Imidazole antimycotics: Inhibitors of steroid aromatase

Mason, J. Ian; Murry, Barbara A.; Olcott, Michael C.; Sheets, Joel J.

doi:10.1016/0006-2952(85)90613-6

Cited by 134 publications

(37 citation statements)

References 17 publications

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“…However, the mechanism of the antimalarial activity of CLT is unknown. CLT has been shown to have a multiplicity of effects on cell proliferation (32), steroid metabolism (33)(34)(35), and sickle cell dehydration (36,37). The mechanism of these actions has been variously attributed to its inhibitory effect on cytochrome P450-dependent enzymes (38), sarcoplasmic reticulum Ca 2ϩ pump (39), capacitative Ca 2ϩ channels (32,40,41), and the intermediate-conductance Gardos channel (18).…”

Section: Discussionmentioning

confidence: 99%

Potent antimalarial activity of clotrimazole in in vitro cultures of Plasmodium falciparum

Tiffert

Ginsburg

Krugliak

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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The increasing resistance of the malaria parasite Plasmodium falciparum to currently available drugs demands a continuous effort to develop new antimalarial agents. In this quest, the identification of antimalarial effects of drugs already in use for other therapies represents an attractive approach with potentially rapid clinical application. We have found that the extensively used antimycotic drug clotrimazole (CLT) effectively and rapidly inhibited parasite growth in five different strains of P. falciparum, in vitro, irrespective of their chloroquine sensitivity. The concentrations for 50% inhibition (IC50), assessed by parasite incorporation of [ 3 H]hypoxanthine, were between 0.2 and 1.1 M. CLT concentrations of 2 M and above caused a sharp decline in parasitemia, complete inhibition of parasite replication, and destruction of parasites and host cells within a single intraerythrocytic asexual cycle (Ϸ48 hr). These concentrations are within the plasma levels known to be attained in humans after oral administration of the drug. The effects were associated with distinct morphological changes. Transient exposure of ring-stage parasites to 2.5 M CLT for a period of 12 hr caused a delay in development in a fraction of parasites that reverted to normal after drug removal; 24-hr exposure to the same concentration caused total destruction of parasites and parasitized cells. Chloroquine antagonized the effects of CLT whereas mefloquine was synergistic. The present study suggests that CLT holds much promise as an antimalarial agent and that it is suitable for a clinical study in P. falciparum malaria. In the course of an investigation on the homeostasis of human red cells infected in vitro with the human malaria parasite Plasmodium falciparum, we found that clotrimazole (CLT), an imidazole derivative used as an antifungal agent (1), had a powerful growth-inhibiting effect on the parasite. The vast clinical experience, proven tolerance, and unique lack of acquired fungal resistance to CLT prompted a detailed investigation of its antimalarial effects in cultures of P. falciparum to assess its clinical potential. In this study, we report the in vitro effects of CLT on P. falciparum cultures by assessing the timeand concentration-dependent changes in parasite growth, parasite morphology, stage-specific development, and parasite replication. Materials and MethodsCultures. Five different laboratory strains of P. falciparum [A4 (2), W2, NF54, HB3, and FCR] were cultured in human erythrocytes by standard methods (3) under a low oxygen atmosphere. The culture medium was RPMI 1640, supplemented with 40 mM Hepes, 25 mg͞liter gentamicin sulfate, 10 mM D-glucose, 2 mM glutamine, and either 8.5% (vol͞vol) pooled human serum (A4 clone), or 10% heat-inactivated plasma (strains W2, NF54, HB3, and FCR). Culture media, with or without CLT, were changed daily, unless otherwise indicated. Parasites were synchronized at the ring stage with D-sorbitol (4) for all experiments. Initial parasitemias varied between 2% and 7% for the different e...

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Section: Discussionmentioning

confidence: 99%

Potent antimalarial activity of clotrimazole in in vitro cultures of Plasmodium falciparum

Tiffert

Ginsburg

Krugliak

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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“…Decline in mitotic activity was observed on GD 17, which seemed to be an inverse rebound to trophoblastic proliferation. On the other hand, ketoconazole is shown to inhibit 17α-hydroxylase/C17,20-lyase and aromatase activity in the steroid biosynthesis pathway [19,23]. It is also known that administration of estrogen inhibits ketoconazole induced-placental hypertrophy in rats [16].…”

Section: Discussionmentioning

confidence: 99%

Histopathological Effect of Ketoconazole on Rat Placenta

Furukawa

Hayashi

Usuda

et al. 2008

The Journal of Veterinary Medical Science

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ABSTRACT. In order to investigate the morphological effects of ketoconazole on hypertrophied placentas, we examined the sequential histopathological changes in the placenta from rats exposed to ketoconazole. Ketoconazole was administered orally at 0 and 25 mg/kg/day during gestation days (GDs) 12 to 14, and the placentas were sampled on GDs 15, 17 and 21. All dams showed neither effect on body weight nor any abnormal clinical signs during the experimental period. In the treated group, the placentas appeared more hypertrophic with increases in the weight, diameter and thickness on GD 21. Histopathologically, increased thickness was noted in the labyrinth zone and basal zone on GDs 17 and 21, while on GD 15 the change had been already evident in the former zone. In the labyrinth zone, the mitotic figures of the trophoblasts were significantly elevated on GD 15. A multiple cystic dilatation of maternal sinusoids was observed in some placentas on GDs 15, 17 and 21. In the basal zone, an increase in spongiotrophoblasts and clusters of glycogen cells were detected on GDs 17 and 21. In the decidua basalis, there were no significant changes in either histology or thickness between the control and treated group during GDs 15 to 21. In conclusion, ketoconazole increased the population of composed cells in the labyrinth and basal zone, leading to placental hypertrophy in pregnant rats.

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“…Ketoconazole has been reported to reduce serum oestrogen in rats (Watanabe & Menzies, 1985) by inhibition of aromatase, the cytochrome P-450 enzyme involved in the production of oestrogen (Mason et al, 1985). Interpretation of the effects of ketoconazole on oestrogens is complicated by the fact that the synthesis of androgens, the precursors of oestrogens, is also blocked by the drug.…”

Section: Discussionmentioning

confidence: 99%

Metabolic effects of low‐dose fluconazole in healthy female users and non‐users of oral contraceptives.

Devenport

Crook

Wynn

et al. 1989

Brit J Clinical Pharma

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1. Azole antifungal agents such as ketoconazole act by inhibiting cytochrome P‐450 mediated sterol synthesis in the fungal cell membrane and thus have the potential to interfere with mammalian steroidogenesis. Fluconazole is a novel orally‐effective antifungal triazole which has been reported to have more specific effects on the cytochrome P‐450 enzymes involved in fungal sterol synthesis. 2. Due to the potential value of systemic antifungal agents in the treatment of infections commonly occurring in women, we assessed the effect of oral fluconazole on the metabolic profile of 18 healthy premenopausal women, 10 of whom were taking combined oral contraceptives (OC). Each woman acted as her own control, being studied both before and 21‐28 days after fluconazole therapy (50 mg daily), in the luteal phase of consecutive menstrual cycles. 3. The endocrinological profile included measurement of serum oestradiol, progesterone, testosterone and sex hormone binding globulin (SHBG) concentrations, short tetracosactrin adrenal stimulation test and thyroid function tests. Carbohydrate metabolism was investigated by means of an oral glucose tolerance test with measurement of plasma glucose, insulin and C‐peptide concentrations. Serum lipids, lipoproteins and apolipoproteins were analysed on samples taken after an overnight fast. 4. Minor biochemical changes associated with fluconazole treatment included increases in serum thyroxine and testosterone concentrations (but not in women taking OC as well as fluconazole) and in insulin and apolipoprotein B levels (but only in women taking OC as well as fluconazole). In general, these changes were small and of no clinical significance with the values remaining within the laboratory normal range. There were no adverse side‐effects.(ABSTRACT TRUNCATED AT 250 WORDS)

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Imidazole antimycotics: Inhibitors of steroid aromatase

Cited by 134 publications

References 17 publications

Potent antimalarial activity of clotrimazole in in vitro cultures of Plasmodium falciparum

Potent antimalarial activity of clotrimazole in in vitro cultures of Plasmodium falciparum

Histopathological Effect of Ketoconazole on Rat Placenta

Metabolic effects of low‐dose fluconazole in healthy female users and non‐users of oral contraceptives.

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