Leishmania donovani: Oral efficacy and toxicity of formycin B in the infected hamster

Berman, Jonathan; Keenan, C. M.; Lamb, S.R.; Hanson, William L.; Waits, Virginia B.

doi:10.1016/0014-4894(83)90065-6

Cited by 14 publications

(12 citation statements)

References 12 publications

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“…They are therefore considered responsible for the pathogenesis and for the continuance of the infection (14). The apparent absence of toxic side effects of formycin B after prolonged treatment of mice, which was noted by us in this work and by others after using shorter courses of treatment for Leishmania infection in hamsters (5,11), suggests that adverse effects may not complicate the use of this drug as a chemotherapeutic agent. Other investigators, however, have reported that formycin B has considerable toxicity for other experimental animals, particularly for dogs (15,16).…”

Section: Discussionsupporting

confidence: 54%

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In vitro and in vivo activities of formycin B against Trypanosoma cruzi

McCabe¹,

Remington²,

Araujo³

1985

Antimicrob Agents Chemother

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The inosine analog formycin B was examined for in vitro and in vivo activities against Trypanosoma cruzi. A concentration of formycin B as low as 0.1 ,ug/ml markedly inhibited intracellular multiplication of T. cruzi strains both in macrophages and in L929 cells. Mice infected with 105 blood form trypomastigotes of the highly virulent strain Y of T. cruzi were completely protected against death by treatment with 11.8 or 5.9 mg of formycin B per kg administered intraperitoneally each day for 19 days. Four different strains of T. cruzi were used, and each was susceptible to formycin B administered either intraperitoneally or orally. Parasitological cure, however, was not achieved with any of the treatments used, including prolonged treatment for up to 10 weeks. Formycin B has a remarkable capacity for inhibiting the in vitro intracellular replication of T. cruzi and protecting mice against death due to the acute infection with the organism. It does not appear, however, to be able to completely eliminate T. cruzi from infected mice. Recent reviews on the chemotherapy of Chagas' disease have emphasized the deficiencies of presently available therapeutic agents and the need for new ones (10, 13).Allopurinol (4-hydroxypyrazolo[3,4-d]pyrimidine) has recently been shown to be active against Trypanosoma cruzi both in vitro and in vivo (1)(2)(3)17). A related compound, formycin B (7-hydroxypyrazolo[4,3-d]pyrimidine), an inosine analog, has been shown to inhibit replication of epimastigotes of T. cruzi (16,20) and to inhibit the in vivo and in vitro replication of Leishmania donovani and Leishmania mexicana in vitro and in vivo (4-6, 11, 16).We examined the in vitro and in vivo effects of formycin B against T. cruzi. In vitro the drug significantly inhibited the replication of intracellular amastigotes. In vivo formycin B completely protected mice against death when a lethal inoculum of any of four different strains of T. cruzi was administered. Parasitological cure of the infected mice, however, was not achieved even after treatment regimens that lasted for 10 weeks.MATERIALS AND METHODS In vitro experiments. The epimastigote and the intracellular amastigote stages of the Y strain of T. cruzi (9) were used. Epimastigotes were from cultures in brain heart infusion medium supplemented with 5% newborn bovine serum and hemoglobin; amastigotes were isolated from spleens of mice infected 7 days earlier as previously described (18,19). Epimastigotes were cultured at 28°C in brain heart infusion medium containing 0.2 to 60 ,ug of formycin B per ml. Isolated amastigotes were suspended in RPMI 1640 medium (GIBCO Laboratories, Grand Island, N.Y.) supplemented with 10% fetal calf serum and used to infect monolayers of either normal mouse peritoneal macrophages or L929 cells at a ratio of 1 amastigote per cell. Infection was carried out for 10 h in an incubator at 37°C under an atmosphere of 5% CO2. Thereafter, the extracellular organisms were removed by several washes with medium. Fresh medium without formycin B or containing 0.1, 1,...

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Section: Discussionsupporting

confidence: 54%

“…Formycin B has been shown to be effective both in vitro and in vivo (5,11) against Leishmania spp. As with the results reported for Leishmania in a tissue culture model (7), our results showed that replication of the intracellular stage of T. cruzi was significantly inhibited by concentrations of formycin B as low as 0.1 ,ug/ml.…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo activities of formycin B against Trypanosoma cruzi

McCabe¹,

Remington²,

Araujo³

1985

Antimicrob Agents Chemother

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“…Pilot study has demonstrated itraconazole to be a well-tolerated alternative treatment of mucocutaneous leishmaniasis (3) whereas the leaf extract of Kalanchoe pinnata was reported to reduce lesion size in cutaneous leishmaniasis (4). Various compounds, such as atovaquone (5), WR6026 (6), licochalcone A (7), ilmfosine (8), and formycin B (9) have been reported to inhibit Leishmania donovani infection, the causative agent of visceral leishmaniasis. Unfortunately, all such compounds are effective only at higher doses and none of them have been recognized as oral drugs.…”

Section: Introductionmentioning

confidence: 99%

Dihydrobetulinic Acid Induces Apoptosis in Leishmania donovani by Targeting DNA Topoisomerase I and II: Implications in Antileishmanial Therapy

Chowdhury

Mandal

Goswami

et al. 2003

Mol Med

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Leishmaniasis is the second-most dreaded parasitic disease in the modern world, behind malaria. The lack of effective vaccines demand improved chemotherapy along with the development of lead compounds and newer targets. We report here that the pentacyclic triterpenoid, dihydrobetulinic acid (DHBA), is a novel lead compound for antileishmanial therapy. It acts by targeting DNA topoisomerases. DNA topoisomerase I and II activity was studied using relaxation and decatenation assays. Mechanistic studies were based on the decreased mobility of enzyme-bound DNA compared with free DNA and the differential mobility of nicked and supercoiled monomers in 1% agarose gel. Pulsed field gradient gel electrophoresis, confocal microscopy, and transmission electron microscopy were performed to assess cytotoxicity of the compound and ultrastructural damage of the parasite. Apoptosis was studied by the isolation of DNA from DHBA-treated parasites and subsequent electrophoresis in 1% agarose gel. DHBA inhibits growth of Leishmania donovani promastigotes and amastigotes with an IC 50 of 2.6 and 4.1 M respectively. The compound is a dual inhibitor of DNA topoisomerases that fails to induce DNA cleavage and acts by preventing the formation of enzyme-DNA binary complex, ultimately inducing apoptosis. Treatment of infected golden hamsters with the compound markedly reduces (> 92%) parasitic burden, both in spleen and liver. Interestingly, the 17-decarboxylated analogue, dihydrolupeol, does not inhibit DNA topoisomerase I and II, has no effect on parasitic growth, and also fails to induce apoptosis. DHBA is a potent antileishmanial agent that induces apoptosis by primarily targeting DNA topoisomerases. Therefore it is a strong candidate for use in designing new antileishmanial drugs.

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“…Other treatments for kala-azar are now under investigation. These include liposomal amphothericin B (Croft,Davidson & Thornton,199 l), allopurinol and derivatives (Kager et al, 1981;Chung et al, 1985) bis(benzy1) polyamine analogues (Baumann, McCann & Bitonti, 1991), formycin B (Berman et al, 1983), 8-aminoquinoline derivatives (Kinnamon et al, 1978;, an alkylphosphocholine compound, hexadecylphosphocholine (Croft et al, 1987;Kuhlencord et al, 1992), acivicin (Mukherjee, Roy & Bhaduri, 1990) and recently hydroxynaphthoquinones, whose activity in vivo is limited (Croft et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

The activity of 2-substituted quinoline alkaloids in BALB/c mice infected with Leishmania donovani

Fournet¹,

Gantier²,

Gautheret³

et al. 1994

J Antimicrob Chemother

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Potent antileishmanial activity has recently been described in vivo when certain 2-substituted quinoline alkaloids are administered to mice with cutaneous leishmaniasis. We now report the antileishmanial activity of four 2-substituted quinoline alkaloids, namely chimanine D or 2-(1',2'-trans-epoxypropyl) quinoline (I), 2-n-propylquinoline (II), 2-styrylquinoline (III) and 2-(2'-hydroxypropyl) quinoline (IV), for experimental treatment of visceral leishmaniasis in infected BALB/c mice. Subcutaneous treatment with chimanine D for 10 days at 0.54 mmol/kg per day resulted in 86.6% parasite suppression in the liver. Oral administration of 0.54 mmol/kg of 2-n-propylquinoline once daily for 5 or 10 days to L. donovani-infected mice suppressed parasite burdens in liver by 87.8 and 99.9%, respectively. Cutaneous administration of meglumine antimonate for 10 days resulted in 97.4% parasite suppression in the liver. This study is, to our knowledge, the first to demonstrate the activity of 2-substituted quinoline alkaloids in experimental treatment of visceral leishmaniasis. Further biological and chemical studies of these products might yet prove helpful for the development of new antileishmanial drugs.

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Leishmania donovani: Oral efficacy and toxicity of formycin B in the infected hamster

Cited by 14 publications

References 12 publications

In vitro and in vivo activities of formycin B against Trypanosoma cruzi

In vitro and in vivo activities of formycin B against Trypanosoma cruzi

Dihydrobetulinic Acid Induces Apoptosis in Leishmania donovani by Targeting DNA Topoisomerase I and II: Implications in Antileishmanial Therapy

The activity of 2-substituted quinoline alkaloids in BALB/c mice infected with Leishmania donovani

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