Ketoconazole and other potent antimycotic azoles exhibit pronounced activity againstTrypanosoma cruzi, Plasmodium berghei andEntamoeba histolytica in vivo

Raether, W.; Seidenath, H.

doi:10.1007/bf00929583

Cited by 34 publications

(6 citation statements)

References 7 publications

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“…Other examples of successful use of ketoconazole (Jolliffe, 1986; Navin et al , 1992; Saenz et al , 1990), itraconazole (Borelli, 1987; Dogra & Saxena, 1996; Momeni et al , 1996; White et al , 2006), posaconazole (Paniz Mondolfi et al , 2011), and even fluconazole (Alrajhi et al , 2002; Daly et al , 2014; Sousa et al , 2011; Toubiana et al , 2006) for treatment of human cutaneous leishmaniasis are known. The antifungal azoles clearly accelerate the healing process and are tolerated much better than the regular medicine (Raether & Seidenath, 1984). But the question, why they have low efficiency, particularly against visceral leishmaniasis, both in humans (Momeni et al , 1996; Sundar et al , 1990) and in animal models (Al-Abdely et al , 1999), remains unresolved.…”

Section: Repurposing Of Systemic Antifungals Forhuman Infections Withmentioning

confidence: 99%

CYP51 as drug targets for fungi and protozoan parasites: past, present and future

2018

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The efficiency of treatment of human infections with the unicellular eukaryotic pathogens such as fungi and protozoa remains deeply unsatisfactory. For example, the mortality rates from nosocomial fungemia in critically ill, immunosuppressed or post-cancer patients often exceed 50%. A set of six systemic clinical azoles [sterol 14α-demethylase (CYP51) inhibitors] represents the first-line antifungal treatment. All these drugs were discovered empirically, by monitoring their effects on fungal cell growth, though it had been proven that they kill fungal cells by blocking the biosynthesis of ergosterol in fungi at the stage of 14α-demethylation of the sterol nucleus. This review briefs the history of antifungal azoles, outlines the situation with the current clinical azole-based drugs, describes the attempts of their repurposing for treatment of human infections with the protozoan parasites that, similar to fungi, also produce endogenous sterols, and discusses the most recently acquired knowledge on the CYP51 structure/function and inhibition. It is our belief that this information should be helpful in shifting from the traditional phenotypic screening to the actual target-driven drug discovery paradigm, which will rationalize and substantially accelerate the development of new, more efficient and pathogen-oriented CYP51 inhibitors.

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Section: Repurposing Of Systemic Antifungals Forhuman Infections Withmentioning

confidence: 99%

CYP51 as drug targets for fungi and protozoan parasites: past, present and future

2018

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“…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%

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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“…These compounds can also block the proliferation of protozoan parasites such as Leishmania tropica, Leishmania mexicana, and T. (S.) cruzi, both in vitro and in vivo (2-5, 9, 11, 16, 25, 41). However, studies with murine model systems (16,25) have revealed that the doses of ketoconazole required to protect the hosts from fatal infections by T. (S.) cruzi are in a range that can interfere with the production of steroid hormones, particularly tetosterone, in humans (1).…”

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confidence: 99%

Antiproliferative synergism of the allylamine SF 86-327 and ketoconazole on epimastigotes and amastigotes of Trypanosoma (Schizotrypanum) cruzi

Urbina

Lazardi

Aguirre

et al. 1988

Antimicrob Agents Chemother

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We have investigated the growth-inhibitory effects of two ergosterol biosynthesis inhibitors, the dioxolane imidazole ketoconazole and the allylamine SF 86-327, alone and in combination, on the proliferative stages of Trypanosoma (Schizotrypanum) cruzi, the causative agent of Chagas' disease. Proliferation of epimastigotes in liver infusion-tryptose medium at 28 degrees C was immediately arrested by any of these drugs at greater than or equal to 3 x 10(-5) M; cell lysis occurred 24 h later. Below that concentration, SF 86-327 at concentrations down to 1 x 10(-6) M stopped growth after 48 h. In contrast, ketoconazole slowed cell growth only moderately, but proliferation finally stopped and cell lysis occurred after 120 h at 3 x 10(-6) M. Synergistic effects could be observed when the two drugs were used in combination: the concentration of SF 86-327 required to reduce the cell growth to 25% of controls in 144 h was reduced 33-fold in the presence of 1 x 10(-6) M ketoconazole, which by itself reduced growth only by 30%. Amastigotes, proliferating in Vero cells at 37 degrees C, were much more susceptible to both drugs, but ketoconazole was definitely a more potent antiparasitic agent than the allylamine in this system: whereas the concentration of SF 86-327 required to reduce the number of infected cells to 50% of controls was 1 x 10(-7) M and that required to completely eradicate the parasite was 3 x 10(-6) M, for ketoconazole these concentrations were 1 x 10(-10) M and 1 x 10(-8) M, respectively. Again, strong synergistic effects were observed when the drugs were used in combination: the concentration of SF 86-327 required to reduce the number of infected cells to 50% of controls was 100-fold lower in the presence of 10(-11) M ketoconazole, which by itself had no effects on amastigote proliferation. The parasite was completely eradicated when the drugs were used in combination at concentrations as low as 10(-9) M. Synergy of the antiproliferative effects of the drugs on both froms of the parasite was further demonstrated by concave isobolograms. On the other hand, SF 86-327 at 10(-5) M had no effects on the proliferation of Vero cells, whereas ketoconazole at 10(-7) M reduced the proliferation of these cells by 50%.

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Ketoconazole and other potent antimycotic azoles exhibit pronounced activity againstTrypanosoma cruzi, Plasmodium berghei andEntamoeba histolytica in vivo

Cited by 34 publications

References 7 publications

CYP51 as drug targets for fungi and protozoan parasites: past, present and future

CYP51 as drug targets for fungi and protozoan parasites: past, present and future

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

Antiproliferative synergism of the allylamine SF 86-327 and ketoconazole on epimastigotes and amastigotes of Trypanosoma (Schizotrypanum) cruzi

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