Pulse itraconazole vs. continuous terbinafine for the treatment of dermatophyte toenail onychomycosis in patients with diabetes mellitus

BACKGROUND: Oral terbinafine and oral itraconazole are two of the most common agents used for the treatment of toenail dermatophyte onychomycosis. Despite the fact that diabetic patients are more likely to have onychomycosis than normal individuals are, there is little research into the efficacy of standard oral regimens of terbinafine and itraconazole for onychomycosis in the diabetic population. STUDY DESIGN: We present a prospective, randomized, single-blind, parallel group, comparator-controlled, multi-centre study designed to assess the efficacy of the pulse itraconazole (200 mg twice daily, 1 week on, 3 weeks off, for 12 weeks) vs. continuous terbinafine (250 mg once daily for 12 weeks) oral therapies in the treatment of dermatophyte toenail distal and lateral subungual onychomycosis (DLSO) in the diabetic population. EFFICACY PARAMETERS: Primary efficacy measures included mycological cure rate (negative KOH and culture) and effective cure (mycological cure plus nail plate involvement of 10% or less) at Week 48. RESULTS: At Week 48, mycological cure was attained by 88.2% (30 of 34) and 79.3% (23 of 29) of patients in the itraconazole and terbinafine groups, respectively (P not significant). Effective cure (mycological cure with 相似文献   

特比萘芬治疗糖尿病患者甲真菌病疗效和对血糖水平的影响

目的:评价特比萘芬连续疗法治疗糖尿病患者甲真菌病的有效性、安全性、耐受性和对患者血糖水平的影响。方法:90例糖尿病甲真菌病患者口服特比萘芬250mg,每日1次,指甲癣患者连续口服12周,趾甲癣患者连续口服16周;停药第24周观察最终疗效和血糖水平。结果:在第36周时,指甲真菌病的临床治愈率84.8%,有效率90.9%,真菌学治愈率93.9%;第40周时,趾甲真菌病的临床治愈率78.9%,有效率87.7%,真菌学治愈率89.5%;治疗前后空腹血糖和糖化血红蛋白水平无显著性差异。结论:特比萘芬治疗糖尿病患者甲真菌病有效、安全,耐受性良好;对患者血糖水平无明显影响。     

伊曲康唑间歇冲击治疗趾甲真菌病疗效和血清及甲中药物水平临床研究

目的:研究伊曲康唑间歇冲击疗法治疗趾甲真菌病(甲母质未受累)的疗效和在血清及甲中药物水平的变化。方法:41例趾甲真菌病患者应用伊曲康唑连续3个冲击治疗,第52周进行最终疗效评价;采用高压液相色谱仪(HPLC)法对其中15例趾甲真菌病患者进行了血清及甲中药物测定。结果:每次冲击后4周,血清中均未测得伊曲康唑;甲组织中伊曲康唑水平较高,在8或12周时达到高峰,停药后,伊曲康唑仍能以较高的水平在甲中储留36周;同一时间点,指甲和趾甲中的药物水平相似(P>0.05)。在第52周时,趾甲真菌病的临床治愈率为66.7％,临床有效率为79.5％,真菌学清除率为64.1％。结论:伊曲康唑口服吸收后从血液迅速向甲组织分布,停药后仍以较高水平储留在甲组织中并持续存在36周以上。     

A randomized trial of amorolfine 5% solution nail lacquer combined with oral terbinafine compared with terbinafine alone in the treatment of dermatophytic toenail onychomycoses affecting the matrix region

In view of recent advances in the development of antifungal agents, this study examined the possible synergy of two new antifungal agents, terbinafine and amorolfine. The study compared two different courses of terbinafine treatment combined with amorolfine 5% solution nail lacquer. Terbinafine was given orally for 6 (AT6 group) or 12 weeks (AT12 group) and amorolfine nail lacquer applied weekly for 15 months. A control group received terbinafine alone for 12 weeks. This was a randomized, prospective, open study of severe dermatophyte toenail onychomycosis with matrix region involvement. Nail samples were taken before the start of the study, at inclusion and at the visits at 6 weeks, 3, 9, 15 and 18 months. To assess the value of such combined therapy we chose an early parameter as the principal outcome variable, which was the result of mycological examination, including direct microscopy and culture, at 3 months (allowing a margin of 15 days). The secondary parameters of success were the mycological results at the later visits, clinical evaluation and a combined mycological-clinical response. Safety and tolerance were also assessed. Adverse events were recorded and liver function tests were performed monthly during the terbinafine treatment. Of the 147 patients included in the trial, 121 attended the 3-month visit, within a time limit of 15 days of 3 months after the beginning of treatment: 40 in the AT6 group, 40 in the AT12 group and 41 in the control group. In all, 32 of 121 patients (26. 4%) had negative mycological results on direct microscopy and culture: 14 of 40 (35.0%) in the AT6 group, 11 of 40 (27.5%) in the AT12 group and seven of 41 (17.1%) in the control group. The cure rate for the global (mycological and clinical cure) response measured at 18 months in 145 patients was 44.0% (22 patients) in the AT6 group, 72.3% (34 patients) in the AT12 group and 37.5% (18 patients) in the terbinafine group. These results suggest that the combination of amorolfine and terbinafine may be of value in the treatment of severe onychomycosis. At the same time a pilot pharmacoeconomic analysis was performed demonstrating a better cost per cure ratio for the patients receiving combination treatment.     

Prognostic factors for cure following treatment of onychomycosis

Objective To examine if host baseline factors and week 24 mycology results are associated with mycological and clinical cure in patients with onychomycosis treated with oral terbinafine. Design Open pilot study to determine prognostic factors in the treatment of onychomycosis. Setting Outpatient dermatology clinic. Patients A total of 199 patients from the Icelandic arm of a trial comparing continuous terbinafine with intermittent terbinafine in onychomycosis were recruited for additional observation. Main outcome measures Mycological, clinical and complete cure of the target toenail 72 weeks after treatment was initiated. Results Patients with matrix involvement or slow nail growth were less likely to reach mycological, clinical and complete cure. Lateral involvement affected complete and mycological cure rates negatively. Patients with a dermatophytoma were less likely to reach mycological cure. Patients with a history of prior infection, men and older patients were less likely to reach clinical cure. Positive culture at 24 weeks affected mycological and clinical cure at 72 weeks negatively. Limitations Only patients treated with terbinafine were considered. Conclusions Several host‐related factors at baseline and positive culture at 24 weeks had negative effects on cure of onychomycosis 72 weeks after treatment was initiated. This finding merits a large study on prognostic outcome factors in onychomycosis.     

Terbinafine (Lamisil) treatment of toenail onychomycosis in patients with insulin-dependent and non-insulin-dependent diabetes mellitus: a multicentre trial

BACKGROUND: Diabetes mellitus (DM) affects an estimated 175 million people world-wide. Approximately one-third of patients with DM have toenail onychomycosis. OBJECTIVES: To determine the efficacy and safety of terbinafine treatment of toenail onychomycosis in patients with DM receiving insulin and/or oral antidiabetic agents. Special interest was focused on potential drug interactions with oral hypoglycaemic substances. METHODS: In a multicentre trial, patients suffering from insulin-dependent DM (IDDM) or non- insulin-dependent DM (NIDDM) with toenail onychomycosis were treated for 12 weeks with oral terbinafine 250 mg daily and followed up to 48 weeks. In addition to clinical, mycological and laboratory investigations, blood glucose levels were monitored. RESULTS: At the end of the trial (week 48), a mycological cure rate of 73% was achieved. The rates of clinical cure and complete cure (mycological cure plus clinical cure) were 57% and 48%, respectively. There was no statistically significant difference between the NIDDM and IDDM groups with respect to the cure rates (P > 0.05). No hypoglycaemic episode was reported and none of the patients had hypoglycaemia during the treatment phase. CONCLUSIONS: With excellent cure rates and a good tolerability profile, terbinafine should continue to be a drug of choice for the treatment of toenail onychomycosis in the rising number of NIDDM patients receiving multiple medication.     

特比萘芬合用地巴唑治疗甲真菌病的随机双盲对照研究

目的 观察特比萘芬与地巴唑联合治疗甲真菌病的疗效。方法 甲真菌病患者随机分组,治疗组口服特比萘芬250mg每日1次,同时口服地巴唑10mg每日3次;对照组口服特比萘芬250mg每日1次,同时口服安慰剂。治疗组指甲真菌病疗程为6周,趾甲疗程为8周;对照组指甲真菌病疗程为8周,趾甲疗程为10周。观察2种方法的疗效。结果 治疗后第24周随访,治疗组54例痊愈率为70.4%(38/54例),有效率为83.3%(45/54例);对照组51例痊愈率为66.7%(34/51例),有效率为80.4%(41/51例),两组比较差异均无显著性(P>0.05)。结论 特比萘芬与血管扩张剂联合治疗甲真80.4%(41/51例),两组比较差异均无显著菌病能缩短疗程,且无明显不良反应。     

Long-term effectiveness of treatment with terbinafine vs itraconazole in onychomycosis: a 5-year blinded prospective follow-up study

OBJECTIVE: To examine long-term cure and relapse rates after treatment with continuous terbinafine and intermittent itraconazole in onychomycosis. DESIGN: Long-term prospective follow-up study. SETTING: Three centers in Iceland. SUBJECTS: The study population comprised 151 patients aged 18 to 75 years with a clinical and mycological diagnosis of dermatophyte toenail onychomycosis. INTERVENTIONS: In a double-blind, double-dummy study, patients were randomized to receive either terbinafine (250 mg/d) for 12 or 16 weeks or itraconazole (400 mg/d) for 1 week in every 4 for 12 or 16 weeks (first intervention). Patients who did not achieve clinical cure at month 18 or experienced relapse or reinfection were offered an additional course of terbinafine (second intervention). MAIN OUTCOME MEASURES: The primary efficacy criterion was mycological cure, defined as negative results on microscopy and culture at the end of follow-up and no requirement of second intervention treatment. Secondary efficacy criteria included clinical cure without second intervention treatment and mycological and clinical relapse rates. RESULTS: Median duration of follow-up was 54 months. At the end of the study, mycological cure without second intervention treatment was found in 34 (46%) of the 74 terbinafine-treated subjects and 10 (13%) of the 77 itraconazole-treated subjects (P<.001). Mycological and clinical relapse rates were significantly higher in itraconazole vs terbinafine-treated patients (53% vs 23% and 48% vs 21%, respectively). Of the 72 patients who received subsequent terbinafine treatment, 63 (88%) achieved mycological cure and 55 (76%) achieved clinical cure. CONCLUSION: In the treatment of onychomycosis, continuous terbinafine provided superior long-term mycological and clinical efficacy and lower rates of mycological and clinical relapse compared with intermittent itraconazole.     

Prediction of outcome in the treatment of onychomycosis

Patients with toenail onychomycosis remain a therapeutic challenge despite the introduction of new systemic therapies. Around 20% of patients remain uncured even with optimal oral therapy, but the reasons for treatment failure are unclear. Thus far there are no data to suggest that treatment failures can be identified on the basis of their presenting features or progress during treatment. In a series of patients, we have attempted to identify clinical parameters that determine the patient response to 12 weeks of oral terbinafine for confirmed dermatophyte onychomycosis. As part of a dose-defining randomized multicentre study, 35 patients were followed for 48 weeks. The unaffected nail length, growth rate, hyperkeratosis, onycholysis and presence of a dermatophytoma were assessed prospectively. To confirm our findings, at the end of the study period we analysed retrospectively photographs that had been taken regularly throughout the trial. The average degree of hyperkeratosis was less severe in the group achieving a disease-free nail, meaning clinical and mycological cure. For mycological cure alone, no predictive factors could be identified.     

Amorolfine and itraconazole combination for severe toenail onychomycosis; results of an open randomized trial in Spain

Objective In an open, randomized, clinical study of toenail onychomycosis with matrix area involvement, two alternative regimens of topical amorolfine/oral itraconazole therapy were compared with itraconazole monotherapy.
Patients/Methods A total of 131 patients were randomized to treatment. Patients in the combination groups were treated with amorolfine 5% nail lacquer (Loceryl®, Galderma Laboratories) once weekly for 24 weeks and 200 mg itraconazole once daily for 6 weeks (Group AI-6) or 12 weeks (Group AI-12). A control group received itraconazole monotherapy for 12 weeks (Group I-12). Strict inclusion criteria specified that subjects had to have onychomycosis of the toenails with matrix area involvement and/or > 80% total nail surface involvement. Mycological evaluations using both microscopic examination and culture of nail samples were performed at weeks 12 and 24. A stringent assessment of outcome at study end combined the results of mycological and clinical outcomes into a global cure rate. Safety was also assessed.
Results At week 12, mycological cure was attained in 42 of 45 patients (93·3%) in group AI-6, 29 of 35 patients (82·9%) in group AI-12, and 14 of 34 patients in group I-12. The difference between both combination groups and the control group were significant ( P  < 0·001). The global cure rate at week 24 was 83·7% (36 patients) in group AI-6, 93·9% (31 patients) in group AI-12, and 68·8% (22 patients) in group I-12. The difference between the AI-12 group and itraconazole monotherapy was significant ( P  < 0·05).
Conclusions These results indicate that amorolfine combination therapy represents an improved treatment strategy for patients with severe onychomycosis.     

Itraconazole for the treatment of onychomycosis

Background The broad spectrum of activity of itraconazole in vitro manifests itself clinically with the drug being effective for the treatment of onychomycosis caused by dermatophytes, Candida and some non-dermatophyte molds. The pharmacokinetics of itraconazole in the nail results in drug remaining at therapeutic levels for 6–9 months after completion of therapy.
Methods An overview of studies where continuous or pulse itraconazole therapy has been used in the treatment of fingernail and toenail onychomycosis.
Results Following continuous therapy at 200 mg/day for 3 months for toenail onychomycosis ( n = 1741), the rates of clinical cure, clinical response and mycologic cure were: (meta-average ± 95% standard error (SE)), 52 ± 9%, 86 ± 2%, and 74 ± 3%, respectively, at follow-up 12 months following start of therapy. In fingernail onychomycosis ( n = 211), the duration of therapy was 6 weeks and the corresponding efficacy rates at follow-up, 9 months after start of therapy, were meta-average (± S.E.) 82 ± 5%, 90 ± 2%, and 86 ± 3%, respectively. In toenail onychomycosis treated with 3 pulses of therapy ( n = 1389), the clinical response, clinical cure and mycologic cure were observed in meta-average (± S.E.) 58 ± 10%, 82 ± 3%, and 77 ± 5% patients, respectively, at follow-up 12 months after the start of therapy. In fingernail onychomycosis treated with 2 pulses of therapy ( n = 210), at follow-up 9 months after the start of therapy, the corresponding efficacy rates were meta-average (± S.E.) 78 ± 10%, 89 ± 6%, and 87 ± 8%, respectively.
Conclusions Both the continuous and pulse therapy regimens are safe with few adverse effects. Compared to continuous therapy, the pulse regimen has an improved adverse-effects profile, is more cost-effective, and is preferred by many patients.     

Prognostic factors of mycological cure following treatment of onychomycosis with oral antifungal agents

BACKGROUND: There is considerable literature on the efficacy and safety of various drugs used in treating onychomycosis; however, little information is available regarding prognostic factors which may be associated with non-response to conventional treatment. OBJECTIVES: To identify parameters influencing mycological cure at 72 weeks following treatment of toenail onychomycosis with oral antifungal agents. METHODS: Univariate and multivariate logistic regression analysis from a randomized double-blind controlled trial including 496 patients with toenail onychomycosis caused by dermatophytes. RESULTS: Baseline parameters including patient's age, gender, weight, number of toenails involved, percentage of nail involvement, duration of infection, history of previous treatment were not associated with mycological cure. In the multivariate prognostic factor analysis based on factors assessed at week 12, positive mycological culture at 12 weeks [odds ratio (OR): 0.583; 95% confidence interval (CI): 0.370-0.918] was negatively associated with mycological cure at 72 weeks. Similarly, in the multivariate prognostic factor analysis based on factors assessed at week 24, positive direct microscopy at 24 weeks (OR: 0.373; 95% CI: 0.211-0.659) and mycological culture at 24 weeks (OR: 0.293; 95% CI: 0.168-0.513) were negatively associated with mycological cure at 72 weeks. CONCLUSIONS: Mycological culture at 12 and 24 weeks and direct microscopic examination at 24 weeks can help in early identification of patients failing to respond to conventional oral antifungal treatment.     

A double-blind, randomized study to compare the efficacy and safety of terbinafine (Lamisil) with fluconazole (Diflucan) in the treatment of onychomycosis

In a randomized, double-blind, double-placebo, multicentre study, terbinafine 250 mg daily for 12 weeks was compared with fluconazole 150 mg once weekly for 12 or 24 weeks in the treatment of onychomycosis. A total of 137 patients with culture-confirmed onychomycosis was divided into three groups: group A received terbinafine for 12 weeks, group B received fluconazole for 12 weeks, while group C received fluconazole for 24 weeks. At completion of the study (week 60), the mycological cure rate was higher in the terbinafine group than in the fluconazole groups: 89% vs. 51% and 49%, respectively (P < 0.001). The length of unaffected nail increased until week 24 in group B and until week 36 in group C, but was still increasing in group A at the final visit (week 60). Complete clinical cure of the target nail at week 60 was 67% in the terbinafine group, compared with 21% and 32% in the fluconazole groups, respectively. The incidence of adverse events was low for both study agents. We conclude that terbinafine 250 mg daily for 12 weeks is significantly more effective in the treatment of onychomycosis than fluconazole 150 mg once weekly for either 12 or 24 weeks.     

Randomized double-blind comparison of short-term itraconazole and terbinafine therapy for toenail onychomycosis.

Previous studies evaluating short-term itraconazole and terbinafine therapy for onychomycosis have varied in protocol and size; this double-blind study enabled a large-scale, standardized, direct comparison. Patients with toenail onychomycosis were randomized to itraconazole 200 mg daily (n = 146) or terbinafine 250 mg daily (n = 146) for 12 weeks, with a 36-week follow-up. Mycological cure rates at the follow-up end-point were significantly equivalent (61% with itraconazole vs. 67% with terbinafine). A similar proportion of patients in each group experienced adverse events during treatment (itraconazole, 22%; terbinafine, 23%). More patients receiving terbinafine stopped treatment permanently because of treatment-related adverse events (8% vs. 1%).     

Therapeutic efficacy and safety of one-week intermittent therapy with itraconazole for onychomycosis in a Chinese patient population.

OBJECTIVE: To evaluate the efficacy and safety of a 1-week intermittent itraconazole dosing schedule for onychomycosis. METHODS: In this multicenter, open-label study, 646 patients received itraconazole 200 mg twice daily for 1 week/month, followed by 3 weeks without therapy. Patients with fingernail infections received 2 treatment cycles, patients with toenail or combined toenail and fingernail infections received 3 cycles. Efficacy was evaluated at week 9 (2-month regimen), week 13 (3-month regimen) and 3, 6 or 9 (toenails only) months after completion of therapy. RESULTS: Clinical and mycologic cure rates for fingernails were greater than 90% 6 months after completion of 2 treatment cycles. Clinical and mycologic cure rates for toenails were 84 and 98%, respectively, 9 months after completion of 3 cycles. Treatment was well tolerated; adverse events (mostly mild) occurred in 4.6% of patients. CONCLUSION: A 1-week intermittent itraconazole dosing regimen is a safe and effective treatment for onychomycosis.     

A randomized trial of amorolfine 5% solution nail lacquer in association with itraconazole pulse therapy compared with itraconazole alone in the treatment of Candida fingernail onychomycosis

BACKGROUND: Treatment failures and relapses are not uncommon in onychomycosis. Therefore, it is worthwhile to consider the combination of systemic and topical antifungals to improve the cure rates further and to reduce the duration of systemic treatment. OBJECTIVES: To evaluate and compare itraconazole pulse therapy combined with amorolfine with itraconazole alone in the treatment of Candida fingernail onychomycosis. METHODS: Ninety patients with moderate to severe Candida fingernail onychomycosis were randomized into two treatment groups of 45 subjects each. Group 1 received itraconazole pulse therapy for 2 months and applied amorolfine 5% solution nail lacquer for 6 months, while group 2 received monotherapy with three pulses of itraconazole. The primary efficacy criterion was the result of mycological examination at 3 months. The secondary criterion was the combined mycological and clinical response at 9 months. A pharmacoeconomic analysis was also performed to compare the cost-effectiveness of combined therapy vs. monotherapy. RESULTS: Eighty-five patients were analysed (73 women and 12 men, mean +/- SD age 44.2 +/- 12.9 years). Patients had a mean +/- SD of 3.64 +/- 2.0 nails involved and 228.6 +/- 148.0 mm2 of their nail surface diseased. The mean duration of onychomycosis was 11 months. Paronychial involvement was evident in 71 patients. C. albicans was isolated in 85 cases, C. parapsilosis in three and other Candida species in two cases. Side-effects were uncommon and in only one case led to withdrawal. At the 3-month visit, mycological cure was seen in 32 (74%) of 43 patients in group 1 and in 25 (60%) of 42 patients in group 2. At the 9-month visit, a global cure was seen in 40 patients (93%) in group 1 and in 34 patients (81%) in group 2. Statistical analysis showed no statistically significant difference (P > 0.1) between the two treatment groups. The cost per cure ratio was 1.63 and 1.70euro for groups 1 and 2, respectively. CONCLUSIONS: The combination of amorolfine and oral itraconazole, which interfere with different steps of ergosterol synthesis, exhibited substantial synergy. Compared with oral itraconazole alone, the combination achieved greater mycological cure and increased total cure rate. However, no statistically significant difference was documented for this number of observations. Combination treatment with amorolfine and two pulses of itraconazole is at least as safe and effective as three pulses of itraconazole, with a lower cost per patient. In our opinion, the addition of amorolfine to oral itraconazole pulse therapy is of value in the treatment of moderate to severe Candida fingernail onychomycosis.     

Fifth toenail clinical response to systemic antifungal therapy is not a marker of successful therapy for other toenails with onychomycosis

BACKGROUND: Onychodystrophy is a major manifestation of onychomycosis. However, nail trauma may also result in onychodystrophy. The fifth toenail, due to its location, suffers repeated friction/pressure trauma from shoes. OBJECTIVE: To test the hypothesis that treatment failure of fifth toenail onychomycosis is not a marker of treatment failure of other toenails with onychomycosis. METHODS: Fifty patients who had fifth toenail deformity (with or without onychomycosis) and onychomycosis of the other toenails were treated with oral terbinafine, 250 mg/day, for 4 months. RESULTS: Forty-three patients completed the study. Before the study, 26/43 (61%) had callus lateral to the fifth toe (suggesting mechanical pressure in that area). Twenty-one/43 (49%) of the fifth toenails had onychomycosis. At the end of the treatment period, only 4/21 (19%) of the fifth toenails (with initial onychomycosis), compared with 12/21 (57%) of the other toenails, were completely cured (CC). Out of the whole group (n=43), the clinical cure rate of the fifth toenail was 4/43 (9%) and for the other toenails, 20/43 (47%) (P<0.05). The mycological cure rates were 11/21 (52%) for the fifth toenail and 25/43 (58%) for the other toenails. Callus lateral to the fifth toe was associated with a poor clinical result (P<0.01). CONCLUSIONS: Clinical improvement of the fifth toenail after systemic antifungal therapy is less favourable and does not correspond with the clinical cure of the other toenails, mostly because of mechanical factors. Therefore, patients should be told to adjust their expectations as to the visual results of their antifungal treatment.     

Long-term outcomes in the treatment of toenail onychomycosis

Most clinical studies in subjects with toenail onychomycosis end with a final assessment at 48–52 weeks. This fails to take full account of the physiology of toenail growth, as toenails can take up to 12–18 months to grow out fully. Accurate assessment of long-term outcomes therefore requires follow-up of at least 2 years after completion of the study. We have evaluated long-term outcomes of treatment in the patients whom we contributed to two multicentre studies of oral therapy for toenail onychomycosis caused by dermatophyte infection. In the first, a dose-finding study for terbinafine (Lamisil^®), the high rates of mycological and clinical cure achieved by terbinafine at week 48 were maintained more than 2 years after completion of the study. In the second, a comparative study between terbinafine and itraconazole (Sporanox^®), the excellent mycological and clinical cure rates achieved by terbinafine at week 48 were again maintained more than 2 years after completion of the study. By contrast, the failure and relapse rates seen with itraconazole were much higher. Other studies undertaken in recent years have confirmed these positive findings with respect to terbinafine, and have demonstrated its superiority over itraconazole in maintaining mycological and clinical cure over long periods. These long-term benefits of terbinafine probably relate to its primarily fungicidal action against dermatophytes, compared to the fungistatic action of itraconazole and other triazole agents. Future clinical studies should therefore incorporate at least 2 years' follow-up.     

Terbinafine: a review of its use in onychomycosis in adults

Terbinafine, an orally and topically active antimycotic agent, inhibits the biosynthesis of the principal sterol in fungi, ergosterol, at the level of squalene epoxidase. Squalene epoxidase inhibition results in ergosterol-depleted fungal cell membranes (fungistatic effect) and the toxic accumulation of intracellular squalene (fungicidal effect). Terbinafine has demonstrated excellent fungicidal activity against the dermatophytes and variable activity against yeasts and non-dermatophyte molds in vitro. Following oral administration, terbinafine is rapidly absorbed and widely distributed to body tissues including the poorly perfused nail matrix. Nail terbinafine concentrations are detected within 1 week after starting therapy and persist for at least 30 weeks after the completion of treatment. Randomized, double-blind trials showed oral terbinafine 250 mg/day for 12 or 16 weeks was more efficacious than itraconazole, fluconazole and griseofulvin in dermatophyte onychomycosis of the toenails. In particular, at 72 weeks' follow-up, the multicenter, multinational, L.I.ON. (Lamisil vs Itraconazole in ONychomycosis) study found that mycologic cure rates (76 vs 38% of patients after 12 weeks' treatment; 81 vs 49% of recipients after 16 weeks' therapy) and complete cure rates were approximately twice as high after terbinafine treatment than after itraconazole (3 or 4 cycles of 400 mg/day for 1 week repeated every 4 weeks) in patients with toenail mycosis. Furthermore, the L.I.ON. Icelandic Extension study demonstrated that terbinafine was more clinically effective than intermittent itraconazole to a statistically significant extent at 5-year follow-up. Terbinafine produced a superior complete cure rate (35 vs 14%), mycologic cure rate (46 vs 13%) and clinical cure rate (42 vs 18%) to that of itraconazole. The mycologic and clinical relapse rates were 23% and 21% in the terbinafine group, respectively, compared with 53% and 48% in the itraconazole group. In comparative clinical trials, oral terbinafine had a better tolerability profile than griseofulvin and a comparable profile to that of itraconazole or fluconazole. Post marketing surveillance confirmed terbinafine's good tolerability profile. Adverse events were experienced by 10.5% of terbinafine recipients, with gastrointestinal complaints being the most common. Unlike the azoles, terbinafine has a low potential for drug-drug interactions. Most pharmacoeconomic evaluations have shown that the greater clinical effectiveness of oral terbinafine in dermatophyte onychomycosis translates into a cost-effectiveness ratio superior to that of itraconazole, fluconazole and griseofulvin. CONCLUSION: Oral terbinafine has demonstrated greater effectiveness than itraconazole, fluconazole and griseofulvin in randomized trials involving patients with onychomycosis caused by dermatophytes. The drug is generally well tolerated and has a low potential for drug interactions. Therefore, terbinafine is the treatment of choice for dermatophyte onychomycosis.     

Single-blind, randomized, prospective study of sequential itraconazole and terbinafine pulse compared with terbinafine pulse for the treatment of toenail onychomycosis

OBJECTIVE: Efficacy and safety of sequential pulse therapy with itraconazole and terbinafine were compared with pulse terbinafine alone in the treatment of toenail onychomycosis. METHODS: This was a 72-week prospective, single-blind, randomized, multicenter, comparative, parallel group, nonindustry-sponsored trial. A total of 190 patients were recruited from 3 outpatient dermatology offices in North America. Patients were at least 18 years old and had a clinical and mycologic diagnosis of dermatophyte toenail onychomycosis. Patients were randomly assigned to receive sequential pulse therapy (IIT) with 2 pulses of itraconazole followed by 1 or 2 pulses of terbinafine (itraconazole pulse is 200 mg twice daily for 1 week and terbinafine pulse is 250 mg twice daily for 1 week) versus 3 or 4 pulses of terbinafine (TTT). Main outcome measures at week 72 evaluated mycologic cure rate (negative light microscopy and culture), clinical cure (nail appears completely or totally normal), complete cure (clinical and mycologic cure), and effective therapy (mycologic cure and clinical response with at least 5 mm of new, uninvolved nail growth). RESULTS: At week 72, in the IIT versus TTT groups, the mycologic cure rate was 54 of 75 (72.0%) versus 44 of 90 (48.9%), clinical cure rate was 42 of 75 (56.0%) versus 35 of 90 (38.9%), effective therapy 49 of 75 (65.3%) versus 41 of 90 (45.6%), and complete cure 39 of 75 (52.0%) versus 29 of 90 (32.2%), respectively. Both regimens were well tolerated with no new adverse effects being identified. The rate of permanent discontinuation of therapy because of adverse effects was 2 of 81 (2.5%) with IIT and 2 of 95 (2.1%) with TTT. Each of the adverse effects normalized over time. The number of patients who reported an adverse effect in the 2 groups was 12 of 81 (14.8%) versus 22 of 95 (23.2%), respectively. All these adverse effects were reversible and mild to moderate in severity. CONCLUSION: Sequential pulse therapy with itraconazole and terbinafine is effective and safe for the treatment of dermatophyte toenail onychomycosis.