The Antileishmanial Activity of Lepidines *

Kinnamon, Kenneth E.; Steck, Edgar A.; Loizeaux, Peter S.; Hanson, William L.; Chapman, Willie L.; Waits, Virginia B.

doi:10.4269/ajtmh.1978.27.751

Cited by 60 publications

(32 citation statements)

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“…Many aminoquinoline compounds, substituted at positions 8, 7, 6 and 4, have been synthesized at the Walter Reed Army Institute for Research and have previously been shown to be effective against cutaneous leishmaniasis and visceral leishmaniasis (11)(12)(13)15), malaria (5), and recently, against Pneumocystis carinii-caused pneumonia (2). An examination of the data obtained in the present study demonstrates that interesting biological activities also exist in the 2-substituted quinoline alkaloids.…”

Section: Discussionmentioning

confidence: 80%

2-substituted quinoline alkaloids as potential antileishmanial drugs

Fournet

Barrios

Muñoz

et al. 1993

Antimicrob Agents Chemother

140

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Ten 2-substituted quinoline alkaloids isolated from a plant used for treatment of New World cutaneous leishmaniasis have antileishmanial in vitro activities against the extracellular forms ofLeishmania spp. BALB/c mice infected with Leishmania amazonensis PH8 or H-142 or Leishmania venezuelensis were treated 1 day after the parasitic infection with a quinoline alkaloid (100 mg/kg of body weight per day) or with reference drug N-methylglucamine antimonate (Glucantime) (56 mg of pentavalent antimony [Sbv] per kg per day) for 14 days.Lesion development was the criterium used to assess disease severity. Two three-carbon chain quinolines [2-n-propylquinoline and 2-(l',2'-trans-epoxypropyl)quinoline (chimanine D)] were more potent than N-methylglucamine antimonate against L. amazonensis PH8, and five quinoline alkaloids [2-(3,4-methylenedioxyphenylethyl)quinoline, cusparine, 2-(3,4-dimethoxyphenylethyl)quinoline, 2-(E)-prop-1'-enylquinoline (chimanine B), and skimmianinel were as effective as the reference drug. Single treatment near the site of infection, 14 days after infection with L. amazonensis, with 2-n-propylquinoline or chimanine B reduced the severity of lesions but less notably than N-methylglucamine antimonate. 2-n-Propylquinoline exhibited significant activity against the virulent strain L. venezuelensis. The active products did not show any apparent toxicities during the experiment. This study is, to our knowledge, the first to show the activity of 2-substituted quinoline alkaloids for experimental treatment of New World cutaneous leishmaniasis. Further investigations of these compounds might yet prove helpful for the development of new antileishmanial drugs.

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Section: Discussionmentioning

confidence: 80%

2-substituted quinoline alkaloids as potential antileishmanial drugs

Fournet

Barrios

Muñoz

et al. 1993

Antimicrob Agents Chemother

140

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“…Therefore, there is a great need for the development of effective and safe drugs for the treatment of leishmaniasis. A number of studies of chemotherapy of leishmaniasis have been carried out during the last two decades (4,11,14,15,17,19,25). These studies indicate that amphotericin B, liposomal amphotericin B, and paromomycin are more active than the antimonial agents for visceral leishmaniasis and pentamidine for cutaneous leishmaniasis and that allopurinol is being clinically tested in treatment of cutaneous leishmaniasis (15).…”

Section: Resultsmentioning

confidence: 99%

Antileishmanial activity of licochalcone A in mice infected with Leishmania major and in hamsters infected with Leishmania donovani

Chen

Christensen

Theander

et al. 1994

Antimicrob Agents Chemother

130

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This study was designed to examine the antileishmanial activity of the oxygenated chalcone licochalcone A in mice and hamsters infected with Leishinunia parasites. Intraperitoneal administration of licochalcone A at doses of 2.5 and 5 mg/kg of body weight per day completely prevented lesion development in BALB/c mice infected with Leishmania major. Treatment of hamsters infected with L. donovani with intraperitoneal administration of licochalcone A at a dose of 20 mg/kg of body weight per day for 6 consecutive days resulted in a >96% reduction of parasite load in the liver and the spleen compared with values for untreated control animals. The [3H]thymidine uptake by the parasites isolated from the treated hamsters was only about 1% of that observed in parasites isolated from the controls. Oral administration of licochalcone A at concentrations of 5 to 150 mg/kg of body weight per day for 6 consecutive days resulted in >65 and 85% reductions ofL. donovani parasite loads in the liver and the spleen, respectively, compared with those of untreated control hamsters. These data clearly demonstrate that licochalcone A is a promising lead for the development of a new drug against leishmaniases.The World Health Organization has identified leishmaniases as a major and increasing public health problem (23,26). The visceral form of the disease, known as kala-azar, is widely distributed in many parts of the world, particularly Africa, Asia, Latin America, the Middle East, and the Mediterranean Basin (13,23,26

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“…The lack of orally administered effective agents for VL prompted the clinical development of WR6026, a primaquine analog found to be highly active in animal testing. [1][2][3] The only previous phase 2 study of the efficacy of WR6026 was performed in Kenya. 4 In that study, 16 patients with VL underwent treatment with WR6026 at doses ranging from 0.75-1.0 mg/kg/day for 2 weeks (8 patients) or 1 mg/ kg/day for 4 weeks (8 patients).…”

Section: Introductionmentioning

confidence: 99%

Phase 2 trial of WR6026, an orally administered 8-aminoquinoline, in the treatment of visceral leishmaniasis caused by Leishmania chagasi.

Dietze¹,

Carvalho²,

Valli³

et al. 2001

The American Journal of Tropical Medicine and Hygiene

109

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Abstract. There are no recognized orally administered treatments for any of the leishmaniases. The 8-aminoquinoline WR6026 is an orally administered analog of primaquine that cured 50% of patients with kala-azar in Kenya at a dose of 1 mg/kg/day for 28 days. A further phase 2, open-label, dose-escalating safety and efficacy study was performed for kala-azar in Brazil. Cure rates for Brazilian patients treated for 28 days were as follows: 1 mg/kg/day: 0 of 4 (0%); 1.5 mg/kg/day: 1 of 6 (17%); 2.0 mg/kg/day: 4 of 6 (67%); 2.5 mg/kg/day: 1 of 5 (20%); and 3.25 mg/ kg/day: 0 of 1 (0%). Nephrotoxicity that was not anticipated from preclinical animal studies or from phase 1 studies was seen at 2.5 mg/kg/day in 2 patients and in the single patient administered 3.25 mg/kg/day. WR6026 demonstrated the unusual clinical features of lack of increased efficacy against Brazilian kala-azar with increased dosing above 2 mg/kg/day and toxicity that was not present in previous investigations.

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The Antileishmanial Activity of Lepidines *

Cited by 60 publications

References 0 publications

2-substituted quinoline alkaloids as potential antileishmanial drugs

2-substituted quinoline alkaloids as potential antileishmanial drugs

Antileishmanial activity of licochalcone A in mice infected with Leishmania major and in hamsters infected with Leishmania donovani

Phase 2 trial of WR6026, an orally administered 8-aminoquinoline, in the treatment of visceral leishmaniasis caused by Leishmania chagasi.

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