Imidazole유도체의 항진균력에 대한 실험적 연구

Abstract

[한글]

피부진균증은 작은 발생빈도를 보이는 인체감염증중의 하나로써 그 치료에 대한 관심이 차츰 높아짐에 따라 근래 꾸준한 합성공학의 연구노력으로 제한된 균종에만 유효했던 종래의 항진균약물과는 달리, 모든 병원성진균에 대해 광범위 항균효과를 나타내는 새로운 imidazole유도체들이 개발되어 쓰여지고 있다. (Godefroi등, 1969; Sawyer등, 1975 a, b; Kobayashi 및 Medoff, 1977; Raab, 1977; Heel등, 1978; Plempel, 1979).

분리균주에 대한 약물의 항균력검사는 효과적인 치료제 선택에 중요하며, 각 imidazole유도체의 항균력에 대하여는 여러 학자들 (Shadomy, 1971; Holt등, 1972; Van Cutsem등, 1972; Plempel등, 1974; Thienpont등, 1975; Heeres등, 1979) 이 연구한 바 많으나 같은

조건하에서 여러 imidaxole 유도체를 함께 다룬 실험 (Haller 및 Plempel, 1978; Odds, 1980)은 그 수가 매우 적고 또한 실험조건이 각기 달라서 그 성적에 있어 상당한 차이를 보임으로써 문헌간의 직접적인 비교평가는 어렵다(Hoeprich 및 Finn, 1972; Odds, 1979).

저자는 우리나라에서 빈번히 분리되는 Trichophyton rubrum, Trichophyton mentagrophytes, Microsporum canis 및 Sporothrix schenckii등 4균종 10균주에 대해 Sabouraud 액체배지를 이용하여 4mm**2 크기의 고형균대를 접종 3주후에 miconazole, econazole, clotrimazole, ketoconzaole 및 griseofulvin의 최저발육억제농도와 Vanbreuseghem등 (1967)이 기술하였던 방법으로 Trichophyton mentagrophytes와 Microsporum canis에 대하여 miconazole 및 econzaole의 살균효과를 관찰하여 다음과 같은 결론을 얻었다.

1. 3종의 피부사상균은 대부분 모든 imidazole 유도체의 1∼10㎍/㎖에서 발육 억제되었으며 균종간에는 차이를 보이는 반면 동일균종의 각 균주간에는 차이가 없었다. 각 약물에 대한 균종 별 감수성은 T.rubrum (0.01∼10㎍/㎖), T.mentagrophytes (0.1∼10㎍/㎖), M.canis (0.1∼100㎍/㎖)로써 T.rubrum이 특히 높았으며 T.mentagrophytes 및 M.canis순이었다.

2. 심재성 진균 Sporothrix schenckii에 대해 clotrimazole은 항진균 효과가 없었으며 miconazole 및 econazole의 MIC(최저발육억제농도)는 10∼100㎍/㎖로써 비교적 고농도에

서만 발육이 억제됨을 보여 주었다.

3. 피부사상균에 대한 정진균력은 clotrimazole(0.1∼10㎍/㎖), miconzole (0.1∼100㎍/㎖), econazole(0.01∼10㎍/㎖), Ketoconzaole (0.1∼100㎍/㎖), griseofulvin (10∼1000㎍/㎖)로써 econazole이 비교적 우수한 정진균작용을 보여 주었으나 전체적으로 imidazole 유도체간에는 큰 차이가 없는 반면 griseofulvin에 비해 이들 약제는 현저히 높은 정진균력을 나타내었다.

4. T.mentagrophytes, M.canis에 대한 econazole 및 miconazole의 살진균효과를 보면 econazole이 miconazole에 비해 살균작용이 다소 높게 나타났으며, M.canis 및 T.mentagrophytes간 감수성에는 큰 차이가 없음을 보여 주었다.

이상의 실험으로 imidazole 유도체가 피부사상균에 대해 강력한 항진균력이 있음을 관찰하였다. 임상에서 진균증 환자로부터 분리된 균종에 대한 유효한 약제의 선택에 도움을 줄 수 있으리라 생각된다.

[영문]

As a result of the continued search for new antimycotics, several anew conpounds whose common feature is an imidazole nucleus substituted at the 1-position have been introduced during the past few years. Clotrimazole, miconazole, econazole and ketoconazole have recently become widely available for clinical use as they have broad-spectrum antifungal and antibacterial properties.

There are numerous reports of their antifungal potencies in in vitro and in clinical trials, but rare studies, comparing the relative antifungal potencies of two or more imidazole derivatives have been performed. also, it is difficult to derive overall comparative figures for imidazole from such experimental datas since the test methods used differ from each other.

The present study was designed to obtain comparative date on in vitro antifungal activities of imidazole derivatives.

Minimum inhibitory concentrations of clotrimazole, miconazole, econazole, ketoconazole and griseofulvin on 4 strains of Trichophyton mentagrophytes, 3 strains of Trichophyton rubrum, 2 strains of Microsporum canis and 1 strain of Sporothrix schenckii were determined after 3 weeks' incubation at room temperature

on Sabouraud's dextrose liquid media.

In addition, the fungicidal activities of miconazole and econazole were tested against Trichophyton mentagrophytes and Microsporum canis, using the techniques described by Vanbreuseghem (1967).

The results are summarized as follows:

1. In most of the dermatophytes studied, 1 to 10 mcg/ml of MIC were detected. Diverse susceptibility pattern was observed among different fungal species, but no or minor variability was noted within the same species. the susceptibility of Trichophyton rubrum showed at MIC of 0.01 to 10mcg/ml, trichophyton mentagrophytes and Microsporum canis at 0.1 to 10mcg/ml and 0.1 to 1000 mcg/ml, respectively. the Trichophyton rubrum was the most sensitive.

2. In the susceptibility test of Sporothrix schenckii, the high resistance to clotrimazole and griseofulvin was observed. The fungistatic activities of miconazole, econazole and ketoconzaole were observed only at concentrations higher than 100 mcg/ml.

3. MICs of clotrimazole against dermatophytes tested were in the range of 0.1 to 10mcg/ml, econazole 0.01 to 10 mcg/ml, miconazole 0.1 to 100 mcg/ml and ketoconazole 0.1 to 100 mcg/ml and griseofulvin 10 to 1000 mcg/ml. econazole had relatively higher inhibitory activity against all dermatophy tes, especially

against Microsporum canis. However, no distinctively different inhibitory activity among imidazole derivatives had been shown.

4. Fungicidal activity of econazole against Trichophyton mentagrophytes was complete after 5 min. contact time at 1 mg/ml, after 90 min. at 0.1 mg/ml and after 120 min. at 0.01 mg/ml. Miconazole was less potent as compared with; inhibition was

observed at 10 mg/ml, 1 mg/ml and 0.01 mg/ml after 5 min., 20 min. and 180 min. of contact, respectively. No major difference was noted between Micosporum canis and Trichophyton mentagrophytes in fungicidal activity of both drugs.

The results showed that the imidazole derivatives studied can be regarded as potent antimycotics against common dermatophytes in Korea.