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NISHIYAMA, Y.; ASAGI, Y.; HIRATANI, T.; YAMAGUCHI, H.; YAMADA, N.; OSUMI, M.
doi: 10.1111/j.1365-2230.1992.tb00271.xpmid: 1458657
SummaryAmorolfine inhibited the in‐vitro growth of Trichophyton mentagrophytes to some extent at a low drug concentration of 0·8 ng/ml. Corresponding to the growth inhibition, SEM studies revealed a slight modification of hyphal morphology, i.e. a waving of the hyphal surface. These morphological alterations were more extensive with increases in drug concentration and treatment period: collapsed and distorted hyphae and exfoliation of the surface of T. mentagrophytes occurred at 8 ng/ml and marked deformation and disruption of the hyphal structure at 80 ng/ml of amorolfine. TEM revealed thickening of the cell walls and the accumulation of electron‐dense granular structures in both the wall and cytoplasm in thin‐sectioned cells pretreated with 8 ng/ml or more of amorolfine, although the nuclear and mitochondrial architecture was not noticeably influenced. Cytoplasmic membranes and other membranous structures of organelles such as nuclei and mitochondria were disrupted or fused, thereby losing their essential physiological activity in hyphal cells pretreated with 80 ng/ml of amorolfine. The ultrastructural study thus supports the observation that morphological changes of T. mentagrophytes caused by amorolfine were associated with its growth‐inhibitory and killing activity, which depended on the drug concentration and treatment time.
MÜLLER, J.; POLAK‐WYSS, A.; MELCHINGER, W.
doi: 10.1111/j.1365-2230.1992.tb00272.xpmid: 1458658
SummaryAmorolfine applied in concentrations of 0·1‐100 μg/ml causes considerable damage to the ultrastructure of Candida albicans and Trichophyton mentagrophytes: electron‐lucent areas appear in the cytoplasm; extracytoplasmic membrane vesicles are formed and deposited in the cell wall; starved fungal cells, with normal ultrastructure, can be found; lysed, dead cells demonstrate the process of severe ultrastructural damage; T. mentagrophytes cell walls especially increase in thickness. The extent of the damage caused by amorolfine is comparable to that produced by azole antifungals.
PITTROF, F.; GERHARDS, J.; ERNI, W.; KLECAK, G.
doi: 10.1111/j.1365-2230.1992.tb00273.xpmid: 1458660
SummaryLoceryl® nail lacquer was developed to provide the effective antifungal drug, amorolfine, in a once‐weekly dosage regimen combined with a convenient mode of application. Traditional formulations such as creams and nail solutions do not fulfil these requirements because they are wiped or washed off very rapidly. Amorolfine nail lacquer builds a non‐water‐soluble film on the nail plate, and this film remains in place for 1 week. The film contains a high concentration of amorolfine and forms a depot from which the drug is delivered and which allows the drug to permeate the nail plate.The film‐forming polymer and the solvent were optimized for drug release, stability, and convenience of application (drying time, no gloss, transparency). In preclinical development, porcine hoof horn was used as a screening model to differentiate between formulations and dosage strengths with respect to the penetration rate. A high drug concentration of 11·72 μg/specimen (10 mm in diameter) was reached in the hoof horn after 6 h, increasing to 39·5 μg/specimen within 7 days, the maximum duration of the investigation. The drug concentration achieved was far above its minimum inhibitory concentration. Furthermore, the penetration model clearly indicated that amorolfine crossed the horn barrier and was found in the moistened gauze which simulated the nail bed. After a 7‐day penetration period, 1·8% of the applied dose (500 μg) was available under the nail.
MENSING, H.; POLAK‐WYSS, A.; SPLANEMANN, V.
doi: 10.1111/j.1365-2230.1992.tb00274.xpmid: 1458661
Onychomycosis is common worldwide, about 10% of all dermatomycosis being fungal infections of the nails.1 Up until now no satisfactory topical treatment has been available. Therefore, the development of any new antifungal gives rise to high expectations with regard to its effectiveness in onychomycosis. Amorolfine is a phenylpropyl morpholine derivative which has been found to be more effective than imidazole derivatives and polyene antibiotics both in vitro and in experimental infections against dermatophytes and yeasts.2,3Amorolfine possesses two properties which give rise to hopes that it may be used to treat onychomycosis. First, it is effective at low concentrations,2 and secondly, studies of in‐vitro penetration on human nails show the presence of amorolfine in sufficient concentrations in the nail plate and the nail bed to give fungistatic and fungicidal levels.4 Furthermore, the persistence of amorolfine in the subungual keratin for 7 days5 would allow physicians to reduce the frequency of application.Two different lacquer formulations, one methylene chloride‐based and the other ethanol based, were developed as vehicles for amorolfine for treating onychomycosis with one or two applications per week. This study was carried out in order to test the bioequivalence of the two different lacquer formulations and to see whether the antifungal activity of amorolfine in the subungual area would last longer than 7 days, as shown in a previous study.5 The measurement of the antifungal activity in the subungual area will be taken as one of the criteria for penetration of amorolfine through the human nail.
RONCARI, G.; PONELEE, CH.; ZUMBRUNNEN, R.; GUENZI, A.; DINGEMANSE, J.; JONKMAN, J.H.G.
doi: 10.1111/j.1365-2230.1992.tb00275.xpmid: 1458662
SummaryIn an open‐label, parallel‐group, randomized study percutaneous absorption of 14C‐labelled amorolfine incorporated into a cream formulation was assessed in healthy male volunteers (n= 12). A single dose of 0·5 g of the 0·25% cream formulation was applied to 100 cm2 of intact (n= 6) and stripped (n= 6) skin for 24 h using occlusive dressing. The remaining drug was removed and the treated skin area of both groups was stripped with adhesive tape. Total urine and faeces were collected in portions up to 3 weeks after the experiment and blood samples were taken at intervals for 3 weeks. Radioactivity was measured in the skin strippings and in the urine, faeces and plasma samples. The intact drug was assessed in the plasma samples.Using mass balance techniques it could be shown that a mean of 92% (range: 84–101%) of the applied radioactivity could be recovered. Small differences in the absorption and elimination of the radioactivity were observed between the two groups but they were not statistically significant (α= 0·05). Therefore data from the two groups were pooled. Elimination of drug and drug‐related material from the body was very slow. During the 3‐week collection period, a mean of 7% (range; 3·8–10·2%) of the dose was excreted in urine and faeces. Another 0·9–3·3% of the dose was retained in the upper layers of the skin as shown by the skin strippings after treatment. Levels of radioactivity and of intact drug in plasma were below the detection limit of 0·5 ng‐equiv./ml, respectively. Present data suggest that mean percutaneous absorption of amorolfine following topical application of the 0·25% cream formulation should not exceed 8–10% of the dose applied.
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