Antifungal Activity of Tioconazole (UK-20,349), a New Imidazole Derivative

A total of 80 patients were equally randomized to receive a single dose of 6.5% tioconazole ointment or a 3-day course of 100-mg clotrimazole vaginal tablets for the treatment of vulvovaginal candidiasis. Of the 32 evaluable patients treated with tioconazole, 27 (84%) remained asymptomatic 4 weeks posttreatment, compared with 28 of 33 patients (85%) treated with clotrimazole. A total of 34 patients in each group could be evaluated for mycological response based on culture results 1 and 4 weeks after treatment. Twenty patients (59%) who received tioconazole and twenty-one patients (62%) who received clotrimazole remained culture negative 4 weeks after therapy. Of 40 patients who received tioconazole, 12 (30%) experienced local irritation or itching, compared with 2 of 40 patients (5%) treated with clotrimazole (P < 0.01). Single-dose tioconazole ointment was as effective as a 3-day course of clotrimazole tablets, but significantly more patients in the tioconazole-treated group experienced local side effects.The duration of treatment for Candida vaginitis has changed dramatically over the past several years. New high-dose imidazole derivatives have produced excellent short-term cure rates with treatment durations as short as 1 to 3 days (1,3,4,13,16,21). In addition, 4-week follow-up cultures of patients undergoing short-term treatment have not shown a higher incidence of recolonization by Candida organisms compared with cultures from patients undergoing longer periods of treatment (3,13,16,20,21). Shorter courses of therapy also encourage compliance and decrease expense and inconvenience (1,3,12,16).Tioconazole is a new imidazole antifungal agent similar to miconazole and clotrimazole. It has a broad spectrum of activity and is more active than other imidazoles against Candida albicans in vitro (10,11,18). In a randomized study of 109 women with vaginal candidiasis, a 3-day course of treatment with 2% tioconazole vaginal cream produced higher cure rates 7 to 10 days (P = 0.01) and 4 weeks (P < 0.05) after therapy than did clotrimazole vaginal tablets (6).Houang and Lawrence reported a mean vaginal concentration of 21.4 ,ug/ml 24 h after insertion of a single 300-mg ovule of tioconazole in 10 patients with vaginal candidiasis (8). This concentration is significantly higher than the MIC (1.6 to 12.5 ,ug/ml) of tioconazole for C. albicans (10). These studies suggest that a single application of the agent could be clinically effective in the treatment of Candida vaginitis.The study reported here was designed to compare the efficacy and acceptability of a single intravaginal application of 6.5% tioconazole ointment (325 mg) with a 3-day regimen of clotrimazole vaginal tablets in women with vulvovaginal candidiasis.(The study was presented in part at the 23rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Las Vegas, Nev., 24 Before admission to the study, written informed consent was obtained from each patient. A medical history was taken, and a physical and gynecological examination, including a Pa...

mentioning

confidence: 70%

mentioning

confidence: 99%

Single-dose tioconazole compared with 3-day clotrimazole treatment in vulvovaginal candidiasis

Stein¹,

Gurwith²,

Mummaw³

et al. 1986

“…These modifications have resulted in several active compounds which have proceeded to clinical use in topical or systemic administration or both. Some in vitro comparisons of activity have been made with various organisms (2,6,14,15,21,23). Conclusions about mechanisms of action have sometimes been related to the results (21), although it is unclear whether the differences seen would apply to different fungal species.…”

mentioning

confidence: 99%

Inhibition and killing of Candida albicans in vitro by five imidazoles in clinical use

Lefler¹,

Da²

1984

Five imidazoles (clotrimazole, econazole, ketoconazole, miconazole, and tioconazole) in clinical use were compared for their ability to inhibit and kill Candida albicans. Eleven isolates were obtained from patients before therapy. By spectrophotometric determination of 5%o growth inhibition, all isolates were inhibited at low concentrations, with clotrimazole slightly less active than the other four drugs. By the conventional MIC determination, tioconazole was more active than all of the others (P < 0.01) except clotrimazole. In killing (minimum fungicidal concentration [MFC] assay), tioconazole was the most active by several analyses. Studies of the kinetics of killing indicated that the drugs studied could kill under conditions used for the MFC determination and that tioconazole and ketoconazole could kill particularly rapidly. If the drug was washed from the cells before subculturing, concentrations above the MFC were required to kill, but tioconazole could produce a lethal lesion in all cells virtually instantaneously. These findings are pertinent to MFC and killing kinetics methodology and to the observation of drug persistence after topical application. The results differ from some previous in vitro comparisons made with different methods. They are relevant to conclusions about drug mechanisms based on their abilities to inhibit and to kill, and they underscore the need to study various assay methods and fungal species.

“…Lungs were removed, weighed, and homogenized in saline. Serial 10-fold dilutions of the homogenate were plated on SDA plates and incubated at 37°C for 48 h. The number of viable Aspergillus cells per gram of lung tissue was calculated (6). The 50% effective dose (ED50) was calculated with Probit analysis by fitting survival data for each group at the time when all the control mice were dead (10).…”

Section: Methodsmentioning

confidence: 99%

Activity of SM-4470, a new imidazole derivative, against experimental fungal infections

Ichise¹,

Tanio²,

Saji³

et al. 1986

The antifungal activity of orally active SM-4470, (R)-3-(n-butylthio)-2-(2,4-dichlorophenyl)-1-(imidazole-1-yl)-Z-propanol hydrochloride, was compared with that of ketoconazole. SM-4470 showed twofold-higher activity than ketoconazole in the oral treatment of systemic infection with Candida albicans in mice. In addition, SM-4470 was effective against aspergillosis in mice, but ketoconazole was ineffective. The efficacy of SM-4470 was similar to that of ketoconazole in curing experimental candidal vaginitis in rats and trichophytosis in guinea pigs, although its serum concentrations in these animals were lower than those of ketoconazole. These data suggest that SM-4470 may be of value in the treatment of both systemic and superficial fungal infections in humans.Several new imidazole and triazole antifungal agents have been developed in the last few years. These are effective topically in the treatment of dermatophytosis and vaginal candidiasis, but ketoconazole is the only commercially available imidazole that is orally effective against these infections (3-5). Ketoconazole has shown variable activity against life-threatening systemic infections (3); the polyene amphotericin B is still used for treating these infections, but its use is limited by toxicity and the need to give it by intravenous infusion. The other agent of significance is 5-fluorocytosine, which has a limited spectrum of antifungal activity, and its use in therapy frequently leads to the emergence of resistant strains. We recently succeeded in developing SM-4470 (Fig. 1), a new imidazole derivative. In this report we compare its activity with that of ketoconazole against experimental systemic and superficial infections in laboratory animals. MATERIALS AND METHODSFungi. All fungi used in these studies were from the culture collection in our laboratory. Cultures of these organisms were freeze-dried and stored, and subcultures on Sabouraud dextrose agar (SDA) were made as needed. Candida albicans and Aspergillus fumigatus strains were grown at 30°C on SDA with 5% rabbit blood for 3 days, and Trichophyton mentagrophytes was grown on SDA at 30°C for 7 days.Compounds. SM-4470 and ketoconazole were synthesized in the Research Laboratories, Sumitomo Pharmaceuticals Co. For this experimental study, both compounds were formulated as suspensions in 0.5% methylcellulose solution. This gave reproducible, homogeneous drug dispersions for the comparative studies.Laboratory animals. Male albino mice of the strains ICR and ddY