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Safety and efficacy of allylamines in the treatment of cutaneous and mucocutaneous leishmaniasis: A systematic review

  • Jacob M. Bezemer ,

    Roles Conceptualization, Formal analysis, Investigation, Methodology, Project administration, Writing – original draft

    j.m.bezemer@amsterdamumc.nl

    Affiliations Experimental Parasitology Unit, Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands, Fundación Misión Cristiana de Salud, Shell, Pastaza, Ecuador

  • Jacob van der Ende,

    Roles Conceptualization, Formal analysis, Investigation, Methodology, Writing – review & editing

    Affiliation Fundación Quina Care Ecuador, Puerto el Carmen de Putumayo, Sucumbíos, Ecuador

  • Jacqueline Limpens,

    Roles Conceptualization, Formal analysis, Investigation, Methodology, Software, Validation, Writing – review & editing

    Affiliation Medical Library, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

  • Henry J. C. de Vries,

    Roles Conceptualization, Resources, Supervision, Writing – review & editing

    Affiliation Department of Dermatology, Amsterdam Institute for Infection and Immunity, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

  • Henk D. F. H. Schallig

    Roles Conceptualization, Resources, Supervision, Validation, Writing – review & editing

    Affiliation Experimental Parasitology Unit, Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

Abstract

Cutaneous and mucocutaneous leishmaniasis affect a million people yearly, leading to skin lesions and potentially disfiguring mucosal disease. Current treatments can have severe side effects. Allylamine drugs, like terbinafine, are safe, including during pregnancy. This review assesses efficacy and safety of allylamines for the treatment of cutaneous and mucocutaneous leishmaniasis. It followed the PRISMA statement for reporting and was preregistered in PROSPERO(CRD4201809068). MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Global Health Library, Web of Science, Google Scholar, and clinical trial registers were searched from their creation to May 24th, 2020. All original human, animal, and in vitro studies concerning allylamines and cutaneous or mucocutaneous leishmaniasis were eligible for inclusion. Comparators—if any—included both placebo or alternative cutaneous or mucocutaneous leishmaniasis treatments. Complete cure, growth inhibition, or adverse events served as outcomes. The search identified 312 publications, of which 22 were included in this systematic review. There were one uncontrolled and two randomised controlled trials. The only well-designed randomised controlled trial that compared the treatment efficacy of oral terbinafine versus intramuscular meglumine antimoniate in 80 Leismania tropica infected patients showed a non-significant lower cure rate for terbinafine vs meglumine antimoniate (38% vs 53%). A meta-analysis could not be performed due to the small number of studies, their heterogeneity, and low quality. This systematic review shows that there is no evidence of efficacy of allylamine monotherapy against cutaneous and mucocutaneous leishmaniasis. Further trials of allylamines should be carefully considered as the outcomes of an adequately designed trial were disappointing and in vitro studies indicate minimal effective concentrations that are not achieved in the skin during standard doses. However, the in vitro synergistic effects of allylamines combined with triazole drugs warrant further exploration.

Introduction

Cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL), classified by the World Health Organization (WHO) as emerging neglected diseases, affect more than one million people yearly [1, 2]. CL manifests as skin lesions and MCL as potentially disfiguring mucosal disease of the nose, mouth, and larynx [3]. At least 20 different Leishmania parasite species can cause CL and MCL with differing clinical manifestations and responses to treatment [4]. Depending on the infecting Leishmania species, multiple treatment options are available but pentavalent antimonials (e.g., sodium stibogluconate and meglumine antimoniate) are still the most frequently used for American CL and MCL [5] and frequently used for old world leishmaniasis [6]. Yet, antimonial therapy is painful and requires multiple intralesional, intravenous, or intramuscular injections up to 30 days [5, 6]. Miltefosine, the oral alternative for systemic CL and MCL therapy, is not widely available and very expensive, limiting its use in clinical practice [7]. Moreover, pentavalent antimonials can result in hepatotoxicity, renal insufficiency, pancreatitis, cardiac arrest, and other serious side effects and there is no safe alternative systemic drug for use in pregnant women [8, 9]. Furthermore, depending on the region and species, poor treatment responses exist for pentavalent antimonials and miltefosine [10]. Consequently, there is a pressing need to identify alternative oral, safe, available, affordable, and efficacious treatment options for CL and MCL.

Thirty years ago, Goad et al, reported an inhibitory effect of terbinafine on cultured promastigotes of the Leishmania mexicana complex species [11]. Terbinafine is a member of the allylamine drug group, together with butenafine and naftifine.

Allylamines inhibit squalene-2,3-epoxidase causing accumulation of squalene and depletion of sterols in Leishmania amastigotes, resulting in growth inhibition and parasite death [12]. Terbinafine is used as a first line oral treatment for fungal infections and is the preferred systemic treatment for toenail infections in elderly people for safety reasons. Because of its use as antifungal, terbinafine is widely available in pharmacies all over the world at reasonable prices in oral and topical formulations [13].Terbinafine might be a safe systemic option in pregnancy, as no teratogenic side effects have been described [14, 15].

Since allylamines might be an attractive alternative CL and MCL treatment option, a systematic literature review was performed to assess the efficacy and safety of allylamines in CL and MCL treatment and to define priorities for future investigations. All original human, animal, and in vitro studies concerning allylamines and CL or MCL were eligible for inclusion. Comparators—if any—included both placebo or alternative CL and ML treatments. Cure rate in humans, change in lesion diameter in animals, promastigote and amastigote viability and growth, and adverse events served as outcome.

Methods

Search strategy

This systematic review, registered in PROSPERO (registration number CRD42018090687, 2018) and available at: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=90687, followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [16].

A medical information specialist (JL) searched the following electronic databases for studies on leishmaniasis and allylamines, using controlled terms and text words, from their creation to May 24th, 2020: MEDLINE (OVID), EMBASE (OVID), the Cochrane Central Register of Controlled Trials (CENTRAL), The Global Health Library, Web of Science, Google Scholar (1st 150 hits) and the clinical trial registers, ClinicalTrials.gov and WHO_ICTRP. No language, date or other restrictions were applied. The complete search strategies are presented in the S1 File. Reference lists and the citing articles of the identified relevant papers were cross-checked in Web of Science for additional relevant studies. The records retrieved were imported and de-duplicated in EndNote.

Study eligibility

All original human, animal, and in vitro studies were eligible if they examined the effects of systemic or topical allylamines with the following endpoints: cure rate in humans, skin lesion diameter in animals and promastigote or amastigote in vitro growth or viability in the laboratory. The presence of Leishmania parasites had to be confirmed in the study by either microscopy, culture, or molecular techniques. If one Leishmania species was known to cause >90% of the CL or ML cases in the study area in human studies, this species might be assumed as the causative species in all patients.

Study selection

JB and JvdE independently screened the identified studies using EndNote and resolved differences through discussion or consultation with a third reviewer (HS). Studies included during title and abstract screening were subsequently assessed as full text. Authors of conference abstracts were contacted to request unpublished data. If the full report was written in another language than English, Spanish, German, Dutch, French, or Portuguese authors were requested to provide a translation.

Data extraction

The following data from all included studies were entered in Excel: study setting, study population, probable Leishmania species, allylamine studied and treatment combinations. From human studies the following information was recorded: age, gender, lesion type and duration, drug presentation, treatment scheme, cure rates, adverse events, and information for assessment of risk of bias. Cure rates were calculated according to intention to treat analysis and cure was defined as complete epithelialization of ulcers or decrease in induration size > 75% of nodules at last available follow up.

From animal studies the following information was recorded: age, gender, lesion type and duration, drug presentation, treatment scheme, effect on lesion diameter, adverse events, and information for assessment of risk of bias. From in vitro studies the following information was recorded: drug concentrations, promastigote or amastigote growth or viability, and culture cytotoxicity. JB and JvdE extracted data in duplicate and resolved differences through discussion.

Risk of bias assessment

JB and JvdE independently assessed the quality of the clinical trials and resolved differences through discussion. Randomised controlled trials were assessed using the revised Cochrane collaborations tool (RoB2) and non-randomised controlled trials with the Cochrane tool for non-randomised controlled trials (ROBINS-1) [17, 18]. Animal studies were assessed with the SYRCLE´s risk of bias assessment tool [19]. In vitro studies were assessed with the tool developed by the United States national toxicology program [20]. Results of risk of bias assessments were visualized using the Cochrane risk-of-bias visualization tool [17].

Results

Studies included

The literature search identified 312 manuscripts of which 75 were included for full text assessment after screening of titles and abstract. After full text examination, 22 studies were included. Major reasons for exclusion were: `different topic´ and `textbook or review´. The data of two conference abstracts, could not be retrieved by contacting the authors [21, 22], and were therefore excluded from the study. The authors of a study presented in Chinese and another study in Farsi could not provide the data or the English translation of the report and these studies were therefore excluded [23, 24] (Fig 1).

Characteristics of the included human trials (n = 3) [2527], mice studies (n = 2) [28, 29], and amastigote and promastigote studies (n = 12) [11, 3040] are presented in Tables 1 and 2. The case reports (n = 5) [4145] are presented in S1 Table.

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Table 1. Characteristics of human and mice trials reporting treatment of cutaneous leishmaniasis with terbinafine.

https://doi.org/10.1371/journal.pone.0249628.t001

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Table 2. Characteristics of in vitro studies reporting on effects of allylamines in cutaneous and mucocutaneous leishmania species.

https://doi.org/10.1371/journal.pone.0249628.t002

Risk of bias assessment

Two randomised controlled clinical trials [25, 26], a one arm non randomised trial [27], and two animal trials [28, 29] were assessed for risk of bias. Farajzadehs randomised controlled trial in 2015 had an acceptable risk of bias [25]. The study of Farajzadeh from 2016 lost 73% of patients to follow up [26] and Bahamdans study had severe deviations from intended interventions and 48% loss to follow up [27], leading to an overall judgement of high risk of bias for both. The two mice studies suffered from high risk of bias in various domains including allocation concealment and blinding of outcome assessment [28, 29]. The 12 in vitro studies presented minor methodological risks of bias (Figs 25).

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Fig 2. Risk of Bias assessment of randomised controlled trials.

The Revised Cochrane risk-of-bias tool for randomised trials (RoB2) was applied for the evaluation.

https://doi.org/10.1371/journal.pone.0249628.g002

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Fig 3. Risk of Bias assessment of a non-randomised study in humans.

The Risk Of Bias In Non-randomised Studies–of Interventions (ROBINS-I) assessment tool was applied for the evaluation.

https://doi.org/10.1371/journal.pone.0249628.g003

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Fig 4. Risk of Bias assessment of animal trials.

SYRCLE’s risk-of-bias tool for animal studies was applied for the evaluation.

https://doi.org/10.1371/journal.pone.0249628.g004

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Fig 5. Risk of Bias assessment of in vitro studies.

The risk-of-bias tool to address in vitro studies developed by the United States national toxicology program was applied for the evaluation.

https://doi.org/10.1371/journal.pone.0249628.g005

It was not possible to perform a meta-analysis of the study outcomes, due to the small number of studies, their heterogeneity and low quality.

Efficacy of terbinafine on L. tropica human infections and adverse events

The clinical trial of Farajzadeh 2015 [25] included 80 L. tropica infected patients randomised between two different treatment groups: 1) oral terbinafine 125-500mg (weight dependent) daily during four weeks, combined with cryotherapy every two weeks (n = 40) and 2) meglumine antimoniate 15mg/kg/day for three weeks combined with cryotherapy every two weeks (n = 40). Complete follow up was achieved for all patients at three months. Contrary to the hazard ratios presented by Farajzadeh, in this review the endpoint was the complete cure rate. In the terbinafine arm 15/40 (38%) patients were cured and in the meglumine antimoniate arm 21/40 (53%) cases were cured, a difference that was not statistically significant in Kaplan Meier analysis (p = 0,39). None of the in vivo studies reported adverse events [2529].

Species specific effectivity of allylamine treatments

Growth inhibition of terbinafine in promastigote in vitro studies was reported for the L. major, L. tropica, L. mexicana, L. braziliensis, and L. guyanensis complexes. An interspecies comparison in promastigote cultures with terbinafine 27μM showed higher inhibition levels in old world (L. major, L. tropica, and L. aethiopica) species (Table 3).

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Table 3. Overview of clinical and in vitro Leishmania species specific results of terbinafine in cutaneous leishmaniasis.

https://doi.org/10.1371/journal.pone.0249628.t003

Treatment with butenafine killed in vitro cultured amastigotes of L. amazonensis and L. braziliensis at a mean effective dose of 30–38μM compared to the median cytotoxic concentration of 98μM [35]. Naftifine killed L. major amastigotes with mean effective dose of 45μM whilst cytotoxicity levels were more than 110μM [34].

Case reports reporting cure with terbinafine

There were five case reports showing a curative effect of terbinafine. In two case reports terbinafine cured a L. tropica infected patient although the reason to start terbinafine was unclear [41, 42]. An HIV positive patient infected in Colombia and initially diagnosed with a skin mycosis, was treated, and cured with terbinafine when CL was diagnosed eventually. The causative Leishmania species was unknown [43]. In another case, terbinafine 250mg daily combined with a Crotamiton 10% + Sulphur 2% cream in the absence of other CL treatments cured a Kenyan patient with CL; the causative Leishmania species was unknown [44]. Terbinafine 500mg combined with itraconazole 200mg daily for six months was started without evident reason in a patient suffering from MCL, visceral leishmaniasis, and liver cirrhosis caused by L. infantum. Terbinafine proved surprisingly effective resulting in the cure of the nasal mucosal inflammation and improvement of the liver function [45].

Terbinafine drug combination treatment

Various in vitro studies evaluated the combination of terbinafine with drugs from the triazole group. Up to 300-fold improvement was demonstrated of the inhibition of L. braziliensis promastigotes when combining ketoconazole with terbinafine [37]. Another study reported that ketoconazole and terbinafine had a synergistic effect on the inhibition of L. amazonensis amastigotes resulting in a minimally inhibitory concentration of 0,001μM (Table 4) [39].

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Table 4. Results of in vitro and clinical studies on the combination of terbinafine with other treatment in cutaneous and mucocutaneous leishmaniasis.

https://doi.org/10.1371/journal.pone.0249628.t004

Discussion

This systematic review assesses efficacy and safety of allylamines for the treatment of CL and MCL. It comprises an exhaustive search of eight electronic databases and trial registers. It assesses the risk of bias of two randomised controlled trials, a non-controlled trial, two animal studies, and 12 in vitro studies and summarizes the available evidence including five case reports. Generally, the quality of evidence was low and human studies were done only in L. tropica.

The only well-designed randomised controlled trial of Farajzadeh et al. that compared the treatment efficacy of oral terbinafine versus intramuscular meglumine antimoniate showed a non-significant lower cure rate for terbinafine (38% vs 53% of treated patients) [25].

Farajzadeh [26] and Bahmdans [27] clinical trials with terbinafine reported cure rates of 14% and 15% respectively, but the findings of these studies should be interpreted with caution due to high rates of loss to follow up. Two animal studies lacked allocation concealment and did not blind outcome assessment and therefore should be interpreted with caution [28, 29].

The in vitro studies showed that terbinafine, butenafine, and naftifine eliminated amastigotes at concentrations between 23 and 45μM, that is approximately five times higher than the terbinafine levels achieved in the skin during terbinafine treatment [4648]. Therefore, we conclude that allylamines are not promising for CL and MCL treatment.

Farajzadeh recommends terbinafine as an alternative to meglumine antimoniate in the case of allergy or resistance [25]. Although the work reports on hazard ratios and time to healing, it does not mention the complete cure rates in the abstract and conclusion sections. The cure rate of 38% was not significantly lower than the 53% cure rate with meglumine antimoniate, and we consider it too low to propose it as a new alternative treatment. The lack of significance of the lower cure rate of terbinafine compared to meglumine antimoniate could be explained by a low effectivity of the latter.

Whilst this review shows that there is no evidence for efficacy of terbinafine in the treatment of CL and MCL, it is highly effective in the treatment of mycotic skin disease. The difference may be due to the high sensitivity of skin fungus to terbinafine compared to Leishmania amastigotes. Terbinafine eliminates skin fungus in vitro at a mean concentration of 0,014μM [49], thus is approximately 2500 times more effective than the elimination of Leishmania amastigotes.

Promastigote cultures are relatively easy and cheap to maintain but are not very reliable as predictors of in vivo effectivity as they represent the infective mosquito stage of the parasite whilst human infection is sustained by intracellular amastigotes [50, 51]. Therefore, the results of the in vitro study of Beach et al. that indicates effective concentrations of 1–34μM of terbinafine in L. braziliensis and L. amazonensis promastigotes should be interpreted with caution. Results of promastigote studies must be confirmed in amastigote studies.

Although triazole monotherapy does not seem effective as treatment of CL patients, results from in vitro studies indicate terbinafine combined with triazole drugs may be effective through a synergistic effect. Terbinafine combined with ketoconazole eliminated L. amazonensis amastigotes at levels of 0,001μM of both drugs. Terbinafine would reach those levels with an oral dose of 250mg but the best combination with a triazole drug still has to be defined [46]. Triazole drugs like ketoconazole and fluconazole are inhibitors of the enzymes CYP 2C9 and CYP 3A4, involved in terbinafine metabolism, and may cause significant rise in terbinafine plasma concentrations. Secondary effects of terbinafine combined with triazoles have not been studied extensively and would require large clinical studies before implementation [52, 53].

Conclusion

Based on a systematic review of available literature we conclude that there is no evidence for the efficacy of allylamine monotherapy against CL and MCL. Further trials of allylamines as a treatment for CL and MCL should be carefully considered as the outcomes of an adequately designed trial were disappointing and in vitro studies indicate minimal effective concentrations that are not achieved in the skin during standard doses of 250-1000mg oral terbinafine/day. However, the in vitro synergistic effects of allylamines combined with triazole drugs against amastigotes, warrant more investigation starting with high quality animal studies to define optimal doses and safety profiles and followed by well-designed trials in humans in case of positive findings.

Supporting information

References

  1. 1. Alvar J, Velez ID, Bern C, Herrero M, Desjeux P, Cano J, et al. Leishmaniasis worldwide and global estimates of its incidence. PLoS ONE. 2012;7(5):e35671. pmid:22693548
  2. 2. Molyneux DH, Savioli L, Engels D. Neglected tropical diseases: progress towards addressing the chronic pandemic. Lancet (London, England). 2017;389(10066):312–25. pmid:27639954
  3. 3. Cincura C, De Lima CMF, Machado PRL, Oliveira-Filho J, Glesby MJ, Lessa MM, et al. Mucosal leishmaniasis: A retrospective study of 327 cases from an endemic area of Leishmania (Viannia) braziliensis. American Journal of Tropical Medicine and Hygiene. 2017;97(3):761–6. pmid:28722607
  4. 4. Hodiamont CJ, Kager PA, Bart A, de Vries HJ, van Thiel PP, Leenstra T, et al. Species-directed therapy for leishmaniasis in returning travellers: a comprehensive guide. PLoS neglected tropical diseases. 2014;8(5):e2832. pmid:24787001
  5. 5. Pinart M, Rueda JR, Romero GA, Pinzón-Flórez CE, Osorio-Arango K, Silveira Maia-Elkhoury AN, et al. Interventions for American cutaneous and mucocutaneous leishmaniasis. The Cochrane database of systematic reviews. 2020;8:Cd004834. pmid:32853410
  6. 6. Heras-Mosteiro J, Monge-Maillo B, Pinart M, Lopez Pereira P, Reveiz L, Garcia-Carrasco E, et al. Interventions for Old World cutaneous leishmaniasis. The Cochrane database of systematic reviews. 2017;12(12):Cd005067.
  7. 7. Sunyoto T, Potet J, Boelaert M. Why miltefosine-a life-saving drug for leishmaniasis-is unavailable to people who need it the most. BMJ global health. 2018;3(3):e000709. pmid:29736277
  8. 8. Oliveira LF, Schubach AO, Martins MM, Passos SL, Oliveira RV, Marzochi MC, et al. Systematic review of the adverse effects of cutaneous leishmaniasis treatment in the New World. Acta tropica. 2011;118(2):87–96. pmid:21420925
  9. 9. Coelho DR, De-Carvalho RR, Rocha RC, Saint’Pierre TD, Paumgartten FJ. Effects of in utero and lactational exposure to SbV on rat neurobehavioral development and fertility. Reproductive toxicology (Elmsford, NY). 2014;50:98–107. pmid:25461908
  10. 10. de Vries HJ, Reedijk SH, Schallig HD. Cutaneous leishmaniasis: recent developments in diagnosis and management. American journal of clinical dermatology. 2015;16(2):99–109. pmid:25687688
  11. 11. Goad LJ, Holz GG Jr., Beach DH. Effect of the allylamine antifungal drug SF 86–327 on the growth and sterol synthesis of Leishmania mexicana mexicana promastigotes. Biochem Pharmacol. 1985;34(20):3785–8. pmid:4052119
  12. 12. Petranyi G, Ryder NS, Stutz A. Allylamine derivatives: new class of synthetic antifungal agents inhibiting fungal squalene epoxidase. Science. 1984;224(4654):1239–41. pmid:6547247
  13. 13. Kreijkamp-Kaspers S, Hawke K, Guo L, Kerin G, Bell-Syer SE, Magin P, et al. Oral antifungal medication for toenail onychomycosis. Cochrane Database Syst Rev. 2017;7:Cd010031. pmid:28707751
  14. 14. Kaul S, Yadav S, Dogra S. Treatment of Dermatophytosis in Elderly, Children, and Pregnant Women. Indian dermatology online journal. 2017;8(5):310–8. pmid:28979861
  15. 15. Terbinafine. Drugs and Lactation Database (LactMed). Bethesda (MD): National Library of Medicine (US); 2006.
  16. 16. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS medicine. 2009;6(7):e1000100. pmid:19621070
  17. 17. Higgins JPT SJ, Savović J, Page MJ, Hróbjartsson A, Boutron I, Reeves B, et al. A revised tool for assessing risk of bias in randomized trials. Cochrane Methods Cochrane Database of Systematic Reviews 2016(10):(Suppl 1).
  18. 18. Sterne JAC, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomized studies of interventions. british journal of medicine. 2016;355(4919).
  19. 19. Hooijmans CR, Rovers MM, de Vries RB, Leenaars M, Ritskes-Hoitinga M, Langendam MW. SYRCLE’s risk of bias tool for animal studies. BMC medical research methodology. 2014;14:43. pmid:24667063
  20. 20. Roony A. Extending a Risk-of-Bias Approach to Address In Vitro Studies. In: OHAT, editor. Washington, USA: National Toxicology Program Office of Health Assessment and Translation; 2015.
  21. 21. Ukşal Ü, Şahin İ, Durgut S, Özcan H, Gürel MS. In vitro and in vivo effect of terbinafine in cutaneous leishmaniasis. Journal of the European Academy of Dermatology and Venereology. 1998;11(Suppl 2):s242.
  22. 22. Bonatto AF, Bonatto SF, Sampaio RNR, Vilela H, Vexenat A. Estudo da eficácia da terbinafina, in vitro. Resumos do IV Congresso de Iniciação Científica da Universidade de Brasília 1998. p. 128.
  23. 23. Lu-juan GAO, Jin YU, Yaguchi T, Wei C, Ruo-yu LI. A case of cutaneous leishmaniasis misdiagnosed as cutaneous aspergillosis and successfully treated with terbinafine. Chinese Journal of Dermatology. 2011;44(11):811–3.
  24. 24. Ebrahimian S, Asilian A, Faghihi G. Comparetaive Study on Glucantime and Oral Terbinafine along with Systemic Glucantime on Cutaneous Leishmaniasis. J Isfahan Med Sch. 2011;28(118):1246–52.
  25. 25. Farajzadeh S, Esfandiarpour I, Haghdoost AA, Mohammadi S, Mohebbi A, Mohebbi E, et al. Comparison between Combination Therapy of Oral Terbinafine and Cryotherapy versus Systemic Meglumine Antimoniate and Cryotherapy in Cutaneous Leishmaniasis: A Randomized Clinical Trial. Iranian J Parasitol. 2015;10(1):1–8. pmid:25904940
  26. 26. Farajzadeh S, Heshmatkhah A, Vares B, Mohebbi E, Mohebbi A, Aflatoonian M, et al. Topical terbinafine in the treatment of cutaneous leishmaniasis: triple blind randomized clinical trial. J Parasit Dis. 2016;40(4):1159–64. pmid:27876906
  27. 27. Bahamdan KA, Tallab TM, Johargi H, Nourad MM, Ibrahim K, el Sherbini AH, et al. Terbinafine in the treatment of cutaneous leishmaniasis: a pilot study. Int J Dermatol. 1997;36(1):59–60. pmid:9071621
  28. 28. Zakai HA, Zimmo SK. Effects of itraconazole and terbinafine on Leishmania major lesions in BALB/c mice. Ann Trop Med Parasitol. 2000;94(8):787–91. pmid:11214097
  29. 29. Sampaio RN, Takano GH, Malacarne AC, Pereira TR, de Magalhaes AV. [In vivo Terbinafine inefficacy on cutaneous leishmaniasis caused by Leishmania (Leishmania) amazonensis in C57BL/6 mice]. Rev Soc Bras Med Trop. 2003;36(4):531–3. pmid:12937735
  30. 30. Andrade-Neto VV. Papel do colesterol exógeno nos mecanismos de adaptação de Leishmania spp a condições de estresse metabólico e farmacológico. Rio de Janeiro: Fundação Oswaldo Cruz. Instituto Oswaldo Cruz; 2013.
  31. 31. Andrade-Neto VV, Cicco NN, Cunha-Junior EF, Canto-Cavalheiro MM, Atella GC, Torres-Santos EC. The pharmacological inhibition of sterol biosynthesis in Leishmania is counteracted by enhancement of LDL endocytosis. Acta Trop. 2011;119(2–3):194–8. pmid:21601554
  32. 32. Andrade-Neto VV. Avaliação da utilização de colesterol exógeno por Leishmania amazonensis como possível alvo farmacológico. Rio de Janeiro: Fundação Oswaldo Cruz. Instituto Oswaldo Cruz; 2009.
  33. 33. Beach DH, Goad LJ, Berman JD, Ellenberger TE. Effects of a squalene-2, 3-epoxidase inhibitor on propagation and sterol biosynthesis of Leishmania promastigotes and amastigotes. In: Hart DT, editor. Leishmaniasis. New York, USA: Plenum; 1989.
  34. 34. Berman JD, Gallalee JV. In vitro antileishmanial activity of inhibitors of steroid biosynthesis and combinations of antileishmanial agents. J Parasitol. 1987;73(3):671–3. pmid:3037057
  35. 35. Bezerra-Souza A, Yamamoto ES, Laurenti MD, Ribeiro SP, Passero LF. The antifungal compound butenafine eliminates promastigote and amastigote forms of Leishmania (Leishmania) amazonensis and Leishmania (Viannia) braziliensis. Parasitol Int. 2016;65(6 Pt A):702–7. pmid:27546158
  36. 36. Chance ML, Havercroft PR, Goad LJ. Observations on leucine incorporation into sterol by Leishmania, and its inhibition by terbinafine. Ann Trop Med Parasitol. 1999;93(2):185–8. pmid:10474645
  37. 37. Rangel H, Dagger F, Hernandez A, Liendo A, Urbina JA. Naturally azole-resistant Leishmania braziliensis promastigotes are rendered susceptible in the presence of terbinafine: comparative study with azole-susceptible Leishmania mexicana promastigotes. Antimicrob Agents Chemother. 1996;40(12):2785–91. pmid:9124841
  38. 38. Tariq P, Khan KA. Comparative study on susceptibility of Leishmania isolated from dermal leishmaniasis to antifungal drug terbinafine and classic antileishmanial drugs. Pakistan Journal of Pharmacology. 1994;11(1):9–17.
  39. 39. Vannier-Santos MA, Urbina JA, Martiny A, Neves A, de Souza W. Alterations induced by the antifungal compounds ketoconazole and terbinafine in Leishmania. J Eukaryot Microbiol. 1995;42(4):337–46. pmid:7620457
  40. 40. Zakai HA, Zimmo S, Fouad MA. Effect of itraconazole and terbinafine on Leishmania promastigotes. J Egypt Soc Parasitol. 2003;33(1):97–107. pmid:12739804
  41. 41. Scarisbrick JJ, Chiodini PL, Watson J, Moody A, Armstrong M, Lockwood D, et al. Clinical features and diagnosis of 42 travellers with cutaneous leishmaniasis. Travel Medicine and Infectious Disease. 2006;4(1):14–21. pmid:16887720
  42. 42. Albanese G, Di Cintio R, Galbiati G. Cutaneous leishmaniasis in the north of Italy. Int J Dermatol. 1996;35:223–4. pmid:8655248
  43. 43. Gonzalez-Ruperez J, Javaloyas de Morlius M, Moreno Carazo A. Remission of localized cutaneous leishmaniasis in a HIV-positive patient using systemic terbinafine. Dermatology. 1997;194(1):85–6. pmid:9031802
  44. 44. Mawenzi RL. A case of cutaneous leishmaniasis successfully treated with oral terbinafine in Kenya. International Journal of Research in Dermatology. 2018;4(3):433–6.
  45. 45. Vellin JF, Russier M, Mougeot G, Kemeny JL, Gilain L. Leishmaniose nasale. Annales d’Otolaryngologie et de Chirurgie Cervico-faciale. 2005;122(2):100–4.
  46. 46. Faergemann J, Zehender H, Denouel J, Millerioux L. Levels of terbinafine in plasma, stratum corneum, dermis-epidermis (without stratum corneum), sebum, hair and nails during and after 250 mg terbinafine orally once per day for four weeks. Acta dermato-venereologica. 1993;73(4):305–9. pmid:7904107
  47. 47. Jensen JC. Clinical pharmacokinetics of terbinafine (Lamisil). Clinical and experimental dermatology. 1989;14(2):110–3. pmid:2689012
  48. 48. Jones TC. Overview of the use of terbinafine (Lamisil) in children. The British journal of dermatology. 1995;132(5):683–9. pmid:7772471
  49. 49. Leyden J. Pharmacokinetics and pharmacology of terbinafine and itraconazole. Journal of the American Academy of Dermatology. 1998;38(5 Pt 3):S42–7. pmid:9594936
  50. 50. van den Bogaart E, Schoone GJ, England P, Faber D, Orrling KM, Dujardin JC, et al. Simple colorimetric trypanothione reductase-based assay for high-throughput screening of drugs against Leishmania intracellular amastigotes. Antimicrob Agents Chemother. 2014;58(1):527–35. pmid:24189262
  51. 51. De Muylder G, Ang KK, Chen S, Arkin MR, Engel JC, McKerrow JH. A screen against Leishmania intracellular amastigotes: comparison to a promastigote screen and identification of a host cell-specific hit. PLoS Negl Trop Dis. 2011;5(7):e1253. pmid:21811648
  52. 52. Gupta AK, Daigle D, Paquet M. Therapies for onychomycosis a systematic review and network meta-analysis of mycological cure. Journal of the American Podiatric Medical Association. 2015;105(4):357–66. pmid:25032982
  53. 53. Gupta AK, Versteeg SG, Shear NH. Common drug-drug interactions in antifungal treatments for superficial fungal infections. Expert opinion on drug metabolism & toxicology. 2018;14(4):387–98. pmid:29633864