, '" , jfdle'lzfluimfB DJ : ;;'lufe._flfU:r'IJ n~.Jif fte~t1ltfJD '" ~ ' ,
l'
'll9DiI; 1'1: "~ ~
'
,
~
:
.li!
-110
' '
~
>
' - " '" "
A Comparison of Itraconazole and Griseofulvin in the Treatment of Tinea Corporis and Tinea Cruris: a Double-blind Study T KOUSIDOU2 ,
D PANAGIOTIDOUt, A
2
KALOGEROPOULOU
,
A
TEKNETZIS
1
G CHAIDEMENOS 2 , G KARAKATSANIS 2 , 2 , E CHATZOPOULOU AND D MICHAILIDIS.1
'Department of Dermatology, University of Thessaloniki, Thessaloniki, Greece; 'Department of Dermatology and Mycology, Dermatological and Venereal Diseases Hospital, Thessaloniki, Greece; 3Janssen Research Foundation, Athens, Greece
A total of 40 patients with clinically and mycologically documented tinea corporis or tinea cruris were treated with 100 mg/day itraconazole [n = 19) or 500 mg/day griseofulvin (n = 21) for 15 days. Of the itraconazole-treated patients, 83.3% were healed or markedly improved, i.e, 'responders', after 15 days compared with 85.7% of griseofulvin-treated patients. At 15 days after the end of treatment, 88.2% of itraconazole- and 80.9% ofgriseofulvin-treated patients were classed as 'responders'. The mycological cure rate (both microscopy and culture negative) was generally lower than the clinical response rate. Both treatments were equally effective at the end of 15 days' treatment with 66.7% of patients cured, but itraconazole was superior to griseofulvin at the 15-day follow-up visit (77.8% of itraconazole-treated patients compared with 66. 7% ofgriseofulvin-treated patients were cured). Both therapies were well tolerated; only one patient treated with itraconazole reported minor side-effects (dizziness, headache and gastro-intestinal disturbances). The results confirm those ofearlier comparative trials and suggest
392
that griseofulvin-treated patients are more at risk of relapse than are itraconazole-treated patients.
1:£ evn (JlJVOAO 40 uofh:vwv ,"If: XAtVtXU Xat !-tllxll'tOAoytXU 'tfX!-tllQtW!-ttvll 'tQtxoqJ1J'tlU tou oW!-tu'tO~ tl 'twv !-tllQO~Oll~W Vtxwv 1t1:llXO)V XOQllYtl0llxUV ytU 15 !-ttQf~, 100 mg t'tQuxovu1;OAll~ ll!-tfQllOlW~ (itraconazole, uQtO. uoO. = 19) tl 500 mg YXQt1;fOqJOllA~lVll~ ll!-tfQllolW~ (griseofulvin, uQtO. uoO. = 21). A1to 'tOll~ UOOfV£l~ O'tOll~ 01tOlOll~ XOQllYtl0llXf t'tQuXOVU1;OAll, OfQU1tfUOllXUV T£AflW~ tl Oll!-tflWOUV oll!-tuv'ttxtl ~fATlwoll, ()llA. "uv'tU1tOXQlOllXUV" o'tll OfQU1tfll'ttXtl uywYtl, !-t£'tu 15 !-ttQf~ 83,3%, Of aUYXQtOll !-tf 85,7% 'twv UOOfVWV O'tOll~ 01tOlOll~ XOQllYtl0llxf YXQt1;fOqJOllA~lVll' M£'tu 15 !-tfQf~ U1tO 'to 'ttAo~ 'tll~ OfQU1tflU~, 83,3% U1tO 'tOll~ UOOfVfl~ orou; 01tOlOll~ XOQllYtl0l1Xf t'tQuXOVU1;OAl1 Xat 80,9% U1tO 'tOll~ UOOfVfl~ orouc 01tOlOll~ XOQllYtl0llXf YXQt1;fOqJOllA~lVll U~tOAOYtlOllXUV ouv u'to!-tu 1tOll "uv'tU1toxQlOllXUV" (J'tll OfQU1tfll'ttXtl uywYtl. To nooooro !-tllXll'tOAOYtXtl~ OfQU1trtU~ (UQVll'ttXtl !-ttxQooxo1ttxtl f~t'tUoll Xat XUAAttQYUU) tl'tuv YfVtXU XU!-tllMT£QO U1tO 'to noooero XAtVtXtl~ uv'tU1toxQtOl1~. Kat ot ()uo OfQU1tfll'ttXt~ UYWYf~ tl'tuv f~lOOll U1tOT£Af(J!-tU'ttXt~ oro 'ttAO~ 'tll~ ()fXU1tfVOtl!-tfQl1~ OfQU1tflU~ 01tOll 66,7% U1tO 'tOll~ UOOfVfl~ OfQU1tfU0llxuv, UAAU XU'tu mv f1tUVf~t'tUOll !-t£'tu U1tO UAAf~ 15 !-ttQf~, 11 t'tQuXOVU1;OAl1 tl'tuv UVWT£Ql1 't11~ YXQt1;fOqJOllAqJlVl1~ ue nooooro tUOfW~ 77,8% evuvn 66,7% 'twv UOOfVWV 'tll~ UV'ttO'tOlXOll o!-tU()U~ 'tll~ YXQt1;fOqJOllA~lVll~. Kat or ()UO OfQU1tf1J'ttXf~ UYWYf~ tl'tuv XUAU UVfX'tf~' uovo fVU~ UOOfVtl~ orov 01tOlO XOQllYtl0llXf t'tQuXOVU1;OAll UVtqJfQf fAUqJQf~ UVf1ttOU!-tllT£~ fVfQYUf~ (1;UAll, XfqJUAUAYlU Xat YUO'tQfVT£Qtxt~ ()tU'tuQuxt~). 'Iu U1tOT£AfO!-tU'tU f1tt~f~atWVOllV fXflVU 1tQOllYOll!-tfVWV (J1JyxQt'ttxwv !-tfA£'tWV Xat ll1tobuXVUOllV o'tt Ot UOOfV£l~ (J'tOll~ 01tOlOll~ XOQllYtl0llXf OfQU1tflU ue YXQt1;fOqJOllA~lVll ~Ql OXOV'tUt Of !-tfYUAUT£QO XlV()llVO ll1t01:Q01ttl~ U1tO 'tOll~ UOOfVrt~ O'tOll~ 01tOlOll~ XOQllYtl0llXf OfQU1tfll'ttXW~ t'tQUXOVU1;OAll.
KEY WORDS: ITRACONAZOLE; GRISEOFULVIN; ANTIMYCOTICS; FUNGAL SKIN INFECTIONS; TINEA CORPORIS; TINEA CRURIS
393
INTRODUCTION A large number of in vitro tests as well as studies using animal models have shown that itraconazole, a new lipophilic triazole, is extremely active against a range of fungi.' -6 In addition, the efficacy of itraconazole against common dermatophytoses in experimental models is superior to that of ketoconazole or gri seofulvin." The antimycotic efficacy of itraconazole in humans has already been confirmed by the results of several clinical studies in the treatment dermatophytosis.' - 9 The conventional approach to the treatment of fungal skin infections is to continue antimycotic therapy for several days after the complete disappearance of the clinical signs and symptoms. It has been shown, however, that pharmacokinetic concentrations of itraconazole remain in the skin for up to 4 weeks after the discontinuation of treatment.l'':!' thus suggesting that improvement could continue after the end of therapy. Griseofulvin, on the other hand, has been found to disappear rapidly from the stratum corneum after the discontinuation of administration 12 -16 and this loss of griseofulvin from the stratum corneum parallels a reduction in plasma concentrations. The purpose of the present study was to establish if the difference in the pharmacokinetic profiles of the two drugs results in a different outcome with respect to antimycotic efficacy.
chronic mucocutaneous candidiasis; and systemic mycotic disease. Patients who had received systemic antimycotic treatment within 1 month prior to the start of the study were also excluded, as were pregnant or lactating women, and women not using adequate contraceptive methods.
STUDY DESIGN AND TREATMENT The patients were double-blindly randomized to receive either itraconazole or griseofulvin. Each patient was supplied with 30 capsules of either 250 mg griseofulvin or 50 mg itraconazole. The treatment, consisting of two capsules ofthe double-blind medication to be taken once daily just before breakfast, was continued for 15 days. All patients had to discontinue the treatment after this period irrespective of the clinical and mycological result at that time.
CLINICAL AND MYCOLOGICAL ASSESSMENT The patients were all evaluated clinically and mycologically (microscopy and culture) before entering the trial, after 15 days' therapy and 15 days after completion oftreatment. At each clinical evaluation the following variables were scored using a four-point rating scale (0, absent; 1, mild; 2, moderate; 3, severe): desquamation; exudation; vesiculation; fissures; maceration; erythema; inflammation; and subjective complaints. A mycological evaluation consisted ofa microscopic and a Wood's lamp examination, which were either positive or negative, and a mycological culture with identification of the pathogen, if positive. At the end of 15 days' treatment, as well as at the follow-up (15 days after treatment), a global assessment of the therapy was performed as follows: healed with negative mycological findings; marked improvement with negative mycological findings; marked improvement with positive mycological
PATIENTS AND METHODS PATIENTS Patients with clinical signs and symptoms of a fungal infection and with a positive microscopy and culture for dermatophytes were included in the study, irrespective ofthe extent of the lesions. The following conditions were excluded: yeast infections of the skin, including pityriasis versicolor; tinea pedis or manus; oral thrush; vaginal candidiasis,
394
Patient characteristic in a study comparing the efficacy of itraconazole and griseofulvin in the treatment of tinea corporis and tinea cruris
Itraconazole (n = 19)
Characteristics Sex Male Female
10 9
Griseofulvin (n = 21)
14 7
Age (years) Mean Range
34 17 - 65
37 18 -70
Weight (kg) Mean Range
69 55 - 90
75 48 - 135
Height (ern) Mean Range
168 155 - 180
171 155 - 190
Diagnosis Tinea corporis Tinea cruris Duration of infection (months) Mean Range
10 9
8 13
7.2 0.2 - 36.0
6.3 0.3 - 24.0
No. of patients in which present infection is a relapse
3
0
No. of patients with concomitant disease
1a
0
No. of patients previously treated"
8
3
a
Seborrhoeic dermatitis of the scalp plus psoriasis.
b
Previous treatments included aminoglycosides, antifungals and corticosteroids.
395
findings; considerable residual lesion; no change; deterioration; or unevaluable.
included in the study had a positive microscopy and culture at the start of treatment (Table 2).
STATISTICAL ANALYSIS MYCOLOGICAL RESULTS
Fisher's exact test (two-tailed) was used to evaluate the mycological cure rates. For the clinical results, Wilcoxon signed-rank test was used for intragroup comparison, whereas the Mann - Whitney V-test was used for comparisons between the two treatment groups. Global assessment results were analysed with Fisher's exact test (grouped levels).
The results of the microscopic and Wood's lamp examinations and the cultures performed at each evaluation point (baseline, 15 days of treatment and 15 days post-treatment) are summarized in Table 3. Atthe end of treatment, both treatments were equally active. At the 15 days' post-treatment visit, although statistical significance was not achieved (Fisher's exact test, two-tailed), the mycological cure rate obtained following itraconazole treatment had increased, whereas the mycological cure rate following griseofulvin treatment remained at the same level.
RESULTS A total of 40 patients were included in the trial: 19 patients were treated with itraconazole and 21 patients were treated with griseofulvin. There were no statistically significant differences in patient characteristics between the two treatment groups; patient characteristics are listed in Table 1. All patients
CLINICAL RESULTS There were no statistically significant differences between the two treatment groups in terms of symptom scores at the start of the
Causative organisms isolated at the start of the study comparing the effectiveness of itraconazole and griseofulvin in the treatment of tinea corporis and tinea cruris Griseofulvin Causative organisms
(n=21)
Trichophyton rubrum Epidermophyton floccosum T. mentagrophytes T. violaceum T. ochraceum Microsporum canis Trichopyton rubrum + Candida albicans Candida albicans + T. mentagrophytes var. interd.
Itraconazole (n = 19)
10
11
3 3
3 1
1
1
1
2
2
o
o o
396
w
'1
se
=
15 (71.4%)
12 (66.7%)
0
Negative culture
0
20 (95.2%)
19 (90.5%) 16 (88.9%)
17 (89.5%)
Negative Wood's lamp
16 (76.2%)
13 (72.2%)
0
0
Negative microscopy
Griseofulvin (n 21)
=
=
Itraconazole (n 18)
=
Griseofulvin (n 21)
End of treatment
Evaluation
Itraconazole (n 19)
Baseline
14 (77.8%)
17 (94.4%)
16 (88.9%)
=
Itraconazole (n 18)
15 (71.4%)
20 (95.2%)
16 (76.2%)
Griseofulvin (n=21)
15 days' post-treatment
Incidence of negative microscopic and Wood's lamp examination, and negative cultures following treatment of patients with tinea corporis or tinea cruris with 100 mg/day itraconazole or 500 mg/day griseofulvin for 15 days (end of treatment) and at 15 days following completion of treatment (15 days' post-treatment)
visit. The Fisher exact test for grouped levels showed no statistically significant difference at the end of treatment (P = 1.000) or at the follow-up 15 days' post-treatment visit (P =
study (Mann - Whitney U-test). All symptoms except fissures improved significantly compared with prior to treatment at both posttreatment points in both treatment groups (Pvalues ranged from P < 0.001 to < 0.05; Wilcoxon test). At the end of treatment and 15 days' posttreatment there were no significant differences between the two groups (Mann - Whitney Utest) for all symptoms.
0.672).
DISCUSSION The results of the present double-blind clinical trial indicate that both itraconazole and griseofulvin were effective in the treatment of tinea corporis and tinea cruris. In both treatment groups all signs and symptoms improved significantly by the end of treatment and at 15 days' post-treatment, but there were no significant differences between the two treatment groups at these evaluation points. At the end of the treatment period, the
GLOBAL ASSESSMENTS The investigator's global assessments for each treatment at each evaluation point are shown in Table 4. There were no statistically significant differences in global assessments between the two treatment groups at the end of treatment or at the 15 days' post-treatment
Global assessment of patients with tinea corporis and tinea cruris following treatment with 100 mg/kg itraconazole or 500 mglkg griseofulvin for 15 days (end of treatment) and at 15 days following completion of treatment (15 days' post-treatment) End of treatment
15 days' post-treatment
Itraconazole (n = 18)
Griseofulvin (n = 21)
Itraconazole (n = 18)
Griseofulvin (n = 21)
Clinically and and mycologically healed
4 (22.2%)
5 (23.8%)
10 (55.6%)
11 (52.4%)
Marked clinical improvement Negative mycology Positive mycology
6 (33.3%) 5 (27.7%)
8 (38.1%) 5 (23.8%)
3 (16.7%) 2 (11.1%)
2 (9.5%) 4 (19.0%)
Considerable lesion
3 (16.7%)
3 (14.3%)
1 (5.6%)
3 (14.3%)
Deteriorated
0
0
2 (11.1%)
1 (4.8%)
Assessment
398
precentage of 'responders' (healed plus markedly improved) in the griseofulvin-treated group was higher than in the itraconazoletreated group (85.7% compared with 83.3%), although the mycological cure rates were identical (66.7%). At the follow-up visit, 15 days after the end of treatment, 83.3% of the patients in the itraconazole treatment group and 80.9% ofthe patients in the griseofulvin treatment group were considered to be 'responders' and this trend towards itraconazole being superior to griseofulvin was reflected in the mycological outcome (77.8% compared with 66.7% mycological cure). It seems then that the response rate and the mycological cure rate in the itraconazole treatment group continued to increase in the 15 days following treatment and this can be explained by the high affinity that itraconazole has for the skin. This property of itraconazole produces longer-lasting concentrations of the drug in the epidermis, thus offering an advantage in the treatment of skin dermatophytosis beyong the treatment period. On the other hand, a decrease in response rate and maintenance of the mycological cure rate after discontinuation of treatment with griseofulvin was observed, suggesting an immediate decline in drug concentrations after treatment is discontinued. The clinical efficacy
was good in the short treatment course under study, although griseofulvin should be administered for longer periods of time. The results obtained in the present small-scale study have been confirmed by other studies with larger numbers of patients, in which similar cure rates and clinical response rates were recorded." The tendency for continued im provemen t after discon tin uation of itraconazole has also been reported by others. ' ? Both griseofluvin and itraconazole were well tolerated in the present study: some minor side-effects, such as dizziness, headache and gastro-intestinal disturbances, were reported by one patient who was treated with itraconazole. In conclusion, itraconazole or griseofulvin, given at a daily dose of 100 or 500 mg, respectively, for 15 days, was effective in the treatment of tinea corporis and tinea cruris. The clinical results were marginally better wi th griseofulvin than those with itraconazole at the end oftreatment; however, this situation was reversed at the 15-day follow-up visit. From the mycological point of view, there was a trend towards itraconazole being superior to griseofulvin 15 days after the end oftreatment. These findings indicate a continuing improvement with itraconazole, even after the discontinuation of therapy. Both therapies appeared to be well tolerated.
REFERENCES 1 Heeres J, Backx LJ, Van Cuts em J: Antimycotic azoles. 7. Synthesis and antimycotic properties of R51211 and its congeners.JMed Chern 1984; 27: 894-900. 2 Van Cutsem J: Oral and parenteral treatment with itraconazole in various superficial
and systemic experimental fungal infections: comparisons with other antifungals and combination therapy. Br J Clin Pract 1991; 44(suppl): 32 - 40. 3 Van Cutsem J, Janssen PAJ: Nouveaux antimycosiques: activite in vitro et in vivo.
399
Bull Sci Fr Mycol Med 1985; 14: 131-140. 4 Van CutsemJ, JanssenPAJ: Oral efficacy of griseofulvin, ketoconazole and itraconazole in disseminated dermatophytosis and of azoles in systemic mycoses with skin manifestations. 17th World Congress of Dermatology, Part II. Berlin, Germany, 24 - 29 May 1987; p. 138. 5 Van Cutsem J, Van Gerven F: The in vivo antifungal activity of broad-spectrum azoles. Drug Dev Res 1986; 8: 309 - 316. 6 Van Cutsem J, Van Gerven F, Janssen PAJ: Activity of orally, topically and parenterally administered itraconazole in the treatment of superficial and deep mycoses, animal models. Rev Infect Dis 1987; 9(suppl 1): S15 - S32. 7 Cauwenbergh G, De Doncker P: Itraconazole: a clinical review of its antimycotic activity in dermatology, gynecology, and internal medicine. Drug Dev Res 1986; 8: 317 - 323. 8 Cauwenbergh G, De Doncker P, Stoops K, et al: Itraconazole in the treatment of human mycoses: review of three years of clinical experience. Rev Infect Dis 1987; 9(suppl 1): S146 - S152. 9 Degreef H, Marlen K, De Veylder H, et al: Itraconazole in the treatment of dermatophytoses: a comparison of two daily dosages. Rev InfeetDis 1987; 9 (suppl 1): S104 - S108. 10 Cauwenbergh G, Degreef H, Heykants J, et al: Pharmacokinetic profile of orally administered itraconazole in human skin. JAm Acad Dermatol1988; 18: 263 - 268. 11 Heykants J, Van Peer A, Van de Vel de V, et
12
13
14
15
16
17
al: The clinical pharmacokinetics of itraconazole: an overview. Mycoses 1989; 32(suppl1): 67 - 87. Anderson SW: Griseofulvin: biology and clinical usefulness: a review. Ann Allergy 1965; 23: 103 - 110. Artis WM: Final pathway for delivery of oral antifungals to keratinized cornified skin. In: Oral Therapy in Dermatomycoses: a Step Forward (Meinhof W, ed). Frankfurt: Medicine Publishing Foundation, 1986; pp 61 - 70. Epstein WL, Shah VP, Riegelman S: Griseofulvin levels in stratum corneum: study after oral administration in man. Arch Dermatol1972; 106: 344 - 348. Shah VP, Riegelman S, Epstein WL: Determination of griseofulvin in skin, plasma and sweat. J Pharm Sci 1972; 61: 634 - 636. Shah VP, Epstein WL, Riegelman S: Role of sweat in accumulation of orally administered griseofulvin in skin. J Clin Invest 1974; 53: 1673 - 1678. Saul A, Bonifaz A: Itraconazole in common dermatophyte infections of the skin: fixed treatment schedules. JAm Acad Dematol 1989; 23: 554 - 558.
D Panagiotidou, T Kousidou, G Chaidemenos, G Karakatsanis, A Kalogeropoulou, A Teknetzis, E Chatzopoulou and D Michailidis A Comparison ofltraconazole and Griseofulvin in the Treatment of Tinea Corporis and Tinea Cruris: a Double-blind Study The Journal of International Medical Research 1992: 20: 392 - 400 Received for publication 27 April 1992 Accepted 29 May 1992 © Copyright 1992 Cambridge Medical Publications
Address for correspondence DR D MICHAILIDIS Janssen Pharmaceutica SACI, 282 Kifissias Avenue, 152 32 Halandri, Athens, Greece
400
l'
'll9DiI; 1'1: "~ ~
'
,
~
:
.li!
-110
' '
~
>
' - " '" "
A Comparison of Itraconazole and Griseofulvin in the Treatment of Tinea Corporis and Tinea Cruris: a Double-blind Study T KOUSIDOU2 ,
D PANAGIOTIDOUt, A
2
KALOGEROPOULOU
,
A
TEKNETZIS
1
G CHAIDEMENOS 2 , G KARAKATSANIS 2 , 2 , E CHATZOPOULOU AND D MICHAILIDIS.1
'Department of Dermatology, University of Thessaloniki, Thessaloniki, Greece; 'Department of Dermatology and Mycology, Dermatological and Venereal Diseases Hospital, Thessaloniki, Greece; 3Janssen Research Foundation, Athens, Greece
A total of 40 patients with clinically and mycologically documented tinea corporis or tinea cruris were treated with 100 mg/day itraconazole [n = 19) or 500 mg/day griseofulvin (n = 21) for 15 days. Of the itraconazole-treated patients, 83.3% were healed or markedly improved, i.e, 'responders', after 15 days compared with 85.7% of griseofulvin-treated patients. At 15 days after the end of treatment, 88.2% of itraconazole- and 80.9% ofgriseofulvin-treated patients were classed as 'responders'. The mycological cure rate (both microscopy and culture negative) was generally lower than the clinical response rate. Both treatments were equally effective at the end of 15 days' treatment with 66.7% of patients cured, but itraconazole was superior to griseofulvin at the 15-day follow-up visit (77.8% of itraconazole-treated patients compared with 66. 7% ofgriseofulvin-treated patients were cured). Both therapies were well tolerated; only one patient treated with itraconazole reported minor side-effects (dizziness, headache and gastro-intestinal disturbances). The results confirm those ofearlier comparative trials and suggest
392
that griseofulvin-treated patients are more at risk of relapse than are itraconazole-treated patients.
1:£ evn (JlJVOAO 40 uofh:vwv ,"If: XAtVtXU Xat !-tllxll'tOAoytXU 'tfX!-tllQtW!-ttvll 'tQtxoqJ1J'tlU tou oW!-tu'tO~ tl 'twv !-tllQO~Oll~W Vtxwv 1t1:llXO)V XOQllYtl0llxUV ytU 15 !-ttQf~, 100 mg t'tQuxovu1;OAll~ ll!-tfQllOlW~ (itraconazole, uQtO. uoO. = 19) tl 500 mg YXQt1;fOqJOllA~lVll~ ll!-tfQllolW~ (griseofulvin, uQtO. uoO. = 21). A1to 'tOll~ UOOfV£l~ O'tOll~ 01tOlOll~ XOQllYtl0llXf t'tQuXOVU1;OAll, OfQU1tfUOllXUV T£AflW~ tl Oll!-tflWOUV oll!-tuv'ttxtl ~fATlwoll, ()llA. "uv'tU1tOXQlOllXUV" o'tll OfQU1tfll'ttXtl uywYtl, !-t£'tu 15 !-ttQf~ 83,3%, Of aUYXQtOll !-tf 85,7% 'twv UOOfVWV O'tOll~ 01tOlOll~ XOQllYtl0llxf YXQt1;fOqJOllA~lVll' M£'tu 15 !-tfQf~ U1tO 'to 'ttAo~ 'tll~ OfQU1tflU~, 83,3% U1tO 'tOll~ UOOfVfl~ orou; 01tOlOll~ XOQllYtl0l1Xf t'tQuXOVU1;OAl1 Xat 80,9% U1tO 'tOll~ UOOfVfl~ orouc 01tOlOll~ XOQllYtl0llXf YXQt1;fOqJOllA~lVll U~tOAOYtlOllXUV ouv u'to!-tu 1tOll "uv'tU1toxQlOllXUV" (J'tll OfQU1tfll'ttXtl uywYtl. To nooooro !-tllXll'tOAOYtXtl~ OfQU1trtU~ (UQVll'ttXtl !-ttxQooxo1ttxtl f~t'tUoll Xat XUAAttQYUU) tl'tuv YfVtXU XU!-tllMT£QO U1tO 'to noooero XAtVtXtl~ uv'tU1toxQtOl1~. Kat ot ()uo OfQU1tfll'ttXt~ UYWYf~ tl'tuv f~lOOll U1tOT£Af(J!-tU'ttXt~ oro 'ttAO~ 'tll~ ()fXU1tfVOtl!-tfQl1~ OfQU1tflU~ 01tOll 66,7% U1tO 'tOll~ UOOfVfl~ OfQU1tfU0llxuv, UAAU XU'tu mv f1tUVf~t'tUOll !-t£'tu U1tO UAAf~ 15 !-ttQf~, 11 t'tQuXOVU1;OAl1 tl'tuv UVWT£Ql1 't11~ YXQt1;fOqJOllAqJlVl1~ ue nooooro tUOfW~ 77,8% evuvn 66,7% 'twv UOOfVWV 'tll~ UV'ttO'tOlXOll o!-tU()U~ 'tll~ YXQt1;fOqJOllA~lVll~. Kat or ()UO OfQU1tf1J'ttXf~ UYWYf~ tl'tuv XUAU UVfX'tf~' uovo fVU~ UOOfVtl~ orov 01tOlO XOQllYtl0llXf t'tQuXOVU1;OAll UVtqJfQf fAUqJQf~ UVf1ttOU!-tllT£~ fVfQYUf~ (1;UAll, XfqJUAUAYlU Xat YUO'tQfVT£Qtxt~ ()tU'tuQuxt~). 'Iu U1tOT£AfO!-tU'tU f1tt~f~atWVOllV fXflVU 1tQOllYOll!-tfVWV (J1JyxQt'ttxwv !-tfA£'tWV Xat ll1tobuXVUOllV o'tt Ot UOOfV£l~ (J'tOll~ 01tOlOll~ XOQllYtl0llXf OfQU1tflU ue YXQt1;fOqJOllA~lVll ~Ql OXOV'tUt Of !-tfYUAUT£QO XlV()llVO ll1t01:Q01ttl~ U1tO 'tOll~ UOOfVrt~ O'tOll~ 01tOlOll~ XOQllYtl0llXf OfQU1tfll'ttXW~ t'tQUXOVU1;OAll.
KEY WORDS: ITRACONAZOLE; GRISEOFULVIN; ANTIMYCOTICS; FUNGAL SKIN INFECTIONS; TINEA CORPORIS; TINEA CRURIS
393
INTRODUCTION A large number of in vitro tests as well as studies using animal models have shown that itraconazole, a new lipophilic triazole, is extremely active against a range of fungi.' -6 In addition, the efficacy of itraconazole against common dermatophytoses in experimental models is superior to that of ketoconazole or gri seofulvin." The antimycotic efficacy of itraconazole in humans has already been confirmed by the results of several clinical studies in the treatment dermatophytosis.' - 9 The conventional approach to the treatment of fungal skin infections is to continue antimycotic therapy for several days after the complete disappearance of the clinical signs and symptoms. It has been shown, however, that pharmacokinetic concentrations of itraconazole remain in the skin for up to 4 weeks after the discontinuation of treatment.l'':!' thus suggesting that improvement could continue after the end of therapy. Griseofulvin, on the other hand, has been found to disappear rapidly from the stratum corneum after the discontinuation of administration 12 -16 and this loss of griseofulvin from the stratum corneum parallels a reduction in plasma concentrations. The purpose of the present study was to establish if the difference in the pharmacokinetic profiles of the two drugs results in a different outcome with respect to antimycotic efficacy.
chronic mucocutaneous candidiasis; and systemic mycotic disease. Patients who had received systemic antimycotic treatment within 1 month prior to the start of the study were also excluded, as were pregnant or lactating women, and women not using adequate contraceptive methods.
STUDY DESIGN AND TREATMENT The patients were double-blindly randomized to receive either itraconazole or griseofulvin. Each patient was supplied with 30 capsules of either 250 mg griseofulvin or 50 mg itraconazole. The treatment, consisting of two capsules ofthe double-blind medication to be taken once daily just before breakfast, was continued for 15 days. All patients had to discontinue the treatment after this period irrespective of the clinical and mycological result at that time.
CLINICAL AND MYCOLOGICAL ASSESSMENT The patients were all evaluated clinically and mycologically (microscopy and culture) before entering the trial, after 15 days' therapy and 15 days after completion oftreatment. At each clinical evaluation the following variables were scored using a four-point rating scale (0, absent; 1, mild; 2, moderate; 3, severe): desquamation; exudation; vesiculation; fissures; maceration; erythema; inflammation; and subjective complaints. A mycological evaluation consisted ofa microscopic and a Wood's lamp examination, which were either positive or negative, and a mycological culture with identification of the pathogen, if positive. At the end of 15 days' treatment, as well as at the follow-up (15 days after treatment), a global assessment of the therapy was performed as follows: healed with negative mycological findings; marked improvement with negative mycological findings; marked improvement with positive mycological
PATIENTS AND METHODS PATIENTS Patients with clinical signs and symptoms of a fungal infection and with a positive microscopy and culture for dermatophytes were included in the study, irrespective ofthe extent of the lesions. The following conditions were excluded: yeast infections of the skin, including pityriasis versicolor; tinea pedis or manus; oral thrush; vaginal candidiasis,
394
Patient characteristic in a study comparing the efficacy of itraconazole and griseofulvin in the treatment of tinea corporis and tinea cruris
Itraconazole (n = 19)
Characteristics Sex Male Female
10 9
Griseofulvin (n = 21)
14 7
Age (years) Mean Range
34 17 - 65
37 18 -70
Weight (kg) Mean Range
69 55 - 90
75 48 - 135
Height (ern) Mean Range
168 155 - 180
171 155 - 190
Diagnosis Tinea corporis Tinea cruris Duration of infection (months) Mean Range
10 9
8 13
7.2 0.2 - 36.0
6.3 0.3 - 24.0
No. of patients in which present infection is a relapse
3
0
No. of patients with concomitant disease
1a
0
No. of patients previously treated"
8
3
a
Seborrhoeic dermatitis of the scalp plus psoriasis.
b
Previous treatments included aminoglycosides, antifungals and corticosteroids.
395
findings; considerable residual lesion; no change; deterioration; or unevaluable.
included in the study had a positive microscopy and culture at the start of treatment (Table 2).
STATISTICAL ANALYSIS MYCOLOGICAL RESULTS
Fisher's exact test (two-tailed) was used to evaluate the mycological cure rates. For the clinical results, Wilcoxon signed-rank test was used for intragroup comparison, whereas the Mann - Whitney V-test was used for comparisons between the two treatment groups. Global assessment results were analysed with Fisher's exact test (grouped levels).
The results of the microscopic and Wood's lamp examinations and the cultures performed at each evaluation point (baseline, 15 days of treatment and 15 days post-treatment) are summarized in Table 3. Atthe end of treatment, both treatments were equally active. At the 15 days' post-treatment visit, although statistical significance was not achieved (Fisher's exact test, two-tailed), the mycological cure rate obtained following itraconazole treatment had increased, whereas the mycological cure rate following griseofulvin treatment remained at the same level.
RESULTS A total of 40 patients were included in the trial: 19 patients were treated with itraconazole and 21 patients were treated with griseofulvin. There were no statistically significant differences in patient characteristics between the two treatment groups; patient characteristics are listed in Table 1. All patients
CLINICAL RESULTS There were no statistically significant differences between the two treatment groups in terms of symptom scores at the start of the
Causative organisms isolated at the start of the study comparing the effectiveness of itraconazole and griseofulvin in the treatment of tinea corporis and tinea cruris Griseofulvin Causative organisms
(n=21)
Trichophyton rubrum Epidermophyton floccosum T. mentagrophytes T. violaceum T. ochraceum Microsporum canis Trichopyton rubrum + Candida albicans Candida albicans + T. mentagrophytes var. interd.
Itraconazole (n = 19)
10
11
3 3
3 1
1
1
1
2
2
o
o o
396
w
'1
se
=
15 (71.4%)
12 (66.7%)
0
Negative culture
0
20 (95.2%)
19 (90.5%) 16 (88.9%)
17 (89.5%)
Negative Wood's lamp
16 (76.2%)
13 (72.2%)
0
0
Negative microscopy
Griseofulvin (n 21)
=
=
Itraconazole (n 18)
=
Griseofulvin (n 21)
End of treatment
Evaluation
Itraconazole (n 19)
Baseline
14 (77.8%)
17 (94.4%)
16 (88.9%)
=
Itraconazole (n 18)
15 (71.4%)
20 (95.2%)
16 (76.2%)
Griseofulvin (n=21)
15 days' post-treatment
Incidence of negative microscopic and Wood's lamp examination, and negative cultures following treatment of patients with tinea corporis or tinea cruris with 100 mg/day itraconazole or 500 mg/day griseofulvin for 15 days (end of treatment) and at 15 days following completion of treatment (15 days' post-treatment)
visit. The Fisher exact test for grouped levels showed no statistically significant difference at the end of treatment (P = 1.000) or at the follow-up 15 days' post-treatment visit (P =
study (Mann - Whitney U-test). All symptoms except fissures improved significantly compared with prior to treatment at both posttreatment points in both treatment groups (Pvalues ranged from P < 0.001 to < 0.05; Wilcoxon test). At the end of treatment and 15 days' posttreatment there were no significant differences between the two groups (Mann - Whitney Utest) for all symptoms.
0.672).
DISCUSSION The results of the present double-blind clinical trial indicate that both itraconazole and griseofulvin were effective in the treatment of tinea corporis and tinea cruris. In both treatment groups all signs and symptoms improved significantly by the end of treatment and at 15 days' post-treatment, but there were no significant differences between the two treatment groups at these evaluation points. At the end of the treatment period, the
GLOBAL ASSESSMENTS The investigator's global assessments for each treatment at each evaluation point are shown in Table 4. There were no statistically significant differences in global assessments between the two treatment groups at the end of treatment or at the 15 days' post-treatment
Global assessment of patients with tinea corporis and tinea cruris following treatment with 100 mg/kg itraconazole or 500 mglkg griseofulvin for 15 days (end of treatment) and at 15 days following completion of treatment (15 days' post-treatment) End of treatment
15 days' post-treatment
Itraconazole (n = 18)
Griseofulvin (n = 21)
Itraconazole (n = 18)
Griseofulvin (n = 21)
Clinically and and mycologically healed
4 (22.2%)
5 (23.8%)
10 (55.6%)
11 (52.4%)
Marked clinical improvement Negative mycology Positive mycology
6 (33.3%) 5 (27.7%)
8 (38.1%) 5 (23.8%)
3 (16.7%) 2 (11.1%)
2 (9.5%) 4 (19.0%)
Considerable lesion
3 (16.7%)
3 (14.3%)
1 (5.6%)
3 (14.3%)
Deteriorated
0
0
2 (11.1%)
1 (4.8%)
Assessment
398
precentage of 'responders' (healed plus markedly improved) in the griseofulvin-treated group was higher than in the itraconazoletreated group (85.7% compared with 83.3%), although the mycological cure rates were identical (66.7%). At the follow-up visit, 15 days after the end of treatment, 83.3% of the patients in the itraconazole treatment group and 80.9% ofthe patients in the griseofulvin treatment group were considered to be 'responders' and this trend towards itraconazole being superior to griseofulvin was reflected in the mycological outcome (77.8% compared with 66.7% mycological cure). It seems then that the response rate and the mycological cure rate in the itraconazole treatment group continued to increase in the 15 days following treatment and this can be explained by the high affinity that itraconazole has for the skin. This property of itraconazole produces longer-lasting concentrations of the drug in the epidermis, thus offering an advantage in the treatment of skin dermatophytosis beyong the treatment period. On the other hand, a decrease in response rate and maintenance of the mycological cure rate after discontinuation of treatment with griseofulvin was observed, suggesting an immediate decline in drug concentrations after treatment is discontinued. The clinical efficacy
was good in the short treatment course under study, although griseofulvin should be administered for longer periods of time. The results obtained in the present small-scale study have been confirmed by other studies with larger numbers of patients, in which similar cure rates and clinical response rates were recorded." The tendency for continued im provemen t after discon tin uation of itraconazole has also been reported by others. ' ? Both griseofluvin and itraconazole were well tolerated in the present study: some minor side-effects, such as dizziness, headache and gastro-intestinal disturbances, were reported by one patient who was treated with itraconazole. In conclusion, itraconazole or griseofulvin, given at a daily dose of 100 or 500 mg, respectively, for 15 days, was effective in the treatment of tinea corporis and tinea cruris. The clinical results were marginally better wi th griseofulvin than those with itraconazole at the end oftreatment; however, this situation was reversed at the 15-day follow-up visit. From the mycological point of view, there was a trend towards itraconazole being superior to griseofulvin 15 days after the end oftreatment. These findings indicate a continuing improvement with itraconazole, even after the discontinuation of therapy. Both therapies appeared to be well tolerated.
REFERENCES 1 Heeres J, Backx LJ, Van Cuts em J: Antimycotic azoles. 7. Synthesis and antimycotic properties of R51211 and its congeners.JMed Chern 1984; 27: 894-900. 2 Van Cutsem J: Oral and parenteral treatment with itraconazole in various superficial
and systemic experimental fungal infections: comparisons with other antifungals and combination therapy. Br J Clin Pract 1991; 44(suppl): 32 - 40. 3 Van Cutsem J, Janssen PAJ: Nouveaux antimycosiques: activite in vitro et in vivo.
399
Bull Sci Fr Mycol Med 1985; 14: 131-140. 4 Van CutsemJ, JanssenPAJ: Oral efficacy of griseofulvin, ketoconazole and itraconazole in disseminated dermatophytosis and of azoles in systemic mycoses with skin manifestations. 17th World Congress of Dermatology, Part II. Berlin, Germany, 24 - 29 May 1987; p. 138. 5 Van Cutsem J, Van Gerven F: The in vivo antifungal activity of broad-spectrum azoles. Drug Dev Res 1986; 8: 309 - 316. 6 Van Cutsem J, Van Gerven F, Janssen PAJ: Activity of orally, topically and parenterally administered itraconazole in the treatment of superficial and deep mycoses, animal models. Rev Infect Dis 1987; 9(suppl 1): S15 - S32. 7 Cauwenbergh G, De Doncker P: Itraconazole: a clinical review of its antimycotic activity in dermatology, gynecology, and internal medicine. Drug Dev Res 1986; 8: 317 - 323. 8 Cauwenbergh G, De Doncker P, Stoops K, et al: Itraconazole in the treatment of human mycoses: review of three years of clinical experience. Rev Infect Dis 1987; 9(suppl 1): S146 - S152. 9 Degreef H, Marlen K, De Veylder H, et al: Itraconazole in the treatment of dermatophytoses: a comparison of two daily dosages. Rev InfeetDis 1987; 9 (suppl 1): S104 - S108. 10 Cauwenbergh G, Degreef H, Heykants J, et al: Pharmacokinetic profile of orally administered itraconazole in human skin. JAm Acad Dermatol1988; 18: 263 - 268. 11 Heykants J, Van Peer A, Van de Vel de V, et
12
13
14
15
16
17
al: The clinical pharmacokinetics of itraconazole: an overview. Mycoses 1989; 32(suppl1): 67 - 87. Anderson SW: Griseofulvin: biology and clinical usefulness: a review. Ann Allergy 1965; 23: 103 - 110. Artis WM: Final pathway for delivery of oral antifungals to keratinized cornified skin. In: Oral Therapy in Dermatomycoses: a Step Forward (Meinhof W, ed). Frankfurt: Medicine Publishing Foundation, 1986; pp 61 - 70. Epstein WL, Shah VP, Riegelman S: Griseofulvin levels in stratum corneum: study after oral administration in man. Arch Dermatol1972; 106: 344 - 348. Shah VP, Riegelman S, Epstein WL: Determination of griseofulvin in skin, plasma and sweat. J Pharm Sci 1972; 61: 634 - 636. Shah VP, Epstein WL, Riegelman S: Role of sweat in accumulation of orally administered griseofulvin in skin. J Clin Invest 1974; 53: 1673 - 1678. Saul A, Bonifaz A: Itraconazole in common dermatophyte infections of the skin: fixed treatment schedules. JAm Acad Dematol 1989; 23: 554 - 558.
D Panagiotidou, T Kousidou, G Chaidemenos, G Karakatsanis, A Kalogeropoulou, A Teknetzis, E Chatzopoulou and D Michailidis A Comparison ofltraconazole and Griseofulvin in the Treatment of Tinea Corporis and Tinea Cruris: a Double-blind Study The Journal of International Medical Research 1992: 20: 392 - 400 Received for publication 27 April 1992 Accepted 29 May 1992 © Copyright 1992 Cambridge Medical Publications
Address for correspondence DR D MICHAILIDIS Janssen Pharmaceutica SACI, 282 Kifissias Avenue, 152 32 Halandri, Athens, Greece
400
