Clinical and Experimental Dermatology 1990; 15; 210-216.
A comparative double-blind study of terbinafine (Lamisil) and griseofulvin in tinea corporis and tinea cruris A.DEL PALACIO HERNANZ, S.LOPEZ GOMEZ,* F . G O N Z A L E Z LASTRA, P.MORENO PALANCAR AND L.IGLESIAS DIEZ* Departments of Microbiology and * Dermatology, Hospital 11 de Octuhre, Carretera de Andalucia km 5,4, 28041 Madrid, Spain Accepted for publication 10 November 1989
Summary In a double-blind randomized study, 92 patients with culturally proven tinea corporis and/or tinea cruris were treated orally with either terbinafine (Lamisil) (125 mg b.i.d.) or griseofulvin (500 mg b.i.d.) for up to 6 weeks. The two groups of patients and distribution of the target lesions were similar, but the analysis ofthe clinical scores showed that the terbinafine group had slightly higher mean scores at baseline (P=0-186). At the end of therapy the proportion of patients with negative microscopy and culture was 78% in the terbinafine group and 83% in the griseofulvin-treated group. At the assessment 8 weeks after the end of therapy the percentages of terbinafineand griseofulvin-treated patients with negative mycology were 93 and 95%, respectively. There were three relapses after mycological cure in the griseofulvin group (8%) and two in the terbinafine group (4%). Griseofulvin-treated patients were treated for shorter periods than terbinafinetreated patients (i.e. 58% compared to 26% received only 2-4 weeks of therapy). In terms of overall effectiveness, there were no significant differences between the two treatments. Thirty-seven terbinafine patients (77%) compared to 36 griseofulvin patients (82%) had overall effective therapy. Eight terbinafine patients (16%) compared to 10 griseofulvin patients (20%) experienced at least one adverse event. Five patients in the terbinafine group and six in the griseofulvin group had to stop the treatment due to headaches or gastrointestinal disorders. One terbinafine patient had an elevation of liver function tests after 6 weeks of treatment. Thus, in our study, terbinafine (250 mg daily oral dose) was comparably safe but slightly less effective than griseofulvin (1 g daily) for up to 6 weeks in the treatment of widespread tinea corporis and cruris among patients aged 18-65 years, although at long-term follow-up there was no difference between the two drugs. Correspondence; Dr A.del Palacio Hernanz, Department of Microbiology, Hospital 12 de Octubre, Carretera de Andalucia km 5,4, 28041 Madrid, Spain.-
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Terbinafine (Lamisil), a synthetic allylamine antifungal agent developed for either oral or topical application, is effective in vitro against a range of dermatophyte fungi, as shown by different studies.'"^ An important property of terbinafine is that it has been shown to possess primary fungicidal activity against dermatophytes, Aspergillus, Scopulariopsis brevicaulis and dimorphic fungi.''^ In vivo, terbinafine is not only active after topical application but is very effective in experimental dermatophytosis following oral administration.* * Few published reports are at present available on the effect ofthe drug for the oral treatment of dermatophytosis in man, and the value of oral terbinafine has been studied in a number of open studies in patients and healthy volunteers with experimental dermatophyte lesions.^''" Most of the published clinical studies have concentrated on patients with moccasin-type tinea pedis," 'dry type' Trichophyton rubrum affecting the palm or soles (R.J.Hay, personal communication) and onychomycosis,'^ and in all of these the most prevalent infecting species was T. rubrum. Dermatophytosis can be treated topically with a variety of compounds;'^ oral therapy is necessary for scalp, nail and widespread skin lesions. Since griseofulvin was introduced in the 1960s, it is the drug most commonly used for systemic treatment of dermatophytosis.'^ Later, imidazoles and triazoles with oral activity were obtained;'^"'^ they all act primarily as fungistatic drugs, but terbinafine has the distinctive feature of being primarily fungicidal, and therefore has potential in the oral treatment of skin and hair dermatophyte infections.''^''^ After 30 years of generalized use, griseofulvin has emerged as a safe drug for the treatment of skin and hair dermatophyte infections, and although cure rates for nail infections using this drug are low, it clearly remains the drug of choice for the treatment of tinea capitis. Its excellent safety record over the past 30 years should be kept in mind when considering alternatives." The purpose of the present work was to try to
TERBINAFINE AND GRISEOFULVIN COMPARED
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determine the efficacy and safety of oral terbinafine compared with griseofulvin for the treatment of widespread tinea corporis and tinea cruris.
aud's dextrose agar with added chloramphenicol and actidione) were done in all the assessments. MIC values to both antifungals were determined using a broth dilution test with Sabouraud's dextrose liquid medium (0 05-50 /ig/ml). A diluted inoculum (1:100) of a 120-h Methods culture in Sabouraud's dextrose broth was used. The trial was a double-blind study and patients were Tolerability was assessed by noting adverse events randomized into one of two treatment groups: terbinafine which occurred during the trial and their severity graded (two capsules, one with 125 mg ofthe compound and the (mild, moderate or severe). other one with placebo) after lunch, and two capsules Haematological investigation (haemoglobin, haemaprepared identically after dinner (total daily dose: 250 mg tocrit, total WBC with differential and platelet count) and of terbinafine); or (b) micronized griseofulvin, two biochemical tests (SGOT, SGPT, alkaline phosphatase, capsules of 250 mg after lunch and two capsules after LDH, bilirubin, total protein, albumin, creatinine, gludinner (total daily dose: 1 g of griseofulvin). Neither the cose, cholesterol and triglycerides) and urine tests (proclinician nor the patient knew which was being used. tein, glucose, acetone, bile and sediment) were carried out Treatment was administered for a period of up to 6 at the initial examination and after weeks 2, 4 and 6 of weeks; therapy was concluded earlier if either the patient therapy and at follow-up after the end of the treatment was rated completely cured, both mycologically and when necessary. clinically, before this time, or there was a premature termination of therapy (severe adverse event or lack of Evaluation of drug effectiveness efficacy). Concomitant medication for various chronic diseases, The primary assessment of efficacy was based on a such as cardiac insufficiency, high blood pressure or combined evaluation of mycological tests (microscopy/ diabetes mellitus were maintained during the study. culture) and the sum of clinical scores at each visit during the treatment period and at follow-up according to the following scheme: Patients All patients were assessed prior to treatment with a detailed history and clinical examination. Only patients aged between 18 and 65 years suffering from tinea corporis or cruris confirmed by direct microscopy and culture were included in the study. Written consent was obtained from all patients. Pregnant women and female patients of child-bearing age not using reliable contraceptive measures, those with dermatophytosis of palms or soles, patients with diseases of the digestive system, conditions which might impair absorption from the gastrointestinal tract, such as gastritis, patients with liver disease, nephropathy, blood dyscrasias, disturbances of porphyrin metabolism, patients allergic to griseofulvin, patients receiving radiation therapy, systemic therapy with cytostatic or immunosuppressive drugs, or therapy with anti-infective drugs either at the time ofthe trial or 4 weeks prior to the start of the study were excluded from the trial. Assessments
The patients were seen once a week during treatment and at follow-up (2 months post-therapy). Parameters of clinical disease activity (erythema, scaling, vesiculation, pustules, incrustation, pruritus) were assessed and scored as: 0=absent; l=mild; 2=moderate; 3=severe. Scrapings were taken from the target lesion and mycological examinations (direct microscopy and culture on Sabour-
Effective therapy. This included two categories— either: (a) Complete cure—microscopy and culture negative, no residual clinical signs and symptoms; or (b) Mycological cure—microscopy and culture negative, mild residual erythema and/or desquamation and/or pruritis (total score 2), but no other clinical signs. Ineffective therapy. Premature termination due to adverse side-effects and improvements A, B, C or failures. (a) Improvement A—microscopy and culture negative; clinical signs and symptoms diminished ^ 50% of initial total score; (b) Improvement B—microscopy and culture negative; clinical signs and symptoms diminished 2) or recurrence of positive mycology. Premature terminations due to side-effects were considered in this category for all
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visits following the last assessment, including the followup visit.
Table 1. Patients' demographic characteristics and histories
Overall effectiveness. This was defined as effectiveness at the follow-up visit (2 months after the end of therapy).
Terbinafine («=48)
Griseofulvin («=44)
27/21
28/16
46 2 0 2 2
41 2 1 1 1
20
17
19 36/12
14 35/9
Sex (males/females) Duration range (weeks) 52 Diabetes Psoriasis Previous antifungal therapy (number of patients) Previous topical corticosteroids (number of patients) Lesion: single/multiple
Results One-hundred patients entered the study. Of these, eight were drop-outs (two in the terbinafine group and six in the griseofulvin group). Eleven patients (five in the terbinafine group and six in the griseofulvin group) terminated therapy prematurely due to adverse events. There were no significant differences in the age, sex, weight or height distribution, duration of disease, type and size of lesion, predisposing factors, other diseases in past history, family members with fungal infections and prior medications between the groups. The demographic characteristics and patients' histories are recorded in Table 1. The sites of lesions and infecting organisms responsible for the infection had an even distribution in both groups and are recorded in Table 2. When the distributions of basehne signs and symptoms were compared across treatment groups it was noted that the severity score for pruritus was higher in the terbinafine group (P=0 014). The mean sum of scores at baseline was more severe for the terbinafine patients (81) than for those on griseofulvin (7 4) (P=0186).
Table 2. Sites of target lesion and fungi isolated
Sites involved Face Body Arm/leg Groin
Terbinafine («=48)
Griseofulvin (»=44)
6 3 4/9 26
4 2 4/7 27
0 3 11 16 18
1 0 8 14 21
Fungi T. verrucosum M. canis T. rubrum T. mentagrophytes E. floccosum
Mycological results
The mycological results for each week of evaluation are given in Table 3. The combined analysis represents the number and percentage of patients with negative direct
Table 3. Number and percentage of patients with negative microscopy and culture Week of treatment Evaluation
Treatment group
1
2
3
4
5
6
Microscopy Terbinafine
Follow-up
6/47 18/44 32/44 33/39 28/32 21/23 (13%) (41%) (73%) (85%) (88%) (91%) Griseofulvin 9/42 29/39 33/37 33/33 16/16 6/6 (21%) (74%) (89%) (100%) (100%) (100%)
41/43 (95%) 36/38 (95%)
Culture
Terbinafine
4/47 (9%) Griseofulvin 5/42 (12%)
15/44 (34%) 26/39 (67%)
31/44 30/39 25/32 (70%) (77%) (78%) 31/37 32/33 14/16 (84%) (97%) (88%)
18/23 (78%) 5/6 (83%)
40/43 (93%) 36/38 (95%)
Combined
Terbinafine
15/44 (34%) 25/39 (64%)
28/44 28/39 (64%) (72%) 31/37 32/33 (84%) (97%)
18/23 (78%) 5/6 (83%)
40/43 (93%) 36/38 (95%)
4/47 (9%) Griseofulvin 5/42 (12%)
23/32 (72%) 14/16 (88%)
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Table 4. Mean scores for each of the three major signs and symptoms Week of treatment Sign/ symptom
Treatment group
Erythema
Terbinafine 2-7 2-3 1-8 1-1 1-0 0-9 0-9 Griseofulvin 2-8 1-9 1-2 0-8 0-5 0-3 0-2
0-1 0-1
Desquamation Terbinafine 2-3 2-2 1-7 1-1 1-1 1-1 0-9 Griseofulvin 2-2 1-5 1-2 0-9 0-6 0-4 0-8
0-3 0-1
Pruritus
0-2 0-1
0
1
2
3
4
5
6
Follow-up
Terbinafine 2-4 1-4 0-8 0-5 0-6 0-5 0-3 Griseofulvin 1-9 0-8 0-4 0-2 0-1 0-1 0-2
microscopy and negative mycological culture at each visit. The proportion of patients with negative microscopy was significantly higher in the griseofulvin group at Week 2 (P=: 0-004). The proportion of patients with negative culture results was significantly higher in the griseofulvin group at both Week 2 ( P ^ 0-009) and at Week 4 (P=0-032). Evaluation of mycological tests revealed that the proportion of patients with negative microscopy and culture at the end of therapy and follow-up assessments were similar in the two treatment groups. All the fungi isolated before treatment were sensitive to both antifungals in vitro, having minimal inhibitory concentrations of 0-05-0-1 /ig/ml for terbinafine and 0-86-25 /ig/ml for griseofulvin. None of the strains isolated after treatment was stopped were shown to have developed resistance to either compound in vitro. Clinical results
The most frequently reported signs and symptoms in patients before therapy included erythema (100%), desquamation (100%) and pruritus (92%). When eval-
uated separately, these had virtually all disappeared at the follow-up assessment in both treatment groups (Table 4). The rate of decrease in severity for the three major signs and symptoms appeared to be faster in the griseofulvin group. The score was significantly lower at Week 1 (all P CO-002), Week 2 (all P < 0-005), Week 4 (all P < 0-024) and Week 5 (all />< 0-051). The sum of scores for signs and symptoms decreased markedly in both treatment groups as the trial progressed. These results are shown in Table 4. The terbinafine group had more signs and symptoms at baseline (/'=0-186) than the griseofulvin group, and the latter showed a more rapid reduction in signs and symptoms compared to baseline at Week 1 (/•=0-005) and Week 2 (P=0-042) but not thereafter. Effectiveness evaluation
Table 5 shows the results of the response to treatment at the end of therapy and at follow-up. When all categories of clinical response were considered, there was a significant difference in favour of griseofulvin at the end of therapy, but not at follow-up or overall assessment (as
Table 5. Combined clinical and mycological evaluation
End of therapy Response Complete cure Mycological cure+minimal signs Effective treatment Mycological cure + improvement (Imp A or B) Mycological failure + improvement (Imp C) Failure Ineffective treatment* Total patients
Follow-up (overall assessment)
Terbinafine Griseofulvin Terbinafine Griseofulvin 24 7
28 9
37 0
35 1
31 (65%) 6 5 6 17 (35%)
37 (84%) 0 0 7 7(16%)
37 (77%) 3 1 7 11 (23%)
36 (82%) 0 0 8 8 (18%)
48
44
48
44
' The ineffective treatment group includes premature termination of therapy due to adverse effects.
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A.DEL PALACIO HERNANZ et al.
Table 5 shows, terbinafine was judged to have efficacy in lasting 6 weeks). Four weeks after the end of treatment 77% of patients and griseofulvin in 82%). normal regrowth ofthe hair started. The response to treatment according to the sites of There were five terbinafine patients with side-effects infection and the dermatophyte species involved in the that required discontinuation of therapy (all disappeared infection showed no detectable difference. subsequently): stomach pain (one), headache, dizziness Table 6 shows the sites and infecting organisms in and dyspepsia (two), dizziness and urticaria (one) and those patients in whom the treatment was ineffective (2 urticaria (one). months after the end of therapy) excluding those who Moderate side-effects with griseofulvin appeared early were rated as failures because they had to abandon the in therapy and later subsided. These were: insomnia, treatment due to intolerance. dizziness, nausea and headache (one), insomnia and Griseofulvin-treated patients were treated for shorter headache (one), headache (one) and urticaria (one). periods than terbinafine-treated patients (i.e. 58% comSix griseofulvin-treated patients experience sidepared to 26% received only 2-4 weeks of therapy). effects that required termination of therapy: headache, There were three relapses after mycological cure in the dizziness and nausea (one), headache and widespread griseofulvin group (8%) at the assessment 2 months after urticaria (one), headache, nausea and vomiting (two), the end of the treatment (consisting of 4 and 6 weeks in stomach pain and watery diarrhoea (one), and anorexia, two patients and 12 days in another who had to stop dyspepsia and stomach ache (one). therapy due to intense side-effects). Two of these patients All these side-effects disappeared on discontinuation of had tinea cruris caused by E.Jloccosum and T. rubrum and the treatment. The patients with urticaria either in the third had tinea corporis caused by T. mentagrophytes. terbinafine or griseofulvin groups were not challenged In the terbinafine group two patients (5%) relapsed after with the drug. treatment courses of 5 and 6 weeks. One patient had a groin infection caused by E. floccosum and the other extensive ringworm of the arm caused by Safety laboratory data T. mentagrophytes. Evaluation of bone marrow and renal function before and during the treatment with either terbinafine or griseofulvin revealed no clinically relevant drug-related changes. Overall tolerability In the liver-function tests there were some transient Eighteen patients (36%) showed intolerance to treat- changes in SGOT (one patient in the terbinafine group ment; eight of these (16%) were in the terbinafine group and another on griseofulvin) and SGPT (four patients on and ten (20%) in the griseofulvin group. terbinafine and one on griseofulvin). Two patients treated Three terbinafine-treated patients had moderate side- with terbinafine showed an asymptomatic elevation in effects possibly related to the drug in the first days of liver enzyme activity. One such patient had a high SGPT treatment, but they subsided and all were able to value of 100 u/1 at Week 2, decreasing to 29 u/1 at Week 4 complete their full course of treatment without any and had elevated values for y GT at Weeks 4 and 6 (66 and symptomatic therapy; these side-effects consisted of 54 u/1, respectively). The other patient showed elevated nausea and dizziness in two patients, and alopecia areata SGOT (106 u/1), SGPT (196 u/1), y GT (190 u/1) and of the scalp in another (commencing in Week 4 and alkaline phosphatase (227 u/1) at the end of Week 6. At follow-up, all enzyme activities except y GT (54 u/1) had Table 6. Non-effective treatment at the overall assessreturned to normal. ment (2 months after the end of treatment): sites and fungi isolated*
Discussion Terbinafine
(«=48)
Griseofulvin («=44)
Non-effective (number of patients) Sites: groin/body
6 4/2
3 2/1
Fungi isolated E. floccosum T. rubrum T. mentagrophytes
2 3 1
* Patients who abandoned treatment due to intolerance are excluded.
The results reported here suggest that oral terbinafine is, in general, comparably safe and slightly less effective than griseofulvin in the overall management of tinea corporis and tinea cruris at the end of treatment, although at longterm follow-up both drugs are comparable. Previous published studies have shown that terbinafine given orally is effective in tinea corporis, tinea pedis, candidosis and onychomycosis, but not in pityriasis versicolor.''^ The most appropriate dose for dermatophytosis appears to be 250 mg/day.'" Cure in patients treated systemically (125 mg b.i.d. orally) with terbinafine has been documented to be 75-
TERBINAFINE AND GRISEOFULVIN COMPARED 90% in tinea corporis.'" The results in our population were inferior at the end of the treatment to those published by Villiars and Jones,'" i.e. only 65% of our population treated with terbinafine were show to have achieved an effective treatment; however, at the assessment 2 months later, 77% of our patients were cured, without using other treatment measures. Therefore, in this overall assessment we have confirmed the data reported hy other investigators who have treated orally with terbinafine.'" This observation has been previously documented by other workers using different topical and systemic antifungals: a number of patients who still have moderate signs and symptoms at the end ofthe treatment with positive cultures (carriers) achieve a total clinical and mycological cure a few weeks later.'*'"^" This means that the process of healing of dermatophytosis is complex and therefore not dependent on positive cultures alone. In a study of the use of terbinafine orally (125 mg b.i.d.) compared with griseofulvin (250 mg b.i.d.), terbinafine was significantly better in a group of 252 patients, of whom 84% were infected with Trichophyton rubrum and 74% had chronic disease due to this organism.'" In this latter study the response rates (negative cultures and microscopy and in clinical signs and symptoms) during treatment were similar, in that by 2 weeks of treatment more than 70% of patients had negative mycological tests and marked clearing of signs and symptoms.'" Terbinafine was shown to be more effective after Week 3 of therapy since 11% of griseofulvin-treated patients remained infected and an additional 3% relapsed by 2 weeks after apparently successful treatment.'" R. Savin and R. Hay (personal communication) have reported similar findings in a group of patients with chronic tinea pedis (moccasin type)." Chronic tinea pedis (plantar or moccasin-type) caused by T. rubrum is generally unresponsive to the usual established topical and oral antifungal regimens.^'"^"^ The reasons for this refractory behaviour to therapy have not been fully clarified, although a number of factors are involved, such as drug absorption and penetration into thickened skin and defects in host resistance.^' In our study (see Table 2) other dermatophyte species were more common, T. rubrum was the causative agent in 19 patients (11 on terbinafine and eight on griseofulvin) and the infection was located on glabrous skin. It seems possible from available pharmacokinetic data that oral terbinafine achieves a lower concentration in the most superficial cells ofthe stratum corneum. This fact could account for the results achieved in our study, where patients were treated for widespread lesions but in whom inflammation was minimal and the fungi responsible for the infection were superficially located. This view is indirectly supported by the fact that although terbinafine is active in vitro against Pityrosporum spp. yeasts, the
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compound is exclusively effective for the treatment of pityriasis versicolor when applied topically.'" In our patients, the MIC values after therapy with terbinafine did not show any difference compared to pretreatment values, and therefore the development of resistance to terbinafine after therapy does not seem to be a problem, although this has to be confirmed studying larger populations. In our patients there were no significant differences in terms of tolerance between terbinafine and griseofulvin; however, one terbinafine-treated patient had an unexplained elevation in liver-function tests after 6 weeks of treatment—although this finding in one single patient is not necessarily relevant to the general population, it remains necessary to monitor liver function in patients on long-term therapy with terbinafine, at least until there is more clinical experience. Long-term follow-up and comparative studies with other antifungals will help to establish the place of terbinafine in the management of fungal infections. Acknowledgments We would like to thank Sandoz (Spain) for supplying the medication and the assistance and help of Dr J.A.Matilla Blasco during the trial. References 1. Petranyi G, Meingassner IG, Mieth H. Antifungal activity ofthe allylamine derivative terbinafine in vitro. Antimicrobial Agents and Chemotherapy 1987; 31: 1365-1368. 2. Shadomy S, Espinel-Ingroff A, Gembhart RJ. In vitro studies vjfith SF 86-327, a nevt orally active allylamine derivative. _7oMr«a/ of Medical and Veterinary Mycology 1985; 23: 125-132. 3. Clayton YM. SF 86-327. A laboratory evaluation of 5 antifungal agents. In: Spitzy KH, Karrer K, eds. Proceedings of the 13th International Congress of Chemotherapy. Vienna: Verlag H, Igermann 1983: 116/13-116/14. 4. Goudard M, Buffard Y, Ferrari H, Regli P. Spectre d'action in vitro d'un nouvel antifongique derive de la naftifine: la terbinafine (SF 86-327). Pathologie Biologie 1986; 34: 680-683. 5. Clayton YM. In vitro activity of terbinafine. Clinical and Experimentat Dermatology 1989; 14: 101-103. 6. Petranyi G, Meingassner JG, Mieth H. Activity of terbinafine in experimental fungal infections of laboratory animals. Antimicrobial Agents and Chemotherapy 1987; 31: 1558-1561. 7. Mieth H, Petranyi G. Preclinical evaluation of terbinafine in vivo. Clinical and Experimental Dermatology 1989; 14: 104-107. 8. Yamaguchi H, Uchida K. Once daily administration of terbinafine to guinea-pigs with experimental dermatophytosis. Clinical and Experimental Dermatology 1989; 14: 108-109. 9. Stephen A, Czok R, Male O. Terbinafine: Initial clinical results. In: Fromtling RA, ed. Recent Trends in the Discovery, Development and Evaluation of Antifungal Agents. Barcelona: J.R.Prous Science Publications, 1987: 511-520. 10. Villiars V, Jones TC. Clinical efficacy and tolerability of terbinafine (Lamisil), a new topical and systemic fungicidal drug for treatment of dermatomycoses. Clinical and Experimental Dermatology 1989; 14: 124-127.
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11. Savin R. Successful treatment of chronic tinea pedis (moccasin type) with terbinafine (Lamisil). Clinical and Experimental Dermatology 1989; 14: 116-119. 12. Zaias S, Serrano L. The successful treatment offingerTrichophyton rubrum onychomycosis with oral terbinafine. Clinical and Experimental Dermatology 1989; 14: 120-123. 13. Hay RJ. The current status of antimycotics in the treatment of local mycoses. Acta Dermato-Venereologica {Stockholm) 1986; Suppl. 121: 103-108. 14. Hay RJ. The azole antifungal drugs. Journal of Antimicrobial Chemotherapy 1987; 20: 1-5. 15. Saag MS, Dismukes WE. Azole antifungal agents: emphasis on new triazoles. Antimicrobial Agents and Chemotherapy 1988; 32: 1-8. 16. Hay RJ, Del Palacio Hernanz A. Introduction. First Symposium on terbinafine (Lamisil). Clinical and Experimental Dermatology 1989, 14: 97. 17. Becker LE. Griseofulvin. Dermatologie Clinics 1984; 2: 115-120. 18. Del Palacio Hernanz A, Lopez Gomez S, Moreno Palancar P, Gonzalez Lastra F. A clinical double blind trial comparing amorolfine cream 0-5% (RO 14-4767) with bifonazole cream 1% in the treatment of dermatomycoses. Clinical and Experimental Dermatology 1989; 14: 141-144.
19. Cauwenberg G, de Doncker P. The clinical use ofitraconazole in superficial and deep mycoses. In: Fromtling RA, ed. Recent Trends in the Development and Evaluation of Antifungal Agents. Barcelona: J.R.Prous Science Publications, 1987: 273-284. 20. Del Palacio Hernanz A, Lopez Gomez S, Iglesias Diez L. A clinical and mycological assessment of tioconazole solution in the treatment of superficial dermatomycoses. Clinical Therapeutics 1987; 9: 333-338. 21. Hay RJ, Clayton YM, Midgley G. The use ofitraconazole in chronic Trichophyton rubrum infections. British Journal ofDermatology 1986, US (Suppl iOy i'^22. Hay RJ, Clayton YM. Treatment of chronic dermatophytosis and chronic oral candidosis with itraconazole. Reviews of Infectious Diseases 1987; 9 (Suppl. 1): 114-118. 23. Hay RJ. Failure of treatment in chronic dermatophyte infections. Postgraduate Medical Journal 1979; 55: 608-610. 24. Robertson MH, Rich P et al. Ketoconazole in griseofulvinresistant dermatophytosis. Journal of the American Academy of Dermatology 1982; 6: 224-229. 25. Roberts SOB. Treatment of the superficial and subcutaneous mycoses. In: Speller DCE, ed. Antifungal Chemotherapy. Chichester: John Wiley and Sons, 1980: 225-283.
A comparative double-blind study of terbinafine (Lamisil) and griseofulvin in tinea corporis and tinea cruris A.DEL PALACIO HERNANZ, S.LOPEZ GOMEZ,* F . G O N Z A L E Z LASTRA, P.MORENO PALANCAR AND L.IGLESIAS DIEZ* Departments of Microbiology and * Dermatology, Hospital 11 de Octuhre, Carretera de Andalucia km 5,4, 28041 Madrid, Spain Accepted for publication 10 November 1989
Summary In a double-blind randomized study, 92 patients with culturally proven tinea corporis and/or tinea cruris were treated orally with either terbinafine (Lamisil) (125 mg b.i.d.) or griseofulvin (500 mg b.i.d.) for up to 6 weeks. The two groups of patients and distribution of the target lesions were similar, but the analysis ofthe clinical scores showed that the terbinafine group had slightly higher mean scores at baseline (P=0-186). At the end of therapy the proportion of patients with negative microscopy and culture was 78% in the terbinafine group and 83% in the griseofulvin-treated group. At the assessment 8 weeks after the end of therapy the percentages of terbinafineand griseofulvin-treated patients with negative mycology were 93 and 95%, respectively. There were three relapses after mycological cure in the griseofulvin group (8%) and two in the terbinafine group (4%). Griseofulvin-treated patients were treated for shorter periods than terbinafinetreated patients (i.e. 58% compared to 26% received only 2-4 weeks of therapy). In terms of overall effectiveness, there were no significant differences between the two treatments. Thirty-seven terbinafine patients (77%) compared to 36 griseofulvin patients (82%) had overall effective therapy. Eight terbinafine patients (16%) compared to 10 griseofulvin patients (20%) experienced at least one adverse event. Five patients in the terbinafine group and six in the griseofulvin group had to stop the treatment due to headaches or gastrointestinal disorders. One terbinafine patient had an elevation of liver function tests after 6 weeks of treatment. Thus, in our study, terbinafine (250 mg daily oral dose) was comparably safe but slightly less effective than griseofulvin (1 g daily) for up to 6 weeks in the treatment of widespread tinea corporis and cruris among patients aged 18-65 years, although at long-term follow-up there was no difference between the two drugs. Correspondence; Dr A.del Palacio Hernanz, Department of Microbiology, Hospital 12 de Octubre, Carretera de Andalucia km 5,4, 28041 Madrid, Spain.-
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Terbinafine (Lamisil), a synthetic allylamine antifungal agent developed for either oral or topical application, is effective in vitro against a range of dermatophyte fungi, as shown by different studies.'"^ An important property of terbinafine is that it has been shown to possess primary fungicidal activity against dermatophytes, Aspergillus, Scopulariopsis brevicaulis and dimorphic fungi.''^ In vivo, terbinafine is not only active after topical application but is very effective in experimental dermatophytosis following oral administration.* * Few published reports are at present available on the effect ofthe drug for the oral treatment of dermatophytosis in man, and the value of oral terbinafine has been studied in a number of open studies in patients and healthy volunteers with experimental dermatophyte lesions.^''" Most of the published clinical studies have concentrated on patients with moccasin-type tinea pedis," 'dry type' Trichophyton rubrum affecting the palm or soles (R.J.Hay, personal communication) and onychomycosis,'^ and in all of these the most prevalent infecting species was T. rubrum. Dermatophytosis can be treated topically with a variety of compounds;'^ oral therapy is necessary for scalp, nail and widespread skin lesions. Since griseofulvin was introduced in the 1960s, it is the drug most commonly used for systemic treatment of dermatophytosis.'^ Later, imidazoles and triazoles with oral activity were obtained;'^"'^ they all act primarily as fungistatic drugs, but terbinafine has the distinctive feature of being primarily fungicidal, and therefore has potential in the oral treatment of skin and hair dermatophyte infections.''^''^ After 30 years of generalized use, griseofulvin has emerged as a safe drug for the treatment of skin and hair dermatophyte infections, and although cure rates for nail infections using this drug are low, it clearly remains the drug of choice for the treatment of tinea capitis. Its excellent safety record over the past 30 years should be kept in mind when considering alternatives." The purpose of the present work was to try to
TERBINAFINE AND GRISEOFULVIN COMPARED
211
determine the efficacy and safety of oral terbinafine compared with griseofulvin for the treatment of widespread tinea corporis and tinea cruris.
aud's dextrose agar with added chloramphenicol and actidione) were done in all the assessments. MIC values to both antifungals were determined using a broth dilution test with Sabouraud's dextrose liquid medium (0 05-50 /ig/ml). A diluted inoculum (1:100) of a 120-h Methods culture in Sabouraud's dextrose broth was used. The trial was a double-blind study and patients were Tolerability was assessed by noting adverse events randomized into one of two treatment groups: terbinafine which occurred during the trial and their severity graded (two capsules, one with 125 mg ofthe compound and the (mild, moderate or severe). other one with placebo) after lunch, and two capsules Haematological investigation (haemoglobin, haemaprepared identically after dinner (total daily dose: 250 mg tocrit, total WBC with differential and platelet count) and of terbinafine); or (b) micronized griseofulvin, two biochemical tests (SGOT, SGPT, alkaline phosphatase, capsules of 250 mg after lunch and two capsules after LDH, bilirubin, total protein, albumin, creatinine, gludinner (total daily dose: 1 g of griseofulvin). Neither the cose, cholesterol and triglycerides) and urine tests (proclinician nor the patient knew which was being used. tein, glucose, acetone, bile and sediment) were carried out Treatment was administered for a period of up to 6 at the initial examination and after weeks 2, 4 and 6 of weeks; therapy was concluded earlier if either the patient therapy and at follow-up after the end of the treatment was rated completely cured, both mycologically and when necessary. clinically, before this time, or there was a premature termination of therapy (severe adverse event or lack of Evaluation of drug effectiveness efficacy). Concomitant medication for various chronic diseases, The primary assessment of efficacy was based on a such as cardiac insufficiency, high blood pressure or combined evaluation of mycological tests (microscopy/ diabetes mellitus were maintained during the study. culture) and the sum of clinical scores at each visit during the treatment period and at follow-up according to the following scheme: Patients All patients were assessed prior to treatment with a detailed history and clinical examination. Only patients aged between 18 and 65 years suffering from tinea corporis or cruris confirmed by direct microscopy and culture were included in the study. Written consent was obtained from all patients. Pregnant women and female patients of child-bearing age not using reliable contraceptive measures, those with dermatophytosis of palms or soles, patients with diseases of the digestive system, conditions which might impair absorption from the gastrointestinal tract, such as gastritis, patients with liver disease, nephropathy, blood dyscrasias, disturbances of porphyrin metabolism, patients allergic to griseofulvin, patients receiving radiation therapy, systemic therapy with cytostatic or immunosuppressive drugs, or therapy with anti-infective drugs either at the time ofthe trial or 4 weeks prior to the start of the study were excluded from the trial. Assessments
The patients were seen once a week during treatment and at follow-up (2 months post-therapy). Parameters of clinical disease activity (erythema, scaling, vesiculation, pustules, incrustation, pruritus) were assessed and scored as: 0=absent; l=mild; 2=moderate; 3=severe. Scrapings were taken from the target lesion and mycological examinations (direct microscopy and culture on Sabour-
Effective therapy. This included two categories— either: (a) Complete cure—microscopy and culture negative, no residual clinical signs and symptoms; or (b) Mycological cure—microscopy and culture negative, mild residual erythema and/or desquamation and/or pruritis (total score 2), but no other clinical signs. Ineffective therapy. Premature termination due to adverse side-effects and improvements A, B, C or failures. (a) Improvement A—microscopy and culture negative; clinical signs and symptoms diminished ^ 50% of initial total score; (b) Improvement B—microscopy and culture negative; clinical signs and symptoms diminished 2) or recurrence of positive mycology. Premature terminations due to side-effects were considered in this category for all
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visits following the last assessment, including the followup visit.
Table 1. Patients' demographic characteristics and histories
Overall effectiveness. This was defined as effectiveness at the follow-up visit (2 months after the end of therapy).
Terbinafine («=48)
Griseofulvin («=44)
27/21
28/16
46 2 0 2 2
41 2 1 1 1
20
17
19 36/12
14 35/9
Sex (males/females) Duration range (weeks) 52 Diabetes Psoriasis Previous antifungal therapy (number of patients) Previous topical corticosteroids (number of patients) Lesion: single/multiple
Results One-hundred patients entered the study. Of these, eight were drop-outs (two in the terbinafine group and six in the griseofulvin group). Eleven patients (five in the terbinafine group and six in the griseofulvin group) terminated therapy prematurely due to adverse events. There were no significant differences in the age, sex, weight or height distribution, duration of disease, type and size of lesion, predisposing factors, other diseases in past history, family members with fungal infections and prior medications between the groups. The demographic characteristics and patients' histories are recorded in Table 1. The sites of lesions and infecting organisms responsible for the infection had an even distribution in both groups and are recorded in Table 2. When the distributions of basehne signs and symptoms were compared across treatment groups it was noted that the severity score for pruritus was higher in the terbinafine group (P=0 014). The mean sum of scores at baseline was more severe for the terbinafine patients (81) than for those on griseofulvin (7 4) (P=0186).
Table 2. Sites of target lesion and fungi isolated
Sites involved Face Body Arm/leg Groin
Terbinafine («=48)
Griseofulvin (»=44)
6 3 4/9 26
4 2 4/7 27
0 3 11 16 18
1 0 8 14 21
Fungi T. verrucosum M. canis T. rubrum T. mentagrophytes E. floccosum
Mycological results
The mycological results for each week of evaluation are given in Table 3. The combined analysis represents the number and percentage of patients with negative direct
Table 3. Number and percentage of patients with negative microscopy and culture Week of treatment Evaluation
Treatment group
1
2
3
4
5
6
Microscopy Terbinafine
Follow-up
6/47 18/44 32/44 33/39 28/32 21/23 (13%) (41%) (73%) (85%) (88%) (91%) Griseofulvin 9/42 29/39 33/37 33/33 16/16 6/6 (21%) (74%) (89%) (100%) (100%) (100%)
41/43 (95%) 36/38 (95%)
Culture
Terbinafine
4/47 (9%) Griseofulvin 5/42 (12%)
15/44 (34%) 26/39 (67%)
31/44 30/39 25/32 (70%) (77%) (78%) 31/37 32/33 14/16 (84%) (97%) (88%)
18/23 (78%) 5/6 (83%)
40/43 (93%) 36/38 (95%)
Combined
Terbinafine
15/44 (34%) 25/39 (64%)
28/44 28/39 (64%) (72%) 31/37 32/33 (84%) (97%)
18/23 (78%) 5/6 (83%)
40/43 (93%) 36/38 (95%)
4/47 (9%) Griseofulvin 5/42 (12%)
23/32 (72%) 14/16 (88%)
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Table 4. Mean scores for each of the three major signs and symptoms Week of treatment Sign/ symptom
Treatment group
Erythema
Terbinafine 2-7 2-3 1-8 1-1 1-0 0-9 0-9 Griseofulvin 2-8 1-9 1-2 0-8 0-5 0-3 0-2
0-1 0-1
Desquamation Terbinafine 2-3 2-2 1-7 1-1 1-1 1-1 0-9 Griseofulvin 2-2 1-5 1-2 0-9 0-6 0-4 0-8
0-3 0-1
Pruritus
0-2 0-1
0
1
2
3
4
5
6
Follow-up
Terbinafine 2-4 1-4 0-8 0-5 0-6 0-5 0-3 Griseofulvin 1-9 0-8 0-4 0-2 0-1 0-1 0-2
microscopy and negative mycological culture at each visit. The proportion of patients with negative microscopy was significantly higher in the griseofulvin group at Week 2 (P=: 0-004). The proportion of patients with negative culture results was significantly higher in the griseofulvin group at both Week 2 ( P ^ 0-009) and at Week 4 (P=0-032). Evaluation of mycological tests revealed that the proportion of patients with negative microscopy and culture at the end of therapy and follow-up assessments were similar in the two treatment groups. All the fungi isolated before treatment were sensitive to both antifungals in vitro, having minimal inhibitory concentrations of 0-05-0-1 /ig/ml for terbinafine and 0-86-25 /ig/ml for griseofulvin. None of the strains isolated after treatment was stopped were shown to have developed resistance to either compound in vitro. Clinical results
The most frequently reported signs and symptoms in patients before therapy included erythema (100%), desquamation (100%) and pruritus (92%). When eval-
uated separately, these had virtually all disappeared at the follow-up assessment in both treatment groups (Table 4). The rate of decrease in severity for the three major signs and symptoms appeared to be faster in the griseofulvin group. The score was significantly lower at Week 1 (all P CO-002), Week 2 (all P < 0-005), Week 4 (all P < 0-024) and Week 5 (all />< 0-051). The sum of scores for signs and symptoms decreased markedly in both treatment groups as the trial progressed. These results are shown in Table 4. The terbinafine group had more signs and symptoms at baseline (/'=0-186) than the griseofulvin group, and the latter showed a more rapid reduction in signs and symptoms compared to baseline at Week 1 (/•=0-005) and Week 2 (P=0-042) but not thereafter. Effectiveness evaluation
Table 5 shows the results of the response to treatment at the end of therapy and at follow-up. When all categories of clinical response were considered, there was a significant difference in favour of griseofulvin at the end of therapy, but not at follow-up or overall assessment (as
Table 5. Combined clinical and mycological evaluation
End of therapy Response Complete cure Mycological cure+minimal signs Effective treatment Mycological cure + improvement (Imp A or B) Mycological failure + improvement (Imp C) Failure Ineffective treatment* Total patients
Follow-up (overall assessment)
Terbinafine Griseofulvin Terbinafine Griseofulvin 24 7
28 9
37 0
35 1
31 (65%) 6 5 6 17 (35%)
37 (84%) 0 0 7 7(16%)
37 (77%) 3 1 7 11 (23%)
36 (82%) 0 0 8 8 (18%)
48
44
48
44
' The ineffective treatment group includes premature termination of therapy due to adverse effects.
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A.DEL PALACIO HERNANZ et al.
Table 5 shows, terbinafine was judged to have efficacy in lasting 6 weeks). Four weeks after the end of treatment 77% of patients and griseofulvin in 82%). normal regrowth ofthe hair started. The response to treatment according to the sites of There were five terbinafine patients with side-effects infection and the dermatophyte species involved in the that required discontinuation of therapy (all disappeared infection showed no detectable difference. subsequently): stomach pain (one), headache, dizziness Table 6 shows the sites and infecting organisms in and dyspepsia (two), dizziness and urticaria (one) and those patients in whom the treatment was ineffective (2 urticaria (one). months after the end of therapy) excluding those who Moderate side-effects with griseofulvin appeared early were rated as failures because they had to abandon the in therapy and later subsided. These were: insomnia, treatment due to intolerance. dizziness, nausea and headache (one), insomnia and Griseofulvin-treated patients were treated for shorter headache (one), headache (one) and urticaria (one). periods than terbinafine-treated patients (i.e. 58% comSix griseofulvin-treated patients experience sidepared to 26% received only 2-4 weeks of therapy). effects that required termination of therapy: headache, There were three relapses after mycological cure in the dizziness and nausea (one), headache and widespread griseofulvin group (8%) at the assessment 2 months after urticaria (one), headache, nausea and vomiting (two), the end of the treatment (consisting of 4 and 6 weeks in stomach pain and watery diarrhoea (one), and anorexia, two patients and 12 days in another who had to stop dyspepsia and stomach ache (one). therapy due to intense side-effects). Two of these patients All these side-effects disappeared on discontinuation of had tinea cruris caused by E.Jloccosum and T. rubrum and the treatment. The patients with urticaria either in the third had tinea corporis caused by T. mentagrophytes. terbinafine or griseofulvin groups were not challenged In the terbinafine group two patients (5%) relapsed after with the drug. treatment courses of 5 and 6 weeks. One patient had a groin infection caused by E. floccosum and the other extensive ringworm of the arm caused by Safety laboratory data T. mentagrophytes. Evaluation of bone marrow and renal function before and during the treatment with either terbinafine or griseofulvin revealed no clinically relevant drug-related changes. Overall tolerability In the liver-function tests there were some transient Eighteen patients (36%) showed intolerance to treat- changes in SGOT (one patient in the terbinafine group ment; eight of these (16%) were in the terbinafine group and another on griseofulvin) and SGPT (four patients on and ten (20%) in the griseofulvin group. terbinafine and one on griseofulvin). Two patients treated Three terbinafine-treated patients had moderate side- with terbinafine showed an asymptomatic elevation in effects possibly related to the drug in the first days of liver enzyme activity. One such patient had a high SGPT treatment, but they subsided and all were able to value of 100 u/1 at Week 2, decreasing to 29 u/1 at Week 4 complete their full course of treatment without any and had elevated values for y GT at Weeks 4 and 6 (66 and symptomatic therapy; these side-effects consisted of 54 u/1, respectively). The other patient showed elevated nausea and dizziness in two patients, and alopecia areata SGOT (106 u/1), SGPT (196 u/1), y GT (190 u/1) and of the scalp in another (commencing in Week 4 and alkaline phosphatase (227 u/1) at the end of Week 6. At follow-up, all enzyme activities except y GT (54 u/1) had Table 6. Non-effective treatment at the overall assessreturned to normal. ment (2 months after the end of treatment): sites and fungi isolated*
Discussion Terbinafine
(«=48)
Griseofulvin («=44)
Non-effective (number of patients) Sites: groin/body
6 4/2
3 2/1
Fungi isolated E. floccosum T. rubrum T. mentagrophytes
2 3 1
* Patients who abandoned treatment due to intolerance are excluded.
The results reported here suggest that oral terbinafine is, in general, comparably safe and slightly less effective than griseofulvin in the overall management of tinea corporis and tinea cruris at the end of treatment, although at longterm follow-up both drugs are comparable. Previous published studies have shown that terbinafine given orally is effective in tinea corporis, tinea pedis, candidosis and onychomycosis, but not in pityriasis versicolor.''^ The most appropriate dose for dermatophytosis appears to be 250 mg/day.'" Cure in patients treated systemically (125 mg b.i.d. orally) with terbinafine has been documented to be 75-
TERBINAFINE AND GRISEOFULVIN COMPARED 90% in tinea corporis.'" The results in our population were inferior at the end of the treatment to those published by Villiars and Jones,'" i.e. only 65% of our population treated with terbinafine were show to have achieved an effective treatment; however, at the assessment 2 months later, 77% of our patients were cured, without using other treatment measures. Therefore, in this overall assessment we have confirmed the data reported hy other investigators who have treated orally with terbinafine.'" This observation has been previously documented by other workers using different topical and systemic antifungals: a number of patients who still have moderate signs and symptoms at the end ofthe treatment with positive cultures (carriers) achieve a total clinical and mycological cure a few weeks later.'*'"^" This means that the process of healing of dermatophytosis is complex and therefore not dependent on positive cultures alone. In a study of the use of terbinafine orally (125 mg b.i.d.) compared with griseofulvin (250 mg b.i.d.), terbinafine was significantly better in a group of 252 patients, of whom 84% were infected with Trichophyton rubrum and 74% had chronic disease due to this organism.'" In this latter study the response rates (negative cultures and microscopy and in clinical signs and symptoms) during treatment were similar, in that by 2 weeks of treatment more than 70% of patients had negative mycological tests and marked clearing of signs and symptoms.'" Terbinafine was shown to be more effective after Week 3 of therapy since 11% of griseofulvin-treated patients remained infected and an additional 3% relapsed by 2 weeks after apparently successful treatment.'" R. Savin and R. Hay (personal communication) have reported similar findings in a group of patients with chronic tinea pedis (moccasin type)." Chronic tinea pedis (plantar or moccasin-type) caused by T. rubrum is generally unresponsive to the usual established topical and oral antifungal regimens.^'"^"^ The reasons for this refractory behaviour to therapy have not been fully clarified, although a number of factors are involved, such as drug absorption and penetration into thickened skin and defects in host resistance.^' In our study (see Table 2) other dermatophyte species were more common, T. rubrum was the causative agent in 19 patients (11 on terbinafine and eight on griseofulvin) and the infection was located on glabrous skin. It seems possible from available pharmacokinetic data that oral terbinafine achieves a lower concentration in the most superficial cells ofthe stratum corneum. This fact could account for the results achieved in our study, where patients were treated for widespread lesions but in whom inflammation was minimal and the fungi responsible for the infection were superficially located. This view is indirectly supported by the fact that although terbinafine is active in vitro against Pityrosporum spp. yeasts, the
215
compound is exclusively effective for the treatment of pityriasis versicolor when applied topically.'" In our patients, the MIC values after therapy with terbinafine did not show any difference compared to pretreatment values, and therefore the development of resistance to terbinafine after therapy does not seem to be a problem, although this has to be confirmed studying larger populations. In our patients there were no significant differences in terms of tolerance between terbinafine and griseofulvin; however, one terbinafine-treated patient had an unexplained elevation in liver-function tests after 6 weeks of treatment—although this finding in one single patient is not necessarily relevant to the general population, it remains necessary to monitor liver function in patients on long-term therapy with terbinafine, at least until there is more clinical experience. Long-term follow-up and comparative studies with other antifungals will help to establish the place of terbinafine in the management of fungal infections. Acknowledgments We would like to thank Sandoz (Spain) for supplying the medication and the assistance and help of Dr J.A.Matilla Blasco during the trial. References 1. Petranyi G, Meingassner IG, Mieth H. Antifungal activity ofthe allylamine derivative terbinafine in vitro. Antimicrobial Agents and Chemotherapy 1987; 31: 1365-1368. 2. Shadomy S, Espinel-Ingroff A, Gembhart RJ. In vitro studies vjfith SF 86-327, a nevt orally active allylamine derivative. _7oMr«a/ of Medical and Veterinary Mycology 1985; 23: 125-132. 3. Clayton YM. SF 86-327. A laboratory evaluation of 5 antifungal agents. In: Spitzy KH, Karrer K, eds. Proceedings of the 13th International Congress of Chemotherapy. Vienna: Verlag H, Igermann 1983: 116/13-116/14. 4. Goudard M, Buffard Y, Ferrari H, Regli P. Spectre d'action in vitro d'un nouvel antifongique derive de la naftifine: la terbinafine (SF 86-327). Pathologie Biologie 1986; 34: 680-683. 5. Clayton YM. In vitro activity of terbinafine. Clinical and Experimentat Dermatology 1989; 14: 101-103. 6. Petranyi G, Meingassner JG, Mieth H. Activity of terbinafine in experimental fungal infections of laboratory animals. Antimicrobial Agents and Chemotherapy 1987; 31: 1558-1561. 7. Mieth H, Petranyi G. Preclinical evaluation of terbinafine in vivo. Clinical and Experimental Dermatology 1989; 14: 104-107. 8. Yamaguchi H, Uchida K. Once daily administration of terbinafine to guinea-pigs with experimental dermatophytosis. Clinical and Experimental Dermatology 1989; 14: 108-109. 9. Stephen A, Czok R, Male O. Terbinafine: Initial clinical results. In: Fromtling RA, ed. Recent Trends in the Discovery, Development and Evaluation of Antifungal Agents. Barcelona: J.R.Prous Science Publications, 1987: 511-520. 10. Villiars V, Jones TC. Clinical efficacy and tolerability of terbinafine (Lamisil), a new topical and systemic fungicidal drug for treatment of dermatomycoses. Clinical and Experimental Dermatology 1989; 14: 124-127.
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11. Savin R. Successful treatment of chronic tinea pedis (moccasin type) with terbinafine (Lamisil). Clinical and Experimental Dermatology 1989; 14: 116-119. 12. Zaias S, Serrano L. The successful treatment offingerTrichophyton rubrum onychomycosis with oral terbinafine. Clinical and Experimental Dermatology 1989; 14: 120-123. 13. Hay RJ. The current status of antimycotics in the treatment of local mycoses. Acta Dermato-Venereologica {Stockholm) 1986; Suppl. 121: 103-108. 14. Hay RJ. The azole antifungal drugs. Journal of Antimicrobial Chemotherapy 1987; 20: 1-5. 15. Saag MS, Dismukes WE. Azole antifungal agents: emphasis on new triazoles. Antimicrobial Agents and Chemotherapy 1988; 32: 1-8. 16. Hay RJ, Del Palacio Hernanz A. Introduction. First Symposium on terbinafine (Lamisil). Clinical and Experimental Dermatology 1989, 14: 97. 17. Becker LE. Griseofulvin. Dermatologie Clinics 1984; 2: 115-120. 18. Del Palacio Hernanz A, Lopez Gomez S, Moreno Palancar P, Gonzalez Lastra F. A clinical double blind trial comparing amorolfine cream 0-5% (RO 14-4767) with bifonazole cream 1% in the treatment of dermatomycoses. Clinical and Experimental Dermatology 1989; 14: 141-144.
19. Cauwenberg G, de Doncker P. The clinical use ofitraconazole in superficial and deep mycoses. In: Fromtling RA, ed. Recent Trends in the Development and Evaluation of Antifungal Agents. Barcelona: J.R.Prous Science Publications, 1987: 273-284. 20. Del Palacio Hernanz A, Lopez Gomez S, Iglesias Diez L. A clinical and mycological assessment of tioconazole solution in the treatment of superficial dermatomycoses. Clinical Therapeutics 1987; 9: 333-338. 21. Hay RJ, Clayton YM, Midgley G. The use ofitraconazole in chronic Trichophyton rubrum infections. British Journal ofDermatology 1986, US (Suppl iOy i'^22. Hay RJ, Clayton YM. Treatment of chronic dermatophytosis and chronic oral candidosis with itraconazole. Reviews of Infectious Diseases 1987; 9 (Suppl. 1): 114-118. 23. Hay RJ. Failure of treatment in chronic dermatophyte infections. Postgraduate Medical Journal 1979; 55: 608-610. 24. Robertson MH, Rich P et al. Ketoconazole in griseofulvinresistant dermatophytosis. Journal of the American Academy of Dermatology 1982; 6: 224-229. 25. Roberts SOB. Treatment of the superficial and subcutaneous mycoses. In: Speller DCE, ed. Antifungal Chemotherapy. Chichester: John Wiley and Sons, 1980: 225-283.
