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Clinical evaluation of haloprogin
TOXICOLOGY
AND
APPLIED
PHARMACOLOGY
Clinical
23,598-605
Evaluation
(1972)
of Haloprogin
H. W. HERMANN Medical Research Department, Mead Johnson and Company EvansviNe, Indiana 47721 Received March 20, I972
Clinical Evaluation of Haloprogin.
HERMANN,
H. W. (1972). Toxicol.
Appl. Pharmacol. 23,598-605. One percent haloprogin cream and solution
were determined to be safe and effective topical therapeutics for several human dermatophytoses. Safety studies included evaluation of the potential of the 1% cream and solution formulations for irritancy, allergic contact sensitization, phototoxicity, allergic contact photosensitization and systemic toxicity. The ability of haloprogin to penetrate normal skin was shown to be poor. Clinical efficacy in the therapy of the dermatophytoses studied wasdemonstrated by controlled studies with both haloprogin formulations. Haloprogin’ was shown to have a broad in vitro spectrum for dermatophytes, Candida QlbicQns and related yeasts and certain gram positive bacteria (Seki et al., 1964; Harrison et al., 1970). Harrison et al. also reported the efficacy of haloprogin formulations in the therapy of induced dermatophytoses in animals. Dermal and systemic toxicity studies in several animal species established the prospective safety of haloprogin for use in clinical studies (Weikel and Bartek, 1972). METHODS Safety &dies One percent of haloprogin was incorporated in cream and solution vehicles2 for clinical safety and efficacy evaluation as a topical therapeutic agent. Normal adult volunteers were the subjects in all studies which included positive and/or negative controls. Five dermatological safety studies were performed. The 20 subject cumulative irritancy study (Phillips et al., 1972) evaluated the potential of haloprogin for irritancy after 10 and 20 days of repeated applications to the same skin site under occlusion. Evaluation for phototoxicity potential (Willis and Kligman, 1968b; Marzulli and Maibach, 1970) in stripped and intact skin was conducted in 20 subjects by exposing the haloprogin treated skin site to midday sunlight or Xenon ultraviolet light. Allergic contact photosensitization potential evaluation (Willis and Kligman, 1968a) employed exposure of sites in 28 subjects to filtered Kromayer light before each of 10 repeat applications of the product. Sensitization potential evaluation by the Kligman Maximization method (Kligman, 1966b) in 22 subjects employed five repeat occlusive patch applications of product on sites pretreated with 5 y0 sodium 1 Haloprogin is 3-iodo-2-propynyl2,4,5-trichIoropheny1 ether and is avaiIabIe from Mead Johnson and Company under the trademark, Halotex @. 2 Each gram of Halotex@ Cream contains 10 mg haloprogin dissolved in polyethylene glycol 400, polyethylene glycol 4000, diethyl sebacateand polyvinylpyrrolidone. Each milliliter of Halotex@ Solution contains 10 mg haloprogin dissolvedin alcohol and diethyl sebacate. Copyright All rights
0 1972 by Academic Press, Inc. of reproduction in any form reserved.
598
CLINICAL EVALUATION
OF HALOPROGIN
599
lauryl sulfate with challenge patch testing of detergent treated sites after a 10 day rest period. The Draize-Shelanski method (Draize, 1959; Kligman, 1966a) of determining sensitization potential was also performed in over 200 subjects with 10 repeat applications of product under occlusive patch followed by a challenge patch test to a different site. All except the allergic contact photosensitization and Kligman Maximization studies were performed independently by two investigators.3 Clinical concentrations (1 y0 haloprogin) were used in each of these safety studies. The potential for producing systemic toxicity was determined by the subtotal body inunction method (Goldman and Lasser, 1964) with 15 g or 15 ml of 1 y0 haloprogin cream or solution applied daily to the entire body excluding the head for 10 consecutive days. Appropriate hematologic, biochemical and physical observations4 were included for toxicologic surveillance. Dermal penetration of 14C-haloprogin in each vehicle was determined by the percentage of 14C recovered in 5 day urine collection as compared to that applied to the skin and corrected to recovery following a similar iv dose (Feldman and Maibach, 1969, 1970; Bartek et al., 1972). &Jicacy Studies
Cream and solution formulations containing 1% haloprogin were evaluated for efficacy in the therapy of dermatophytoses by controlled and open studies.s* 6 Clinical evaluation (O-4 lesion score rating) and potassium hydroxide (KOH) slide determinations of lesion scrapings were included in all studies. Cultures and photographs of lesion sites were also obtained in some studies. The initial double-blind study evaluated therapeutic response of induced bilateral Trichophyton rubrum infection in the inguinocrural regions to 1% haloprogin cream and 1 7: tolnaftate cream. Another double-blind paired comparison study of 15 patients with bilateral symmetrical tinea pedis infections compared the haloprogin products with vehicles. Double-blind parallel studies comparing haloprogin therapy with positive and/or negative controls were completed by five investigators. Tinea corporis, tinea cruris, tinea pedis, tinea versicolor and tinea manuum were included. Patients were seen at weekly or fortnightly intervals by the investigator with clinical severity ratings (lesion score) and KOH determinations being made at each visit. One additional double-blind study included the evaluation of three different formulations (cream, solution, and foam7) containing 1 y0 haloprogin and 1% tolnaftate solution in patients with tinea pedis. This study also included 8 day post-treatment clinical and laboratory follow-up evaluation to ascertain the incidence of relapse. Fifteen dermatologists conducted open studies of l”//, haloprogin cream and/or 3 Albert M. Kligman, M.D., Philadelphia, and Howard I. Maibach, M.D., San Francisco. 4 Complete physical examinations supplemented by urinalyses, hemoglobin, hematocrit, white blood count, red blood count, serum albumin, SGOT, PBI, thyroxine, T3, thymol turbidity, blood urea nitrogen, fasting blood sugar and alkaline phosphatase. 5 Participants in these studies included the following dermatologists: W. Akers, M.D., B. Cal-m, M.D., V. Carter, M.D., H. Christianson, M.D., V. De&es, M.D., M. Fliegelman, M.D., R. Goltz, M.D., G. Jansen, M.D., W. Johnson, M.D., R. Katz, M.D., A. Kligman, M.D., L. Lumpkin, M.D., H. Maibach, M.D.,L. Montes, M.D. ,S. Olansky, M.D., W. Sams, M.D., E. B. Smith, M.D., J. G. Smith, M.D., M. Waisman, M.D., P. Winder, M.D., and L. Wise, M.D. 6 Data on file at Mead Johnson Research Center. 7 Each ml of Halotexs Foam contains 10 mg haloprogin dissolved in alcohol and diethyl sebacate with polyoxyethylene stearyl ether and propellants.
600
HERMANN
solution in 556 dermatophytic or candidiasis patients. These investigators were located in diverse geographical sites in the United States. Clinical severity ratings (lesion score), KOH determinations, cultures,8 and photographs of the lesions were obtained in most patients. RESULTS The 1% haloprogin formulations were found to be safe for repeated topical applications in the treatment of human cutaneous infections. No significant potential for irritancy, phototoxicity, allergic contact sensitization or photosensitization, or systemic TABLE 1 DERMAL PENETRATION AFTER
STUDIES”; AMOUNT OF 14C RECOVERED~ THE APPLICATION OF VARIOUS TAGGED COMPOUNDS~
Total absorption Penetrant= Haloprogin Rat Rabbit Pig Man N-Acetylcysteine Rat Rabbit Pig Man Testosterone Rat Rabbit Pig Man Cortisone Rat Rabbit Pig Man Caffeine Rat Rabbit Pig Man Butter Yellow Rat Rabbit Pig Man
Number tested
Percent of dosed
Standard deviation
95.8
13.9
113.0
16.5
19.7
9.92
11.0
3.74
3.50
3.77
1.98
0.95 -
6.00 2.43 4 3 2 17
47.4
69.6 29.4 13.2 24.7 30.3 4.06 3.38
4 3 2 12 4 3 2 4
53.1
69.2 32.4 47.6 48.2
100.0 41.9 21.6 a Data from studies by Bartek et al. (1972).
1.57 2.62 7.81 8.55 3.04 3.62
9.03 1.58 1.64 11.8 5.82 4.82
20.9 2.17 7.90 10.0 4.88
b Recovery of radioactivity in urine following topical administration. c All compounds were applied at 4 pg/cm* in acetone as vehicle. d Corrected for recovery following parenteral administration. * Sabourauds, Mycosel or Dermatophyte Test Medium was used for cultures.
CLINICAL
EVALUATION
601
OF HALOPROGIN
toxicity was revealed by the studies performed with clinical concentrations of the compound. Dermal penetrability of haloprogin in various vehicles showed it to be a poor penetrant (Table 1). TABLE 2 DOUBLE-BLIND
PAIRED
Haloprogin
COMPARISONS“
(Cr/SoBd
Placebo
(Cr/Sol)d
(7/e) (l/l)
4 11 15
(c/5)
Lesionscore Improvedb Not improved Total
13 2 15
(2/2)
p < 0.005 KOH Improved” Not improved Total
5 10 15
1 14 15 0.10
(2/3) (6/4)
(O/l)
V/6)
’ Fifteen cases of tinea pedis;14-28daysof therapy;oneinvestigator. b 50% or greater reduction in lesion score. ’ Reversed from positive to negative. d Number of dermatophytoses patients treated with cream/number treated with solution formulation. TABLE
3
DOUBLE-BLIND PARALLEL COMPARISON 14 DAYS OR MORE OF THERAPY AND
Haloprogin
(Cr/Sol)
.-
Placebo
(Cr/Sol)c
STUDIES
WITH
5 INVESTIGATORS
1 Haloprogin Tolnaftate (Cr/Sol) (Cr/Sol) .-__
Lesionscore Improved”
&5)
($5)
1
(3$6)
(374:O)
(3:;5) 78 p < 0.005
I ~
($3
(5183) 55
Not improved Total
(!$2, 65
80 p CO.90
KOH Improvedb (2ff20)
(3o;o)
&
(2:;)
Not improved Total
$7, 65
(296p31) 78 p
1 !
$2) (I$) 80 536 0.10 cp < 0.25
’ 50% or greater reduction in lesion score. b Reversed from positive to negative. ‘Number of dermatophytoses patients treated with cream/number treated with solution formulation. ‘ Two of the patients did not have both lesion scores and KOH determinations.
602
HERMANN
The initial efficacy study showed haloprogin and tolnaftate comparable in clearing induced inguinocrural T. rubrum infections. All lesions were clinically cured, all infected sites having negative cultures within 17 days of therapy. The double-blind paired comparison tinea pedis study showed significant (p < 0.005) superiority of haloprogin-containing formulations over vehicles in lesions clinically improved9 after 28 days of therapy. The comparative incidence of KOH reversal (positive to negative) was not significant (0.10
Treatment 1% Haloprogin” 1% Tolnaftate solution
PEDIS
No. of patients Improved after Maintained improvement 27 days treatment 8 days posttreatment treated Clinical improvement 61 56 56 20
17
P
NS
16
KOH No. of patients Negative after Maintained negative 27 days treatment 8 days posttreatment treated 1% Haloproginb 1% Tolnaftate solution
62 20
56 12
50 5
p<.oool
Culture No. of patients Negative after Maintained negative 27 days treatment 8 days posttreatment treated 1% Haloprogin“ 1% Tolnaftate solution
52 17
46 11
41 7
p < 0.01
a 1% haloprogin cream (20 patients), 1% haloprogin solution (20 patients) and 1% haloprogin (21 patients). b 1% haloprogin cream (20 patients), 1% haloprogin solution (20 patients) and 1% haloprogin (22 patients). c Final cure rate comparing haloprogin and tolnaftate therapy. d 1% haloprogin cream (14 patients), 1 ‘A haloprogin solution (20 patients) and 1% haloprogin (22 patients). 9 Clinical improvement indicates a 50% or greater reduction of the pretreatment lesion score
foam foam foam rating.
CLINICAL EVALUATION OF HALOPROGIN
603
TABLE 5 EFFICACY vs SELECTEDDIAGNOSES’ Parameter
Tinea pedis
Tinea corporis/cruris
Candidiasisl moniliasis
Other dermatophytes
Total
1% Haloprogin cream Lesion score : g-73.5% g-87.6% 4~69.2% O?(improved KOH determination : 158 193=81.9% ;=81.9% ;=90.0% ok negative Culture: % negative F5 = 89.6% ; = SO.O>; $ = 37.5:;
&83.3x
:;=77.5:/,
a-75.0%
g-82.1%
; = 50.0%
g2 = 84.0:/:,
1% Haloprogin solution Lesion score : I&87.7% ;=88.09:, od improved KOH determination : 118 154 = 76.6% $ = 79.3% ‘A negative Culture : % negative ; = 85.0% ; =94.8x
-
;=33.35/,
-
1 4=25.00/,
-
i-33.3%
$;=86.50; ‘59=73.6x 216 ;;=86.51<
’ All investigators: only readings taken at 21-35 days after initiation of therapy are included. Number of patients responding by specific observation over total number of patients examined and y/, of favorable responses. TABLE 6 SPECIESIDENTIFWATION BY CULTURE vs EFFICACY” Parameter
T. rubrum
T. mentagrophytes
Candida species
Other fungi
Total
1% Haloprogin cream 125 144 = 86.8 % ; = 86.7 %
Lesion score : % improved KOH determination : 110 ~~=.79.1% ;=SO.O% ‘? negative Culture: % negative 122 137 = 89.1% ; = 75.0%
; = 89.7 %
:‘: = 82.4% go = 86.8 p/,
;;=91.3:/,
g-86.796
; = 74.1%
; = 78.6% &
g7=81.2:< = 84.57;
1% Haloprogin solution Lesion score : ‘A improved KOH determination : o/Onegative Culture : % negative
;=89.3%
g-92.9%
$90.0%
i;=69.2%
g-88.25;
54 ,,=78.3%
;;=72.4%
<=88.9x
i;=60.0%
$=76X;
; = 90.0%
$ = 61.5;!
g2 = 84.8%
62 i2 = 86.1% f4 = 88.9%
a All investigators: only readings taken at 21-35 days after initiation of therapy are included. Number of patients responding by specific observation over total number of patients examined and % of favorable responses.
604
HERMANN
Efficacy by diagnosis (Table 5) and species (Table 6) after 21-35 days of haloprogin therapy in open studies by 15 investigators reveals consistently good results as measured by clinical improvement and KOH and culture reversal to negative. Adverse Reactions
Of the 1062 patients exposed to 1% haloprogin cream or solution, 29 reports of burning sensation, scaling or other findings possibly associated with product application were reported. Eighteen of these were reports from the military service personnel when drug application to the feet was immediately followed by wearing heavy combat boots. Twelve patients discontinued therapy because of these reactions. DISCUSSION The safety of products for use in nonlethal diseases is under increasing scrutiny. Further, proof of efficacy requires the study of a formulated compound by several investigators employing well controlled methodology. Safety in an imperfect environment implies relative freedom from risk rather than infinite safety; therefore, the comparative risk of one therapy to another must be considered. Griseofulvin is useful in systemic therapy of dermatophytoses; however, its cost and adverse therapy reactions stimulate the continued search for other therapies. Several topical agents are available which have varying inadequacies so far as safety or efficacy is concerned. Diligent study of haloprogin in various formulations have shown it to be a safe and effective agent for use in therapy of dermatophytoses. ACKNOWLEDGMENTS We thank the staff of the Department of Technical Information and Company, for the statistical analyses of these studies.
Services, Mead Johnson
REFERENCES BARTEK,M. J., LABUDDE,J. A. and MAIBACH,H. I. (1972).Skin permeability in vivo: Rat, rabbit, pig and man. J. Invest. Dermatol. 58, 114-123. CARTER,V. H. (1972).A controlled study of haloprogin and tolnaftate in tinea pedis.Curr. Ther. Res.14, 307-310. DRAIZE, J. H. (1959).Dermal Toxicity. In: TheAppraisalof the Safety of Chemicalsin Food, Drugs, and Cosmetics,pp. 46-59. Association of Food and Drug Officials of the United
States, Austin, Texas. FELDMANN, R. J. and MAIBACH,H. I. (1969).Percutaneouspenetration of steroidsin man.
J. Invest. Dermatol. 52, 89-94. FELDMANN, R. J. and MAIBACH,H. I. (1970).Absorption of someorganiccompoundsthrough
the skin in man.J. Invest. Dermatol. 54, 399-404.
GOLDMAN, L. and LASER, A. E. (1964).Subtotal body inunction test for systemictoxicity of
topical medication.Antimicrob. Ag. and Chemother.,pp. 602-605. HARRISON, E. F., ZWADYK, P., JR., BEQUETTE, R. J., HAMLOW, E. E., TAVORMINA, P. A. and ZYGMUNT, W. A. (1970). Haloprogin: A topical antifungal agent. Appl. Microbial. 19,
746-750. KLIGMAN, A. M. (1966a). The identification of contact allergens by human assay.I. A critique
of standardmethods.J. Invest. Dermatol.47, 369-374. KLIGMAN,
A. M. (1966b). The identification of contact allergens by human assay. III. The
Maximization test: A procedure for screeningand rating contact sensitizers.J. Dermatol.47, 393-409.
Invest.
CLINICAL EVALUATION OF HALOPROGIN
605
MARZULLI, F. N. and MAIBACH, H. I. (1970). Perfume phototoxicity. J. Sot. Cosmet. Chem. 21,695-715. PHILLIPS, L., STEINBERG, M., MAIBACH,H. I. and AKERS,W. A. (1972). A comparisonof rabbit and human skin responseto certain irritants. Toxicol. Appl. Pharmacol. 21,369-382.
SEKI,S., NOMIYA,B., KOEDA,T., UMEMURA,K., ODA, M. and OGAWA,H. (1964).Laboratory evaluation of M-1028 (2,4,5-trichlorophenyl-r-Iodopropargyl ether), a new antimicrobial agent.Antimicrob. Ag. Chemother. 569-572. WEIKEL,J. H. and BARTEK,M. J. (1972).Toxicologic propertiesand metabolic fate of haleprogin, an antifungal agent. Toxicol. Appl. Pharmacol. 22,375-386. WILLIS, I. and KLIGMAN, A. M. (1968a).Diagnosisof photosensitizationreactions by the Scotch Tape@provocative patch test.J. Invest. Dermatol. 51, 116119. WILLIS,I. and KLIGMAN,A. M. (1968b).The mechanismof photoallergic contact dermatitis. J. Invest. Dermatol.
51. 378-384.
AND
APPLIED
PHARMACOLOGY
Clinical
23,598-605
Evaluation
(1972)
of Haloprogin
H. W. HERMANN Medical Research Department, Mead Johnson and Company EvansviNe, Indiana 47721 Received March 20, I972
Clinical Evaluation of Haloprogin.
HERMANN,
H. W. (1972). Toxicol.
Appl. Pharmacol. 23,598-605. One percent haloprogin cream and solution
were determined to be safe and effective topical therapeutics for several human dermatophytoses. Safety studies included evaluation of the potential of the 1% cream and solution formulations for irritancy, allergic contact sensitization, phototoxicity, allergic contact photosensitization and systemic toxicity. The ability of haloprogin to penetrate normal skin was shown to be poor. Clinical efficacy in the therapy of the dermatophytoses studied wasdemonstrated by controlled studies with both haloprogin formulations. Haloprogin’ was shown to have a broad in vitro spectrum for dermatophytes, Candida QlbicQns and related yeasts and certain gram positive bacteria (Seki et al., 1964; Harrison et al., 1970). Harrison et al. also reported the efficacy of haloprogin formulations in the therapy of induced dermatophytoses in animals. Dermal and systemic toxicity studies in several animal species established the prospective safety of haloprogin for use in clinical studies (Weikel and Bartek, 1972). METHODS Safety &dies One percent of haloprogin was incorporated in cream and solution vehicles2 for clinical safety and efficacy evaluation as a topical therapeutic agent. Normal adult volunteers were the subjects in all studies which included positive and/or negative controls. Five dermatological safety studies were performed. The 20 subject cumulative irritancy study (Phillips et al., 1972) evaluated the potential of haloprogin for irritancy after 10 and 20 days of repeated applications to the same skin site under occlusion. Evaluation for phototoxicity potential (Willis and Kligman, 1968b; Marzulli and Maibach, 1970) in stripped and intact skin was conducted in 20 subjects by exposing the haloprogin treated skin site to midday sunlight or Xenon ultraviolet light. Allergic contact photosensitization potential evaluation (Willis and Kligman, 1968a) employed exposure of sites in 28 subjects to filtered Kromayer light before each of 10 repeat applications of the product. Sensitization potential evaluation by the Kligman Maximization method (Kligman, 1966b) in 22 subjects employed five repeat occlusive patch applications of product on sites pretreated with 5 y0 sodium 1 Haloprogin is 3-iodo-2-propynyl2,4,5-trichIoropheny1 ether and is avaiIabIe from Mead Johnson and Company under the trademark, Halotex @. 2 Each gram of Halotex@ Cream contains 10 mg haloprogin dissolved in polyethylene glycol 400, polyethylene glycol 4000, diethyl sebacateand polyvinylpyrrolidone. Each milliliter of Halotex@ Solution contains 10 mg haloprogin dissolvedin alcohol and diethyl sebacate. Copyright All rights
0 1972 by Academic Press, Inc. of reproduction in any form reserved.
598
CLINICAL EVALUATION
OF HALOPROGIN
599
lauryl sulfate with challenge patch testing of detergent treated sites after a 10 day rest period. The Draize-Shelanski method (Draize, 1959; Kligman, 1966a) of determining sensitization potential was also performed in over 200 subjects with 10 repeat applications of product under occlusive patch followed by a challenge patch test to a different site. All except the allergic contact photosensitization and Kligman Maximization studies were performed independently by two investigators.3 Clinical concentrations (1 y0 haloprogin) were used in each of these safety studies. The potential for producing systemic toxicity was determined by the subtotal body inunction method (Goldman and Lasser, 1964) with 15 g or 15 ml of 1 y0 haloprogin cream or solution applied daily to the entire body excluding the head for 10 consecutive days. Appropriate hematologic, biochemical and physical observations4 were included for toxicologic surveillance. Dermal penetration of 14C-haloprogin in each vehicle was determined by the percentage of 14C recovered in 5 day urine collection as compared to that applied to the skin and corrected to recovery following a similar iv dose (Feldman and Maibach, 1969, 1970; Bartek et al., 1972). &Jicacy Studies
Cream and solution formulations containing 1% haloprogin were evaluated for efficacy in the therapy of dermatophytoses by controlled and open studies.s* 6 Clinical evaluation (O-4 lesion score rating) and potassium hydroxide (KOH) slide determinations of lesion scrapings were included in all studies. Cultures and photographs of lesion sites were also obtained in some studies. The initial double-blind study evaluated therapeutic response of induced bilateral Trichophyton rubrum infection in the inguinocrural regions to 1% haloprogin cream and 1 7: tolnaftate cream. Another double-blind paired comparison study of 15 patients with bilateral symmetrical tinea pedis infections compared the haloprogin products with vehicles. Double-blind parallel studies comparing haloprogin therapy with positive and/or negative controls were completed by five investigators. Tinea corporis, tinea cruris, tinea pedis, tinea versicolor and tinea manuum were included. Patients were seen at weekly or fortnightly intervals by the investigator with clinical severity ratings (lesion score) and KOH determinations being made at each visit. One additional double-blind study included the evaluation of three different formulations (cream, solution, and foam7) containing 1 y0 haloprogin and 1% tolnaftate solution in patients with tinea pedis. This study also included 8 day post-treatment clinical and laboratory follow-up evaluation to ascertain the incidence of relapse. Fifteen dermatologists conducted open studies of l”//, haloprogin cream and/or 3 Albert M. Kligman, M.D., Philadelphia, and Howard I. Maibach, M.D., San Francisco. 4 Complete physical examinations supplemented by urinalyses, hemoglobin, hematocrit, white blood count, red blood count, serum albumin, SGOT, PBI, thyroxine, T3, thymol turbidity, blood urea nitrogen, fasting blood sugar and alkaline phosphatase. 5 Participants in these studies included the following dermatologists: W. Akers, M.D., B. Cal-m, M.D., V. Carter, M.D., H. Christianson, M.D., V. De&es, M.D., M. Fliegelman, M.D., R. Goltz, M.D., G. Jansen, M.D., W. Johnson, M.D., R. Katz, M.D., A. Kligman, M.D., L. Lumpkin, M.D., H. Maibach, M.D.,L. Montes, M.D. ,S. Olansky, M.D., W. Sams, M.D., E. B. Smith, M.D., J. G. Smith, M.D., M. Waisman, M.D., P. Winder, M.D., and L. Wise, M.D. 6 Data on file at Mead Johnson Research Center. 7 Each ml of Halotexs Foam contains 10 mg haloprogin dissolved in alcohol and diethyl sebacate with polyoxyethylene stearyl ether and propellants.
600
HERMANN
solution in 556 dermatophytic or candidiasis patients. These investigators were located in diverse geographical sites in the United States. Clinical severity ratings (lesion score), KOH determinations, cultures,8 and photographs of the lesions were obtained in most patients. RESULTS The 1% haloprogin formulations were found to be safe for repeated topical applications in the treatment of human cutaneous infections. No significant potential for irritancy, phototoxicity, allergic contact sensitization or photosensitization, or systemic TABLE 1 DERMAL PENETRATION AFTER
STUDIES”; AMOUNT OF 14C RECOVERED~ THE APPLICATION OF VARIOUS TAGGED COMPOUNDS~
Total absorption Penetrant= Haloprogin Rat Rabbit Pig Man N-Acetylcysteine Rat Rabbit Pig Man Testosterone Rat Rabbit Pig Man Cortisone Rat Rabbit Pig Man Caffeine Rat Rabbit Pig Man Butter Yellow Rat Rabbit Pig Man
Number tested
Percent of dosed
Standard deviation
95.8
13.9
113.0
16.5
19.7
9.92
11.0
3.74
3.50
3.77
1.98
0.95 -
6.00 2.43 4 3 2 17
47.4
69.6 29.4 13.2 24.7 30.3 4.06 3.38
4 3 2 12 4 3 2 4
53.1
69.2 32.4 47.6 48.2
100.0 41.9 21.6 a Data from studies by Bartek et al. (1972).
1.57 2.62 7.81 8.55 3.04 3.62
9.03 1.58 1.64 11.8 5.82 4.82
20.9 2.17 7.90 10.0 4.88
b Recovery of radioactivity in urine following topical administration. c All compounds were applied at 4 pg/cm* in acetone as vehicle. d Corrected for recovery following parenteral administration. * Sabourauds, Mycosel or Dermatophyte Test Medium was used for cultures.
CLINICAL
EVALUATION
601
OF HALOPROGIN
toxicity was revealed by the studies performed with clinical concentrations of the compound. Dermal penetrability of haloprogin in various vehicles showed it to be a poor penetrant (Table 1). TABLE 2 DOUBLE-BLIND
PAIRED
Haloprogin
COMPARISONS“
(Cr/SoBd
Placebo
(Cr/Sol)d
(7/e) (l/l)
4 11 15
(c/5)
Lesionscore Improvedb Not improved Total
13 2 15
(2/2)
p < 0.005 KOH Improved” Not improved Total
5 10 15
1 14 15 0.10
(2/3) (6/4)
(O/l)
V/6)
’ Fifteen cases of tinea pedis;14-28daysof therapy;oneinvestigator. b 50% or greater reduction in lesion score. ’ Reversed from positive to negative. d Number of dermatophytoses patients treated with cream/number treated with solution formulation. TABLE
3
DOUBLE-BLIND PARALLEL COMPARISON 14 DAYS OR MORE OF THERAPY AND
Haloprogin
(Cr/Sol)
.-
Placebo
(Cr/Sol)c
STUDIES
WITH
5 INVESTIGATORS
1 Haloprogin Tolnaftate (Cr/Sol) (Cr/Sol) .-__
Lesionscore Improved”
&5)
($5)
1
(3$6)
(374:O)
(3:;5) 78 p < 0.005
I ~
($3
(5183) 55
Not improved Total
(!$2, 65
80 p CO.90
KOH Improvedb (2ff20)
(3o;o)
&
(2:;)
Not improved Total
$7, 65
(296p31) 78 p
1 !
$2) (I$) 80 536 0.10 cp < 0.25
’ 50% or greater reduction in lesion score. b Reversed from positive to negative. ‘Number of dermatophytoses patients treated with cream/number treated with solution formulation. ‘ Two of the patients did not have both lesion scores and KOH determinations.
602
HERMANN
The initial efficacy study showed haloprogin and tolnaftate comparable in clearing induced inguinocrural T. rubrum infections. All lesions were clinically cured, all infected sites having negative cultures within 17 days of therapy. The double-blind paired comparison tinea pedis study showed significant (p < 0.005) superiority of haloprogin-containing formulations over vehicles in lesions clinically improved9 after 28 days of therapy. The comparative incidence of KOH reversal (positive to negative) was not significant (0.10
Treatment 1% Haloprogin” 1% Tolnaftate solution
PEDIS
No. of patients Improved after Maintained improvement 27 days treatment 8 days posttreatment treated Clinical improvement 61 56 56 20
17
P
NS
16
KOH No. of patients Negative after Maintained negative 27 days treatment 8 days posttreatment treated 1% Haloproginb 1% Tolnaftate solution
62 20
56 12
50 5
p<.oool
Culture No. of patients Negative after Maintained negative 27 days treatment 8 days posttreatment treated 1% Haloprogin“ 1% Tolnaftate solution
52 17
46 11
41 7
p < 0.01
a 1% haloprogin cream (20 patients), 1% haloprogin solution (20 patients) and 1% haloprogin (21 patients). b 1% haloprogin cream (20 patients), 1% haloprogin solution (20 patients) and 1% haloprogin (22 patients). c Final cure rate comparing haloprogin and tolnaftate therapy. d 1% haloprogin cream (14 patients), 1 ‘A haloprogin solution (20 patients) and 1% haloprogin (22 patients). 9 Clinical improvement indicates a 50% or greater reduction of the pretreatment lesion score
foam foam foam rating.
CLINICAL EVALUATION OF HALOPROGIN
603
TABLE 5 EFFICACY vs SELECTEDDIAGNOSES’ Parameter
Tinea pedis
Tinea corporis/cruris
Candidiasisl moniliasis
Other dermatophytes
Total
1% Haloprogin cream Lesion score : g-73.5% g-87.6% 4~69.2% O?(improved KOH determination : 158 193=81.9% ;=81.9% ;=90.0% ok negative Culture: % negative F5 = 89.6% ; = SO.O>; $ = 37.5:;
&83.3x
:;=77.5:/,
a-75.0%
g-82.1%
; = 50.0%
g2 = 84.0:/:,
1% Haloprogin solution Lesion score : I&87.7% ;=88.09:, od improved KOH determination : 118 154 = 76.6% $ = 79.3% ‘A negative Culture : % negative ; = 85.0% ; =94.8x
-
;=33.35/,
-
1 4=25.00/,
-
i-33.3%
$;=86.50; ‘59=73.6x 216 ;;=86.51<
’ All investigators: only readings taken at 21-35 days after initiation of therapy are included. Number of patients responding by specific observation over total number of patients examined and y/, of favorable responses. TABLE 6 SPECIESIDENTIFWATION BY CULTURE vs EFFICACY” Parameter
T. rubrum
T. mentagrophytes
Candida species
Other fungi
Total
1% Haloprogin cream 125 144 = 86.8 % ; = 86.7 %
Lesion score : % improved KOH determination : 110 ~~=.79.1% ;=SO.O% ‘? negative Culture: % negative 122 137 = 89.1% ; = 75.0%
; = 89.7 %
:‘: = 82.4% go = 86.8 p/,
;;=91.3:/,
g-86.796
; = 74.1%
; = 78.6% &
g7=81.2:< = 84.57;
1% Haloprogin solution Lesion score : ‘A improved KOH determination : o/Onegative Culture : % negative
;=89.3%
g-92.9%
$90.0%
i;=69.2%
g-88.25;
54 ,,=78.3%
;;=72.4%
<=88.9x
i;=60.0%
$=76X;
; = 90.0%
$ = 61.5;!
g2 = 84.8%
62 i2 = 86.1% f4 = 88.9%
a All investigators: only readings taken at 21-35 days after initiation of therapy are included. Number of patients responding by specific observation over total number of patients examined and % of favorable responses.
604
HERMANN
Efficacy by diagnosis (Table 5) and species (Table 6) after 21-35 days of haloprogin therapy in open studies by 15 investigators reveals consistently good results as measured by clinical improvement and KOH and culture reversal to negative. Adverse Reactions
Of the 1062 patients exposed to 1% haloprogin cream or solution, 29 reports of burning sensation, scaling or other findings possibly associated with product application were reported. Eighteen of these were reports from the military service personnel when drug application to the feet was immediately followed by wearing heavy combat boots. Twelve patients discontinued therapy because of these reactions. DISCUSSION The safety of products for use in nonlethal diseases is under increasing scrutiny. Further, proof of efficacy requires the study of a formulated compound by several investigators employing well controlled methodology. Safety in an imperfect environment implies relative freedom from risk rather than infinite safety; therefore, the comparative risk of one therapy to another must be considered. Griseofulvin is useful in systemic therapy of dermatophytoses; however, its cost and adverse therapy reactions stimulate the continued search for other therapies. Several topical agents are available which have varying inadequacies so far as safety or efficacy is concerned. Diligent study of haloprogin in various formulations have shown it to be a safe and effective agent for use in therapy of dermatophytoses. ACKNOWLEDGMENTS We thank the staff of the Department of Technical Information and Company, for the statistical analyses of these studies.
Services, Mead Johnson
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CLINICAL EVALUATION OF HALOPROGIN
605
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