouslx, lOx, lOOx useAlbino rabbit Food and DrugNegative on intact skin level Research Labs Acute dermal toxic-20 g/kg (100 mgAlbino rabbit Revlon ResearchNegative ity ZPT) Center * Foodand Drug Research Laboratories, Inc., 58th Street and Maurice Avenue, Maspeth, 78, Queens, N.Y.

TABLE II TABLE III Phase I: Simple clinical evaluation for Phase II: A double-blind evaluation effectiveness (against a positive control)

Severity of disease Severity of disease

No.of I No. of subjects Moder- subjects Moder-Moder- Severe atelyI Moder- Mild Slight Severe Mild ate I ately ate Slight Severe I Severe

85 2 9 38 19 12 Active 200 8 29 81 63 4 Control 67 7 10 25 17 2 Results No. of subjects Results Excellent Good Fair Poor Off Test No. of subjects Excel- lent Good Fair PoorOff Test 85 63 14 1 2 5

Active 200 79 51 21 34 15 of patients appearing by the third week. ContinuedControl 67 18 11 8 24 6 use yielded progressive benefit which was main- tained indefinitely (some cases observed for 3 years) on a reduced schedule of use. There were no instances of adverse reactions. REFERENCES 1. Goodman, L. S. and Gilman, A.: The Pharmaco- SUMMARY AND CONCLUSION logical Basis of Therapeutics, p. 984, New A new compound, zinc pyrithione, 0.5% concen- York, The Macmillan Company, 1965. tration in a cream vehicle, has been demonstrated2. Cox, A. J.: Pyridine-N-Oxides and their uses. to be very effective in the treatment of seborrheic Manufact. Chem., y8: 463, 1957. dermatitis (pityriasis capitis). 3. Snyder, F. H., Buehler, E. V. and Winek, C. L.: The possible usefulness of this remedy in the Safety evaluation of Zinc 2-Pyridinethiol 1- treatment of other dermatologic conditions is be- Oxide in a formulation. Toxic. Appi. ing investigated. Pharmacol., 7: 425, 1965.