Chemotherapy of trypanosomiasis: the potentiation of melarsoprol by concurrent difluoromethylornithine (DFMO) treatment

Fw, Jennings

doi:10.1016/0035-9203(88)90512-3

Cited by 19 publications

(6 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Antimonial drugs were developed as less-toxic analogs of arsenical drugs. Pentavalent antimonial agents are also effective against trypanosomes, particularly when used with difluoromethylornithine, an agent that decreases the intracellular concentration of trypanothione (14). Previous work has shown stable complex formation between antimony and leishmanial proteins after treatment with radiolabeled sodium stibogluconate (4).…”

Section: Discussionmentioning

confidence: 99%

In vitro antileishmanial properties of tri- and pentavalent antimonial preparations

Roberts

Berman

Rainey

1995

Antimicrob Agents Chemother

125

View full text Add to dashboard Cite

To better understand the antileishmanial effects of antimonial agents we synthesized complexes of tri-and pentavalent antimony with mannan. The 50% inhibitory concentrations (IC 50 s) of these agents, along with those of potassium antimony tartrate [Sb(III)] and sodium stibogluconate [Sb(V)], were determined for promastigotes and intramacrophage amastigotes. The trivalent antimonial agents were more potent than the pentavalent agents. Although the IC 50 s were 60-to more-than-600-fold higher for promastigotes than for amastigotes, similar intracellular antimony concentrations in both life forms were measured after incubation with all four drugs at their respective IC 50 s. Macrophages accumulated antimony during a 4-h exposure that was retained intracellularly for at least 3 days. Amastigotes inside macrophages had a higher antimony content 6 days after a single 4-h treatment than they did immediately after treatment, suggesting that macrophages serve as a reservoir for antimonial agents and prolong parasite exposure. Macrophages concentrated antimony from the medium with potassium antimony tartrate, trivalent antimony-mannan, and pentavalent antimonymannan treatments. N-Acetylcysteine antagonized the antileishmanial effects of these three drugs against intracellular amastigotes; in contrast, it had minimal effects on the action of sodium stibogluconate.The leishmaniases are a group of diseases produced by invasion of the reticuloendothelial system of a vertebrate host by a parasite of the genus Leishmania followed by parasite multiplication inside macrophages. Symptomatic visceral leishmaniasis (kala-azar) is characteristically fatal if untreated. Antimonial chemotherapy increases the survival rate to over 90% (1). One of the first antimonial agents used was tartar emetic [potassium antimony(III) tartrate]. Unfortunately, this agent was highly toxic to humans as well as to Leishmania parasites. In the search for agents with higher therapeutic indices, a number of other antimonial agents were prepared and evaluated (for a review, see reference 24). This process produced the current drugs of choice, two closely related pentavalent antimony-carbohydrate complexes, sodium stibogluconate (Pentostam) and meglumine antimoniate (Glucantime). Pentavalent antimony salts are 10-fold less toxic to mammals than trivalent salts (15). Likewise, these pentavalent antimony-containing drugs are less toxic to humans and have a higher therapeutic index than organic trivalent antimony preparations. Despite their clinical use for over half a century, the mechanism of action and basis for selective toxicity of these antileishmanial agents remain unknown.Several properties of the pentavalent antimonial agents have been suggested to contribute to their activity. Carbohydrates form water-soluble complexes with antimony and may serve to deliver antimonial drugs to host macrophages. Relatively nontoxic pentavalent antimony may be a prodrug that is converted to more toxic trivalent antimony at or near the site of action. Interactions of an...

show abstract

Section: Discussionmentioning

confidence: 99%

In vitro antileishmanial properties of tri- and pentavalent antimonial preparations

Roberts

Berman

Rainey

1995

Antimicrob Agents Chemother

125

View full text Add to dashboard Cite

show abstract

“…At the other end of the pathway, trivalent arsenical drugs sequester T[SHh as a dithioarsane adduct, MelT (67), which in tum is a competitive inhibitor of TR (62, 67). Thus the marked synergistic effect between these two compounds could result from their combined action in lowering trypanothione levels (114)(115)(116)142). In the absence of arsenicals, the basis for the selective action of DFMO against the African trypanosome is the subject of much debate.…”

Section: Inhibition Of Trypanothione Biosynthesismentioning

confidence: 98%

Metabolism and Functions of Trypanothione in the Kinetoplastida

Fairlamb

Cerami²

1992

Annu. Rev. Microbiol.

708

397

View full text Add to dashboard Cite

Trypanosomatids differ from all other organisms in their ability to conjugate the sulfur-containing tripeptide, glutathione, and the polyamine, spermidine, to form trypanothione [N1,N8-bis(glutathionyl)spermidine]. Together with the NADPH-dependent flavoprotein, trypanothione reductase, the dithiol form of trypanothione provides an intracellular reducing environment in these parasites, substituting for glutathione and glutathione reductase found in the mammalian host. Trypanothione and its related enzymes are involved in defense against damage by oxidants, certain heavy metals, and possibly xenobiotics. Trypanothione and its metabolic precursor, glutathionylspermidine, are also implicated in the modulation of spermidine levels during growth. Several existing trypanocidal drugs interact with the trypanothione system, suggesting that trypanothione metabolism may be a good target for the development of new drugs. The purification and properties of three key enzymes (glutathionylspermidine synthetase, trypanothione synthetase, and trypanothione reductase) are discussed, and the catalytic mechanism, substrate-specificity, and the three-dimensional structure of trypanothione reductase are compared to that of glutathione reductase.

show abstract

“…Various combinations of melarsoprol, eflornithine, and nifurtimox have been used with some success as compassionate treatment for patients who fail monotherapy with у1 of these drugs [19][20][21]. These limited data from humans are consistent with the observation of synergism in animal models [22]. Additional work in model systems must be done to better define the optimum combinations.…”

mentioning

confidence: 72%

Prospects for Improving African Trypanosomiasis Chemotherapy

Moore¹

2005

J INFECT DIS

View full text Add to dashboard Cite

Chemotherapy of trypanosomiasis: the potentiation of melarsoprol by concurrent difluoromethylornithine (DFMO) treatment

Cited by 19 publications

References 6 publications

In vitro antileishmanial properties of tri- and pentavalent antimonial preparations

In vitro antileishmanial properties of tri- and pentavalent antimonial preparations

Metabolism and Functions of Trypanothione in the Kinetoplastida

Prospects for Improving African Trypanosomiasis Chemotherapy

Contact Info

Product

Resources

About