DRUG RESISTANCE IN TRYPANOSOMES; EFFECTS OF METABOLIC INHIBITORS, <i>p</i>H AND OXIDATION‐REDUCTION POTENTIAL ON NORMAL AND RESISTANT <i>TRYPANOSOMA RHODESIENSE</i>

Williamson, J.

doi:10.1111/j.1476-5381.1959.tb00948.x

Cited by 11 publications

(3 citation statements)

References 34 publications

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“…We tested other potential electron mediators: − phenothiazines (AZA, E ′ 0 = 0.013 V; TA, E ′ 0 = 0.063 V; TDB, E ′ 0 = 0.011 V), indamine (TLB, E ′ 0 = 0.115 V), phenazine (PM, E ′ 0 = 0.080 V), and phenazonium (BCB, E ′ 0 = 0.047 V). Their E ′ 0 values are similar to that of MB + (+0.01 V) and are intermediate between those of Hb(Fe 3+ /Fe 2+ ) (+0.14 V) and NAD(P) + /NAD(P)H (−0.32 V).…”

Section: Discussionmentioning

confidence: 99%

Red Blood Cells Donate Electrons to Methylene Blue Mediated Chemical Reduction of Methemoglobin Compartmentalized in Liposomes in Blood

Sakai

Lim

et al. 2014

Bioconjugate Chem.

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Electron-energy-rich coenzymes in cells, NADH and NADPH, are re-energized repeatedly through the Embden-Meyerhof and pentose-phosphate glycolytic pathways, respectively. This study demonstrates extraction of their electron energies in red blood cells (RBCs) for in vivo extracellular chemical reactions using an electron mediator shuttling across the biomembrane. Hemoglobin-vesicles (HbVs) are an artificial oxygen carrier encapsulating purified and concentrated Hb solution in liposomes. Because of the absence of a metHb-reducing enzymatic system in HbV, HbO2 gradually autoxidizes to form metHb. Wistar rats received HbV suspension (10 mL/kg body weight) intravenously. At the metHb level of around 50%, methylene blue [MB(+); 3,7-bis(dimethylamino)phenothiazinium chloride] was injected. The level of metHb quickly decreased to around 16% in 40 min, remaining for more than 5 h. In vitro mixing of HbV/MB(+) with RBCs recreated the in vivo metHb reduction, but not with plasma. NAD(P)H levels in RBCs decreased after metHb reduction. The addition of glucose facilitated metHb reduction. Liposome-encapsulated NAD(P)H, a model of RBC, reduced metHb in HbV in the presence of MB(+). These results indicate that (i) NAD(P)H in RBCs reacts with MB(+) to convert it to leukomethylene blue (MBH); (ii) MB(+) and MBH shuttle freely between RBC and HbV across the hydrophobic lipid membranes; and (iii) MBH is transferred into HbV and reduces metHb in HbV. Four other electron mediators with appropriate redox potentials appeared to be as effective as MB(+) was, indicating the possibility for further optimization of electron mediators. We established an indirect enzymatic metHb reducing system for HbV using unlimited endogenous electrons created in RBCs in combination with an effective electron mediator that prolongs the functional lifespan of HbV in blood circulation.

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Section: Discussionmentioning

confidence: 99%

Red Blood Cells Donate Electrons to Methylene Blue Mediated Chemical Reduction of Methemoglobin Compartmentalized in Liposomes in Blood

Sakai

Lim

et al. 2014

Bioconjugate Chem.

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“…Mechanisms of drug resistance in Protozoa have been reviewed recently by Geary, Edgar & Jenson (1986) but few examples of drug resistance due to permeability changes towards drugs can be cited; these include amprolium resistance in Eimeria (James, 1980), suramin resistance in African trypanosomes (Williamson, 1959), DHFR antagonists and chloroquine in P.falciparum (Geary et al 1986;Fitch, 1983) and anticoccidial ionophores (Chapman, 1978). This would appear to be an important research topic that is suffering from distinct neglect.…”

Section: Impairment Of Methotrexate Uptake and Drug Resistancementioning

confidence: 99%

The interactions between drugs and the parasite surface

Chappell

1988

Parasitology

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SUMMARYThe interrelationships between drugs and parasite surfaces are considered under the headings of (a) effects on membrane transport, (b) drug uptake mechanisms and (c) effects on surface morphology and function: praziquantel is discussed under a separate heading. The range of chemotherapeutic compounds that cause permeability changes and concomitant morphological disruption is discussed in terms of mode of drug action. Interpretation of the available data renders it difficult to identify the primary mode of action in the drugs considered. Drug uptake mechanisms are known for relatively few compounds; drug resistance as a function of drug acquisition is discussed. The role of the parasite surface as a specific drug target is argued.

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“…50), and the search has been extended using certain antitumor antibiotics whose loci of action have recently been specified with increasing precision; any trypanocidal activity in these compounds has been assumed to indicate that the specific action loci, as determined in other kinds of cell, are also present in trypanosomes. Several are especially active on macromolecular synthesis, so that rapidly dividing cells such as proliferative tumors tend to be selectively inhibited.…”

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confidence: 99%

Trypanocidal Activity of Antitumor Antibiotics and Other Metabolic Inhibitors

Williamson

Scott-Finnigan

1978

Antimicrob Agents Chemother

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A microtest has been devised for the rapid preliminary assay in vitro of the effect of over 100 drugs and inhibitors on African trypanosomes (Trypanosoma brucei and T. rhodesiense). Parasite motility and infectivity for mice are indexes, respectively, of respiration and glycolysis and of cell division; trypanocidal titers based on these indexes can show primary metabolic areas of drug attack. Various specific inhibitors have also been tested to detect metabolic sites which might be therapeutically vulnerable. RNA synthesis inhibitors are highly active (adenine nucleosides, daunorubicin, doxorubicin, chromomycin, actinomycin D, mitomycin C); the activity of the nucleoside cordycepin was increased in vitro and in vivo by an adenosine deaminase inhibitor. In view of the polyanionic nature of the trypanocide suramin, a series of polyanions was tested; several showed activity but only poly-D-glutamic acid was active in vivo. Among various miscellaneous inhibitors, quercetin, disulfiram, and the Ca-complexing agents arsenazo I and III showed marked activity, the latter exclusively on the arsenical-resistant T. brucei. The implications of these results for combination chemotherapy and depot prophylaxis (with polyanions) are indicated.New drugs are urgently required for African human and animal trypanosomiasis, especially the latter (52, 53). In the absence of new products from large-scale commercial drug screening, academic laboratory investigation may provide useful leads by concentrating on aspects of trypanosome metabolism which may be vulnerable to chemotherapeutic attack. Susceptible loci exist because the parasitic mode of pathogenic trypanosomes has induced dependence on host metabolites and loss of major components of the respiratory, glycolytic, and biosynthetic functions normally found in mammalian host cells.These metabolic lesions and adaptations indicate vulnerable points of selective trypanocidal drug attack. A high aerobic glycolysis rate is associated with extreme sensitivity to phenylarsenoxides, and absence of cytochromes has given rise to reliance on a parasite-specific a-glycerophosphate oxidase-mediated respiration which is highly sensitive to inhibition by suranin (11) and by aromatic hydroxamates (10, 31); recent analyses of the function of this system (5, 12) have led to the demonstration that trypanosomes can be killed by using salicylohydroxamate and glycerol for simultaneous selective blockade of aerobic and anaerobic glycolysis. Defective purine biosynthesis is also open to attack by adenine nucleosides such as puromycin and cordycepin (52).A number of drugs and inhibitors with specific action sites in other kinds of cell have been used to look for susceptible loci in trypanosomes (cf. 50), and the search has been extended using certain antitumor antibiotics whose loci of action have recently been specified with increasing precision; any trypanocidal activity in these compounds has been assumed to indicate that the specific action loci, as determined in other kinds of cell, are also prese...

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DRUG RESISTANCE IN TRYPANOSOMES; EFFECTS OF METABOLIC INHIBITORS, pH AND OXIDATION‐REDUCTION POTENTIAL ON NORMAL AND RESISTANT TRYPANOSOMA RHODESIENSE

Cited by 11 publications

References 34 publications

Red Blood Cells Donate Electrons to Methylene Blue Mediated Chemical Reduction of Methemoglobin Compartmentalized in Liposomes in Blood

Red Blood Cells Donate Electrons to Methylene Blue Mediated Chemical Reduction of Methemoglobin Compartmentalized in Liposomes in Blood

The interactions between drugs and the parasite surface

Trypanocidal Activity of Antitumor Antibiotics and Other Metabolic Inhibitors

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