Direct interaction of antifungal azole-derivatives with calmodulin: a possible mechanism for their therapeutic activity.

Azole derivatives, such as ketoconazole and bifonazole, are well-established antifungal drugs. Recently, these compounds have been reported to have therapeutic efficacy also in inflammatory skin disorders. There is increasing evidence that calmodulin is involved in fungal infections as well as in inflammatory skin diseases. Therefore, we investigated the effects of various antifungal drugs on calmodulin activity, using calmodulin-dependent phosphodiesterase as an indicator for the calmodulin activity. All azole derivatives tested competitively inhibited calmodulin activity with 50% inhibitory concentration values in the low micromolar range. In contrast, antifungal drugs belonging to other chemical classes did not display inhibitory activity. Thus, this study provides evidence that direct interaction with calmodulin might contribute to the therapeutic activity of azole derivatives, particularly to their efficacy in the treatment of inflammatory skin disorders.

[1]  J. Traber,et al.  Polymyxin B is a selective and potent antagonist of calmodulin. , 1991, European journal of pharmacology.

[2]  J. Faergemann.  Treatment of seborrhoeic dermatitis of the scalp with ketoconazole shampoo. A double-blind study. , 1990, Acta Dermato-Venereologica.

[3]  A. Taieb,et al.  Topical ketoconazole for infantile seborrhoeic dermatitis. , 1990, Dermatologica.

[4]  T. Lackner,et al.  Bifonazole. A review of its antimicrobial activity and therapeutic use in superficial mycoses. , 1989, Drugs.

[5]  P. Fritsch,et al.  Ketoconazole 2% cream versus hydrocortisone 1% cream in the treatment of seborrheic dermatitis. A double-blind comparative study. , 1988, Journal of the American Academy of Dermatology.

[6]  S. Macneil,et al.  Calmodulin antagonists of improved potency and specificity for use in the study of calmodulin biochemistry. , 1988, Biochemical pharmacology.

[7]  A. Pestarino,et al.  Seborrheic dermatitis in otherwise healthy patients and in patients with lymphadenopathy syndrome/AIDS-related complex: treatment with 1% bifonazole cream. , 1988, Chemioterapia : international journal of the Mediterranean Society of Chemotherapy.

[8]  A. Datta,et al.  A calmodulin inhibitor blocks morphogenesis in Candida albicans , 1987 .

[9]  S. Shuster,et al.  Treatment of seborrhoeic dermatitis with ketoconazole: II. Response of seborrhoeic dermatitis of the face, scalp and trunk to topical ketoconazole , 1987, The British journal of dermatology.

[10]  S. Macneil,et al.  An investigation of the ability of antipsoriatic drugs to inhibit calmodulin activity: a possible mode of action of dithranol (anthralin). , 1986, The Journal of investigative dermatology.

[11]  S. Macneil,et al.  Calmodulin levels in psoriasis—the effect of treatment , 1985, Acta dermato-venereologica.

[12]  D. Berg,et al.  Bifonazole, a New Topical Azole Antimycotic with Specific Properties , 1986 .

[13]  K. Buchel,et al.  Antimycotic sterol biosynthesis inhibitors , 1986 .

[14]  M. Richardson,et al.  Bifonazole Gel in the Treatment of Seborrhoeic Eczema , 1986 .

[15]  H. Döring.  Experience Gained with Topical Therapy with Bifonazole in Unusual Indications , 1986 .

[16]  H. Tronnier,et al.  Investigations into the Anti-inflammatory Effect of Bifonazole , 1986 .

[17]  D. Berg,et al.  Reduction of the in vivo virulence of Candida albicans by pretreatment with subinhibitory azole concentrations in vitro. , 1984, Dermatologica.

[18]  B. Brown,et al.  Calmodulin and cell function. , 1984, Clinical science.

[19]  P. Kerkhof,et al.  Calmodulin levels are grossly elevated in the psoriatic lesion , 1983 .

[20]  M. Plempel.  Experiences, Recognitions and Questions in Azole Antimycotics , 1982 .

[21]  M. Shepherd,et al.  Evidence for the occurrence of calmodulin in the yeasts Candidas albicans and Saccharomyces cerevisiae , 1982, FEBS letters.