Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-11-12
1999-11-16
Weddington, Kevin E.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514650, 514655, 514657, A61K 3141, A61K 31135, A01N 4364, A01N 3302
Patent
active
059859067
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to the treatment of human mycotic infections. It concerns antifungal compositions for use in the treatment of mycotic infections caused by azole resistant yeast strains, comprising terbinafine with an azole 14.alpha.-methyldemethylase inhibitor such as the azole fluconazole and/or itraconazole.
Although they are often present as benign commensal organisms in the digestive tract of healthy individuals, fungi, particularly Candida species produce a broad range of serious illnesses in compromised hosts. Such infections are clearly on the rise. Oropharyngeal candidiasis is the most common fungal infection in patients with human immunodeficiency virus (HIV) infection. With the introduction of azole antifungal agents that are bioavailable after oral administration, the approach to the treatment of serious Candida infections is possible. Ketoconazole, the first of there agents to become available, was quickly found to be efficacious in the setting of chronic mucocutaneous candidiasis. However, not long after the introduction of this agent, clinical failure in association with elevated minimum inhibitory concentrations (MICs) of ketoconazole that developed during prolonged therapy were reported. This problem achieved prominence with the subsequent introduction of fluconazole. Fluconazole, a water-soluble triazole with greater than 90% bioavailability after oral administration, is used extensively to treat a wide range of Candida infections. In particular, it is widely used as therapy for oropharyngeal candidiasis in patients with advanced HIV infection and AIDS. Although oropharyngeal candidiasis usually responds readily to fluconazole, it is difficult to completely eradicate the infection and relapse often occurs within several months following the completion of therapy. For this reason, many AIDS patients receive fluconazole either continuously on intermittently over long periods of time.
To a greater extent than with other azoles, resistance to fluconazole has developed and is becoming a significant clinical problem, as attested by isolation from, in particular, AIDS patients of numerous Candida strains showing resistance (see e.g. D. Law et al., J. Antimicrob. Chemother. 34 [1994] 659-668).
It has now been found that, surprisingly, a combination of the squalene epoxidase inhibitor terbinafine (Lamisil.RTM.) and an azole 14.alpha.-methyldemethylase inhibitor such as fluconazole and/or itraconazole is active against azole-resistant fungal strains. By using this combination of compounds there is provided a method for treating human mycotic infections caused by azole-resistant fungal strains.
Suitable azole 14.alpha.-methyldemethylase inhibitors are in particular imidazole and triazole antifungal agents.
Preferred imidazole antifungal agents include clotrimazole (Arzneim.-Forsch. 22 [1972] 1280), miconazole (Arzneim.-Forsch. 21 [1971] 256; econazole (Arzneim.-Forsch. 25 [1975] 224); isoconazole (Arzneim.-Forsch. 29 [1979] 1344); trioconazole (Antimicrobial Agents Chemotherapy 15 [1979] 597-602); sulconazole (Eumycetes and Mycosis 23 [1982] 314-317; oxiconazole (Arzneim.-Forsch. 32 [1982] 17-24); cloconazole (J. Med. Chem. 26 [1983] 768-770); bifonazole (Arzneim.-Forsch. 33 [1983] 517-524); butoconazole (J. Med. Chem. 21 [1978] 840; fenticonazole (Arzneim.-Forsch. 31 [1981] 2127); zinoconazole (J. Med. Chem. 26 [1983] 442-445) and ketoconazole (J. Med. Chem. 22 [1979] 1003-1005).
Preferred triazole antifungal agents include terconazole (J. Med. Chem. 26 [1983] 611-613); itraconazole (Antimicrobial Agents and Chemotherapy 26 [1984] 5-9); vibunazole (Arzneim.-Forsch. 33 [1983] 546); fluconazole (Antimicrobial Agents and Chemotherapy 27 [1985] 815-818), and (R)(-)-.alpha.-(4-chlorophenyl)-.alpha.-(1-cyclopropyl-1-methylethyl)-1H-1 ,2,4-triazol-1-ethanol in free form or in salt or metal complex form (GB 2'161'483) (hereinafter briefly referred to, in free form, as "compound A").
Especially preferred azoles are itraconazole and fluconazole.
Not all combinations of antifungal drugs show syne
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Meingassner Josef Gottfried
Ryder Neil Stewart
Loeschorn Carol A.
Novartis AG
Weddington Kevin E.
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