Ketoconazole: From an antimycotic to a drug for prostate cancer

Amery, Willem K.; Coster, R. De; Caers, I.

doi:10.1002/ddr.430080134

Cited by 27 publications

(10 citation statements)

References 18 publications

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“…In conclusion, the results of the present study support the notion that combinations of azoles with other ergosterol biosynthesis inhibitors acting at different points of the biosynthetic pathway could be useful in the treatment of human Chagas' disease because they could allow the use of lower levels of those compounds, and particularly lower levels of ketoconazole, which has well-known toxicity problems when used at dosages of greater than 400 mg/day (2,41). This proposition is further supported by the results of our recent studies on the antiproliferative effects of combinations of ketoconazole with lovastatin, a potent inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (1), against T. cruzi both in vitro and in vivo (45).…”

Section: Resultssupporting

confidence: 79%

“…Trypanosomatid protozoa such as T. cruzi and the different species of Leishmania also have a strict requirement for ergosterol and related 4-desmethyl sterols, as shown in both in vitro and in vivo studies (4-11, 17, 19, 20, 22, 26-28, 30-32, 34, 43-47). However, although success has been claimed in the treatment of human cutaneous leishmaniasis with azoles (10,47), the doses of ketoconazole reported to be effective for the prevention death from lethal T. cruzi infections in mice and for the promotion of parasitological cure (30)(31)(32)34) are far greater than those that are known to produce hepatotoxicity and to block steroid hormone synthesis in humans (2,41). We have recently found that the in vitro antiproliferative activity of ketoconazole against the epimastigote and intra-ANTIMICROB.…”

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confidence: 99%

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Experimental chemotherapy with combinations of ergosterol biosynthesis inhibitors in murine models of Chagas' disease

Maldonado

Molina

Payares

et al. 1993

Antimicrob Agents Chemother

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We report the effects of ketoconazole and the bistriazole ICI 195,739 acting alone or in combination with the allylamine terbinafine (Lamisil) on murine models of Chagas' disease. Mice infected with 105 Trypanosoma (Schizotrypanum) cruzi blood trypomastigotes and treated orally with 30 mg of ketoconazole per kg of body weight per day for 7 days, starting at 24 h postinoculation, had 100%o survival after 35 days, while controls (untreated) or animals that received 15 mg of ketoconazole or 100 mg of terbinafine per kg/day by the same route had O0o survival after the same period of time. However, all mice receiving the combination of 15 mg of ketoconazole plus 100 mg of terbinafine per kg/day survived for 35 days after infection; it was shown that the survival of the animals treated with this combination was statistically greater than that obtained with either drug acting alone and was indistinguishable from that observed with the high doses of ketoconazole, indicating a synergistic action of the drugs in vivo. However, most animals that survived after the 7-day treatments were not cured, as indicated by a delayed but persistent parasitemia. When the treatment was extended to 14 days, 100% survival was obtained 10 weeks after inoculation for mice treated with 30 mg of ketoconazole per kg/day and the combination of 15 mg of ketoconazole per kg/day plus 100 mg of terbinafine per kg/day, while two-thirds of the mice treated with 15 mg of ketoconazole per kg/day alone were alive after the 14-day treatment; controls or animals that received 100 mg of terbinafine per kg/day did not survive after 25 days. Parasitemia in all surviving mice was negative after 55 days but parasitological cure, as assessed by subinoculation of organs in naive animals, was predominant only in animals that received the combined drug treatment. We also investigated the bistriazole ICI 195,739 and found, as reported previously, that just 1 mg of the compound per kg/day administered orally for 5 days was enough to protect most mice from death 30 days after inoculation, but no parasitological cures were observed. However, in the protocol used in the present study, the protective activity of ICI 195,739 at suboptimal doses (0.5 mg/kg/day) could be enhanced when it was used in combination with terbinafine at doses of the allylamine that by themselves induced no significant protection. Survival of the mice was inversely correlated with the levels of parasitemia in all cases. Extension of the treatment period with the triazole to 15 days at 1 mg/kg/day afforded definitive protection against death, with parasitological cure being achieved in 50%o of mice at 10 weeks postinoculation, but no enhancement of its activity at suboptimal doses was observed when it was used in combination with terbinafine during this extended observation period. Taken together, these results support the proposition that ketoconazole used in combination with terbinafine could be useful in the treatment of humans with Chagas' disease because it can promote parasitological cure wi...

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Section: Resultssupporting

confidence: 79%

mentioning

confidence: 99%

Experimental chemotherapy with combinations of ergosterol biosynthesis inhibitors in murine models of Chagas' disease

Maldonado

Molina

Payares

et al. 1993

Antimicrob Agents Chemother

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“…We recently showed that the antiproliferative synergism of ketoconazole and terbinafine against T. cruzi observed in vitro (21,35) is also found in vivo and that this potentiating action can lead to parasitological cures in a significant proportion of treated animals (24a, 37). Thus, the results of the present work support the idea of using mevinolin to potentiate the therapeutic effects of azoles, such as ketoconazole or itraconazole, in the treatment of human Chagas' disease and, in doing so, avoiding the risks of interfering with hepatic function or testosterone production that are associated with high doses of the former (3,33). VOL.…”

Section: Discussionsupporting

confidence: 74%

Mevinolin (lovastatin) potentiates the antiproliferative effects of ketoconazole and terbinafine against Trypanosoma (Schizotrypanum) cruzi: in vitro and in vivo studies

Urbina

Lazardi

Marchán

et al. 1993

Antimicrob Agents Chemother

112

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We have studied the antiproliferative effects of mevinolin (lovastatin), an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, on the protozoan parasite Trypanosoma (Schizotrypanum) cruzi and its ability to potentiate the action of specific ergosterol biosynthesis inhibitors, such as ketoconazole and terbinafine, both in vitro and in vivo. Against the epimastigote form in vitro, mevinolin produced a dose-dependent reduction of the growth rate up to 25 ,uM, but at 50 and 75 ,uM, complete growth arrest and cell lysis took place after 144 and 96 h, respectively. A systematic study of the effects of mevinolin combined with ketoconazole and terbinafine, which act at different points in the ergosterol biosynthesis pathway, on the proliferation of epimastigotes indicated a synergic action, as shown by concave isobolograms and fractional inhibitory concentration indexes ranging from 0.17 to 0.54. Analysis of the sterol composition and de novo sterol synthesis in control and treated cells by thin-layer and gas-liquid chromatographies showed that the antiproliferative effects of the drug alone and in combination were correlated with the depletion of the endogenous ergosterol pool and particularly with a critical (exogenous) cholesterol/endogenous 4-desmethyl sterol ratio in the cells. When we studied the effects of mevinolin on the amastigote form proliferating inside Vero cells in vitro, only very modest effects on the parasites were observed up to 0.75 ,M; above this concentration, significant deleterious effects on the host cells were found. However, when the same concentration of the drug was combined with ketoconazole, it was able to reduce by a factor of 10 the concentration of the azole required to eradicate the parasite (from 10 to 1 nM), again indicating a synergic action. On the other hand, a combination of mevinolin and terbinafine had only additive effects on amastigotes, but a ternary combination of mevinolin, ketoconazole, and terbinafine was again clearly synergistic. In vivo studies with a murine model of Chagas' disease showed that mevinolin can also potentiate the therapeutic effects of ketoconazole in this system; combined treatment with the two drugs at doses that alone offered only limited protection against the parasite was able to essentially eliminate circulating parasites and produce complete protection against death. These results confirm the synergic action against the proliferative stages of T. cruzi both in vitro and in vivo of combined ergosterol biosynthesis inhibitors that act at different points in the pathway and suggest that mevinolin combined with azoles, such as ketoconazole, can be used in the treatment of human Chagas' disease.

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“…In most cases, a compensa¬ tory increase in ACTH seems capable of overcom¬ ing the inhibition of cortisol production. Never¬ theless, symptoms suggestive of hypoadrenalism have been reported (for review see Amery et al 1986) and a systematic replacement corticosteroid therapy may be recommended. The cytochrome P-450iig also catalyzes the various steps in the biosynthetic metabolism of aldosterone, starting from 11-deoxycorticosterone (Okamoto et al 1985;Yanagibashi et al 1986).…”

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confidence: 99%

Effects of high-dose ketoconazole treatment on adrenal mineralocorticoid biosynthesis in dogs and rats

Coster¹,

Coene²,

Haelterman³

et al. 1987

Acta Endocrinologica

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At high doses, ketoconazole blocks both testicular and adrenal androgen biosyntheses and partially inhibits the glucocorticoid production. To investigate the effects of this imidazole derivative on the mineralocorticoid biosynthesis, 7 male mongrel dogs received a single oral dose of 15 mg/kg of ketoconazole or placebo, in a cross-over way. From 2 to 4 h after treatment, an iv infusion of angiotensin II (10 ng/kg per min) was performed. Ketoconazole treatment significantly blunted the aldosterone and cortisol increment, whereas 18-hydroxycorticosterone, corticosterone, 11\ x=r eq-\ deoxycorticosterone (DOC), progesterone, and 17\ g=a\ \ x=r eq-\ hydroxyprogesterone rose to peak concentrations, respectively 2.5-, 6-, 8-, 2.5-and 1.5-fold higher than those observed after placebo administration. Plasma 11-deoxycortisol and renin activity levels remained similar in both groups. On the other hand, 2 \ m=x\ 2 groups of 10 male adult rats each were fed with a normal or a sodium-depleted diet. Of the two sets of groups, one was treated ip with ketoconazole (20 mg/kg twice a day), the other with vehicle solution. In animals on either diet, ketoconazole lowered 18-hydroxycorticosterone and aldosterone concentrations. Plasma DOC rose up to 25-fold in the salt-deprived animals. Serum Na+, Cl \ m=-\ , corticosterone and plasma renin activity remained unaffected by the treatment. These results show that high-dose ketoconazole treatment partially inhibits the biosynthesis of aldosterone by affecting the cytochrome P-45011\g=b\. However, this inhibition was detected mainly after angiotensin II or salt-depleted stimulation of the aldosterone production. Also, the renin increase was not modified. Therefore, the accumulation of precursors with mineralocorticoid activity such as DOC might have contributed to the maintenance of a normal ionic homeostasis.

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Ketoconazole: From an antimycotic to a drug for prostate cancer

Cited by 27 publications

References 18 publications

Experimental chemotherapy with combinations of ergosterol biosynthesis inhibitors in murine models of Chagas' disease

Experimental chemotherapy with combinations of ergosterol biosynthesis inhibitors in murine models of Chagas' disease

Mevinolin (lovastatin) potentiates the antiproliferative effects of ketoconazole and terbinafine against Trypanosoma (Schizotrypanum) cruzi: in vitro and in vivo studies

Effects of high-dose ketoconazole treatment on adrenal mineralocorticoid biosynthesis in dogs and rats

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