Topical Antimycotic Agents Research Articles

Real world retrospective analysis of luliconazole 1% and salicylic acid 3% as fixed dose combination in the management of hyperkeratotic dermatophytosis in India

<p class="abstract"><strong>Background:</strong> In recent times, there is increase in prevalence of hyperkeratotic dermatophytosis in India. These hyperkeratotic lesions usually impede the absorption of topical anti-mycotic agent making infection recalcitrant to topical anti-fungal therapy alone. Hence, many times topical keratolytic are used in combination with topical anti-fungal agents which augment the shedding of scales.</p><p class="abstract"><strong>Methods:</strong> To seek for short period therapy in hyperkeratotic dermatophytosis, we conducted multicentre, retrospective data analysis at 61 dermatology clinics to study effectiveness and safety of Luliconazole 1% and Salicylic acid 3% fixed dose combination (FDC) cream for 2 weeks.</p><p class="abstract"><strong>Results: </strong>A data of 191 patients’ were included in this analysis. All patients have received some of the topicals and switched to FDC. Total symptom score of 7.19±1.91 improved to 3.15±1.12 in just 2 weeks (p<0.05). The clinical improvement rate (percentage of ‘marked improvement’ plus ‘moderate improvement’) was 78% after 2 weeks of treatment. Moreover, 5 patients (2.61%) achieved complete clearance. This FDC was found to be safe in 51.83% (n=99) of the patients whereas 37.7% of the patients (n=72) reported it as almost safe. Minor problems with the safety was found in 9.42% of the patients (n=18). Two patients (1.04%) reported it as not safe and thus shifted to another drug. Irritation and burning were reported as most common adverse events (AE).</p><p class="abstract"><strong>Conclusions:</strong> The short combination therapy with luliconazole and salicylic acid as FDC has been found to be effective and safe. It should be a valuable option for hyperkeratotic dermatophytosis for early achievement of clinical cure and better patient compliance.</p>

1% film-forming terbinafine solution in therapy in patients with long-lasting foot mycoses

Topical antimycotic agents are used in the treatment of foot mycosis. Numerous studies have shown the efficacy of terbinafine. Fungistatic activity of the medication is provided by blockade of action of squalene epoxidase enzyme and subsequent inhibition of squalene transformation into squalene epoxy. Further accumulation of squalene inside the fungal cell with its subsequent rupture and death occurs. Various medicinal forms of terbinafine have been developed, which can be used at different stages and at different forms of foot mycosis. The present study shows high efficacy and safety of 1% film-forming solution of Lamisil UNO in therapy in patients suffering from foot mycosis for a long time. The unique form of the drug allows limiting treatment to one application.

The effect of topically applied antimycotic agents on inner ear vestibular and cochlear function

To assess and compare the effect of commonly used topical antimycotic agents and their solvents on the function of the vestibular and cochlear parts of the sand rat's inner ear. Prospective, controlled, animal study. Forty-five fat sand rats were randomly assigned to five major groups, each receiving topical application of a different agent: saline (control), gentamicin (ototoxic control), and three antimycotic agents: nystatin, clotrimazole solution (Agisten), and bifonazole solution (Agispor). All animals underwent a right labyrinthectomy, and a polyethylene tube was inserted into the left middle ear followed by baseline recording of vestibular evoked potentials (VsEPs) and auditory nerve and brainstem responses (ABR). Subsequently, each animal received five consecutive daily applications of the specific agent into the left middle ear. Evoked potential recordings were repeated 3 and 10 days after the last application and compared to baseline. For clotrimazole and bifonazole solutions, the effect of the solvents was assessed by comparing ABR recordings at similar intervals. Administration of saline did not affect VsEPs or ABR. Both could not be recorded following gentamicin application. In all three antimycotic agents, no statistically significant difference was found between VsEPs recordings before and after application. Clotrimazole and bifonazole solutions caused a significant ABR threshold elevation similar to that caused by their solvents. Nystatin caused a less significant ABR threshold elevation. The three commonly used topical antimycotic agents investigated here did not affect vestibular function but had a toxic effect on inner ear cochlear function. It seems the main offenders were the solvents.

Ciclopirox

Ciclopirox is a topical antimycotic agent belonging to the chemical class of hydroxypyridones and not related to azoles or any other class of antifungal agents. Its antimicrobial profile includes nearly all of the clinically relevant dermatophytes, yeasts and moulds, and is therefore broader than that of most other antimycotics. It is also active against certain frequently azole-resistant Candida species and against some bacteria. The mechanism of action of ciclopirox is different from that of other topical antifungal drugs, which generally act through ergosterol inhibition. The high affinity of ciclopirox for trivalent metal cations, resulting in inhibition of the metal-dependent enzymes that are responsible for the degradation of peroxides within the fungal cell, appears to be the major determinant of its antimicrobial activity. This unique and multilevel mechanism of action provides a very low potential for the development of resistance in pathogenic fungi, with cases of resistance rarely reported. Ciclopirox also displays mild anti-inflammatory effects in biochemical and pharmacological models; effects also shown in small clinical studies. Scavenging of reactive oxygen species released from inflammatory cells is a likely contributor to these anti-inflammatory effects. Ciclopirox, and its olamine salt, is available in multiple topical formulations, suitable for administration onto the skin and nails and into the vagina. The pharmaceutical forms most widely investigated are 1% ciclopirox olamine cream and 8% ciclopirox acid nail lacquer, but lotion, spray, shampoo, pessary, solution, gel and douche formulations have also been used. Ciclopirox penetrates into the deep layers of the skin, mucosal membranes and nail keratin, reaching concentrations exceeding the minimal fungicidal concentrations for most medically important fungi. A large number of clinical trials were and are still being performed with ciclopirox, starting in the early 1980s. Ciclopirox was first developed for fungal skin infections and vaginal candidiasis, and is currently well established in these indications. More recently, the drug has been clinically investigated in seborrhoeic dermatitis and onychomycosis, showing good efficacy and excellent tolerability. Emphasis in this review is given to a ciclopirox medicated nail lacquer, which is based on an original technology and has superior properties in terms of its affinity to keratin and nail permeation. It has been found to have superior efficacy and safety to another commercially available formulation in the treatment of onychomycosis. The safety features of ciclopirox are well known. The topical drug is devoid of systemic adverse reactions. Mild local reactions characterized by a burning sensation of the skin, irritation, redness, pain or pruritus, generally in less than 5% of treated patients, can be observed following skin and vaginal application. With nail application, the most common adverse event is the appearance of mild erythema in 5% of the treated population. As a general conclusion, although less effective than some oral antimycotic agents in various indications, ciclopirox compares very well in terms of the benefit/risk ratio due to its excellent tolerability and complete absence of serious adverse effects.

Treatment of tinea capitis: beyond griseofulvin

Tinea capitis is a common pediatric scalp infection caused by dermatophytes. Topical therapy alone is ineffective, so oral griseofulvin has traditionally been the standard treatment. The new antimycotic agents itraconazole, terbinafine, and fluconazole represent effective treatment alternatives that have fewer problems with tolerability and adverse effects. More comparative studies are needed to determine the optimal treatment with these agents and adjuvant therapies such as antifungal shampoos, topical antimycotic agents, and cortico-steroids. (J Am Acad Dermatol 1999;40:S27-30.)

Antimicrobial Susceptibility Testing of Dermatophytes – Comparison of the Agar Macrodilution and Broth Microdilution Tests

Fifty dermatophyte strains, recently obtained from clinical material, belonging to 4 different species were examined for their susceptibility to 5 systemic or topical antimycotic agents using both an agar macrodilution and a broth microdilution test. Antimycotics compared were griseofulvin, itraconazole, sertaconazole, terbinafine and ciclopiroxolamine. A comparison of the minimum inhibitory concentrations (MIC) clearly showed differences between the two test methods applied. For all 5 antimycotics, MIC data were three- to seventyfold lower in the microdilution test system. These differences, depending on the test method, have to be taken into account when comparing MIC data in the literature or when relating the in vitro data to the tissue concentrations determined in vivo.

Allergic contact dermatitis due to topical imidazole antimycotics. The sensitizing ability of active ingredients and cross-sensitivity

Since the introduction of clotrimazole cream to the Japanese market in 1979, topical imidazole antimycotics have been used with increasing frequency in the treatment of superficial fungal infections. Topical imidazole antimycotics are in common use today and new imidazole derivatives continue to be developed. In this study, the author discussed allergic contact dermatitis due to topical imidazole antimycotics and cross-reactions among them. Of the 3,049 outpatients who were patch-tested for contact dermatitis at the Department of Dermatology, Nippon Medical School Hospital from January, 1984 to August, 1994, 218 were patch-tested with topical antimycotic agents. Of these 218 cases, 18 were tested with imidazole derivatives and 66 showed positive. Thirty-five were allergic to the active ingredients; 16 were allergic to sulconazole, 11 to croconazole, 3 to tioconazole, 3 to miconazole, one to bifonazole, and one to clotrimazole. The reason why sulconazole induced the most frequent positive reactions is probably that sulconazole was prescribed most frequently at our department during the period. The duration and the total amount of topical imidazole needed until contact dermatitis occurred, were statistically analyzed by t.test. Croconazole needed a significantly shorter duration and smaller quantity than sulconazole. This means that the sensitizing ability of croconazole is stronger than that of sulconazole. Since 21 of the 35 imidazole-allergic cases cross-reacted to other imidazole(s), the imidazole derivatives are considered to cross-react frequently.

Results of German multicenter study of antimicrobial susceptibilities of Trichophyton rubrum and Trichophyton mentagrophytes strains causing tinea unguium. German Collaborative Dermatophyte Drug Susceptibility Study Group.

Thirty-two strains of Trichophyton rubrum and 16 strains of Trichophyton mentagrophytes isolated from patients with tinea unguium in various parts of Germany were subjected to a microdilution test with six systemic or topical antimycotic agents. Apart from griseofulvin, there were no species-specific differences between the two species. Terbinafine was the most active antimycotic agent, with a MIC not exceeding 0.05 micrograms/ml.

Fungal Infections Of The External Ear

Fungal infections of the external auditory canal can pose a great clinical challenge both in diagnosis and in therapy. Most infections present in patients who have undergone previous medical treatment of the external canal, which has changed the pH and normal canal flora, or in those who have diminished capacity for resisting infections. Diagnosis is made by clinical inspection and selective cultures. Therapy consists of complete cleaning followed by use of topical antimycotic agents. Systemic therapy is rarely required.

Modification of neutrophil functions by naftifine.

Naftifine (NF), a topical antimycotic agent, is highly active in vitro and in vivo against a wide range of pathogenic fungi. NF inhibits human polymorphonuclear leucocyte (PMN) chemotaxis. Following stimulation with zymosan-activated serum, 85-97% of the PMNs exhibited detectable membrane ruffling and polarity. In contrast, NF-treated PMNs did not exhibit such chemotactic factor-induced shape changes. We also analysed the effect of NF on PMN superoxide anion (O2-) and chemiluminescence (CL) production, as a measure of respiratory burst activity. Stimulation of PMNs pre-incubated with NF (37 degrees C for 30 min at 1-150 micrograms/ml) by FMLP, PMA and zymosan resulted in a dose-dependent inhibition in PMN CL. Doses of NF which depressed chemotaxis, inhibited CL and diminished O2- production in a statistically significant manner (P < 0.05-0.001). In conclusion, NF alters membrane-related responses in PMNs, and this alteration may be associated with a change in PMN morphology. Binding of NF to PMN membrane sterol, with a subsequent alteration in membrane configuration, is the most likely cause of the inhibition of PMN function. The data collectively document biochemical and morphological differences between control and NF-treated PMNs as determined by stimulus-specific CL and O2- generation and membrane shape change. Such differences may account, in part, for its efficacy in inflammatory fungal skin diseases.

Laboratory techniques alternative to in vivo experiments for studying the liberation, penetration and fungicidal action of topical antimycotic agents in the skin, including ciclopiroxolamine.

Summary: Short‐term experiments on excised skin (human, pig) gave the following results:1. In the tissue activity test with direct inoculation (D‐TAT) commercial preparations of the non‐azole antimycotics ciclopiroxolamine, tolnaftate and naftifine, produced higher inhibitory activity against Trichophyton mentagrophytes (standard strain) in various levels of the horny layer than were produced by the azole antimycotics econazole, miconazole, clotrimazole, oxiconazole and bifonazole.Fast drying solutions of antimycotics invariably gave higher inhibitory activities than creams.In the ultrafiltration tissue activity test (UFT‐ TAT) against Candida albicans (2 strains), antimycotic agents ranked in order of effectiveness as follows: ciclopiroxolamine – most of the azole antimycotics – bifonazole and naftifine.2. In tests of fungicidal activity against T. mentagrophytes (2 strains) and Microsporum gypseum (1 strain) the first step was to inoculate the skin surface. After the horny layer had been penetrated by fungal mycelia, antimycotic agents of documented fungicidal potency, chiefly in the form of creams, were applied to the skin surface and left to act for up to 18 hours. The horny layer and epidermis were then scraped off and the concentration of viable fungi was determined. Ciclopiroxolamine cream and lotion produced by far the greatest diminution in viable fungi; creams containing oxiconazole and naftifine were moderately effective and those containing tioconazole and bifonazole produced a relatively small decrease in viable fungi.To avoid erroneous results it is important to homogenize and dilute the skin scrapings; if this is not done certain antimycotics will give misleadingly high fungal killing rates. At this early stage the scatter of results is still wide and minor differences in efficacy cannot as yet be detected with certainty.3. From the results of various comparative tests it is evident that pig skin can be used as a substitute for human skin in the tests listed under 1. and 2. above. This discovery may make a valuable contribution towards limiting the need for experiments on living animals and trials on human beings.Zusammenfassung: In Kurzzeitversuchen an exzidierter Haut (Mensch, Schwein) wurde gefunden:1. Im Gewebeaktivitätstest mit direkter Inokulation (D‐GAT) wurde mit Handelspräparaten der Nichtazol‐Antimykotika Ciclopiroxolamin, Tolnaftat und Naftifin in verschiedenen Hornschichtniveaus eine höhere Hemmaktivität gegenüber Trichophyton mentagrophytes (Standard‐Stamm) erzielt als mit solchen der Azol‐Antimykotika Econazol, Miconazol, Clotrimazol, Oxiconazol und Bifonazol.Rasch trocknende Lösungen von Antimykotika ergaben durchweg höhere Hemmaktivitäten als Cremes.Im Ultrafiltrations‐Gewebeaktivitätstest (UFT‐GAT) gegenüber Candida albicans (2 Stämme) ergab sich nach erzielter Wirksamkeit die Rangfolge Ciclopiroxolamine – Mehrzahl der Azolantimykotika – Bifonazol und Naftifin.2. In Fungizidie‐Testen gegenüber T. mentagrophytes (2 Stämme) und Microsporum gypseum (1 Stamm) wurde zunächst die Hautoberfläche inokuliert. Nach Durchdringung der Hornschicht mit Pilzmyzelien wirkten auf die Hautoberfläche bis zu 18 Stunden lang überwiegend Cremes von als fungizid publizierten Antimykotika ein. Während sich in abgeschabter Hornschicht und Epidermis der so bearbeiteten Hautoberflächen mit Ciclopiroxolamin‐Creme und ‐Lotion die weitaus höchste Verminderung lebensfähiger Keime ergab, bewirkten Cremes mit Oxiconazol und Naftifin eine mittlere und solche mit Tioconazol und Bifonazol eine relativ niedrige Keimeliminierung.Zur Vermeidung von fehlerhaften Ergebuissen mußten Homogenisierung und Verdünnung der Hautschabsel erfolgen, anderenfalls bei mehreren Antimykotika eine zu hohe Keimabtötung vorgetäuscht worden wäre. Wegen der vorerst noch hohen Streuung der Ergebnisse können kleinere Wirksamkeitsunterschiede noch nicht sicher erfaßt werden.3. Nach dem Ergebnis verschiedener Vergleichstests kann in den Testen zu 1. und 2. Schweinehaut als Ersatz für Haut vom Menschen dienen und dürfte damit wesentlich zur Einschränkung von Versuchen am lebenden Tier und von Prüfungen am Menschen beitragen.

Contribution to the methodology of testing topical antimycotic agents in guinea pig dermatophytosis.

SummaryIndications for a topical antimycotic activity in compounds can be expediently obtained from tests carried out at the spreading stage of guinea pig dermatophytosis. In this study a description is given of a simple technique which may be regarded as an in vivo analogue to the mycelial growth test on agar media. Our example demonstrates a good activity of ciclopirox (HOE 296). The procedure is strictly selective, the compounds characterized by a low capacity to permeate and a diminished action on a strongly growing mycelium being excluded. If the tests are favourable, recultivation trials can be undertaken, though much care is required to perform them correctly. A presentation of dose‐response curves and a detailed discussion of methods for assessment of viability have been omitted in this paper.ZusammenfassungHinweise für eine nennenswerte örtliche antimykotische Wirkung werden gewonnen anhand der Hemmung der Ausbreitung von Dermytophytien am Meerschweinchen. In dieser Studie wird eine einfache Technik beschrieben, die ein in vivo‐Analogon zum My‐zelwuchstest auf Agarmedium darstellt. Als Beispiel wird der gute Effekt von Ciclopirox (HOE 296) angeführt. Durch das beschriebene Verfahren werden Verbindungen mit nied‐riger Permeation und geringer Wirkung gegen rasch wachsendes Myzel als ungünstig ausgeschieden. Bei guten Testresultaten können Rekultivierungsversuche angestellt werden, zu deren Gelingen jedoch verschiedene Kautelen eingehalten werden müssen, andernfalls resultieren Fehlschlüsse. Auf die Darstellung von Dosis‐Wirkungs‐Kurven und auf eine detailliertere Anführung von Rekultivierungs‐Versuchen wird in dieser Publikation ver‐zichtet.