The Experts below are selected from a list of 15 Experts worldwide ranked by ideXlab platform
T W Goodwin - One of the best experts on this subject based on the ideXlab platform.
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hydrolytic changes in solutions of Stilbamidine
Journal of Pharmacy and Pharmacology, 2011Co-Authors: J D Fulton, T W GoodwinAbstract:Summary and Conclusions The formation of 4—carbamyl—4′—amidinostilbene and 4:4′—dicarbamylstilbene from solutions of Stilbamidine had been shown to occur when the latter were maintained for a number of weeks at 37°C., in diffuse light, and to a lesser extent when kept at the same temperature completely in the dark. When the same solutions were maintained at temperatures which varied from 5° to 20 °C. the formation of amides did not take place. Henry's observations made in the Sudan have been confirmed. Good yields of the amides were obtained by autoclaving solutions of the parent substance at 1 to 2 atmospheres pressure for several hours. The monoamide was inactive against T. rhodesiense or T. congolense infections of mice and does not appear to be selectively absorbed by the trypanosomes like the active Stilbamidine. The fact that solutions of Stilbamidine autoclaved under the conditions employed by Oastler and Fidler undergo no demonstrable change and are not more toxic for mice than similar solutions freshly prepared, suggests that the lesions encountered by these authors in dogs were due to unchanged Stilbamidine.
J D Fulton - One of the best experts on this subject based on the ideXlab platform.
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hydrolytic changes in solutions of Stilbamidine
Journal of Pharmacy and Pharmacology, 2011Co-Authors: J D Fulton, T W GoodwinAbstract:Summary and Conclusions The formation of 4—carbamyl—4′—amidinostilbene and 4:4′—dicarbamylstilbene from solutions of Stilbamidine had been shown to occur when the latter were maintained for a number of weeks at 37°C., in diffuse light, and to a lesser extent when kept at the same temperature completely in the dark. When the same solutions were maintained at temperatures which varied from 5° to 20 °C. the formation of amides did not take place. Henry's observations made in the Sudan have been confirmed. Good yields of the amides were obtained by autoclaving solutions of the parent substance at 1 to 2 atmospheres pressure for several hours. The monoamide was inactive against T. rhodesiense or T. congolense infections of mice and does not appear to be selectively absorbed by the trypanosomes like the active Stilbamidine. The fact that solutions of Stilbamidine autoclaved under the conditions employed by Oastler and Fidler undergo no demonstrable change and are not more toxic for mice than similar solutions freshly prepared, suggests that the lesions encountered by these authors in dogs were due to unchanged Stilbamidine.
H P De Koning - One of the best experts on this subject based on the ideXlab platform.
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uptake of pentamidine in trypanosoma brucei brucei is mediated by three distinct transporters implications for cross resistance with arsenicals
Molecular Pharmacology, 2001Co-Authors: H P De KoningAbstract:The trypanocidal action of pentamidine is dependent on the rapid, selective accumulation of this drug by the parasite. We have investigated pentamidine transport by the bloodstream and procyclic life cycle stages of Trypanosoma brucei brucei. In bloodstream forms, 50 to 70% of [(3)H]pentamidine was transported by an adenosine-sensitive pentamidine transporter (ASPT1) that displayed a K(m) value of 0.26 +/- 0.03 microM and K(i) values of 0.45 +/- 0.04 and 2.5 +/- 0.8 microM for adenine and berenil, respectively. These values are very similar to those for inhibition of [(3)H]adenosine uptake by the P2 adenosine/adenine transporter, suggesting that ASPT1 and P2 may be identical. The remaining 30 to 50% of [(3)H]pentamidine transport was mediated by a low-capacity high-affinity pentamidine transporter (HAPT1) and a high-capacity low-affinity pentamidine transporter (LAPT1), with K(m) values of 36 +/- 6 nM and 56 +/- 8 microM, respectively. HAPT1 was inhibited by propamidine but displayed only low affinity to berenil and Stilbamidine, whereas LAPT1 was not inhibited by any of these diamidines. Neither transporter was inhibited by melarsen oxide. In procyclics, an HAPT1-analog (procyclic pentamidine transporter; PPT1) was characterized, but no adenosine-sensitive pentamidine transport could be detected. Treatment with ionophores revealed that PPT1 may be a proton/pentamidine cotransporter.
Keith Smith - One of the best experts on this subject based on the ideXlab platform.
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characterisation of melarsen resistant trypanosoma brucei brucei with respect to cross resistance to other drugs and trypanothione metabolism
Molecular and Biochemical Parasitology, 1992Co-Authors: Alan H Fairlamb, Mark Cunningham, Nicola S Carter, Keith SmithAbstract:An arsenical resistant cloned line of Trypanosoma brucei brucei was derived from a parent sensitive clone by repeated selection in vivo with the pentavalent melaminophenyl arsenical, sodium melarsen. The melarsen-resistant line was tested in vivo in mice against a range of trypanocidal compounds and found to be cross-resistant to the trivalent arsenicals, melarsen oxide, melarsoprol and trimelarsen (33, 67 and 122-fold, respectively). A similar pattern of cross-resistance was found in vitro using a spectrophotometric lysis assay (greater than 200-fold resistance to melarsen oxide and greater than 20-fold resistance to both trimelarsen and melarsoprol). Both lines were equally sensitive to lysis by the lipophilic analogue phenylarsine oxide in vitro, suggesting that the melamine moiety is involved in the resistance mechanism. Although trypanothione has been reported to be the primary target for trivalent arsenical drugs [1], levels of trypanothione and glutathione were not significantly different between the resistant and sensitive lines. Statistically significant differences were found in the levels of trypanothione reductase (50% lower in the resistant clone) and dihydrolipoamide dehydrogenase (38% higher in the resistant clone). However, the Km for trypanothione disulphide, the Ki for the competitive inhibitor Mel T (the melarsen oxide adduct with trypanothione) and the pseudo-first order inactivation rates with melarsen oxide were the same for trypanothione reductase purified from both clones. The melarsen-resistant line also showed varying degrees of cross-resistance to the diamidines: Stilbamidine (38-fold), berenil (31.5-fold), propamidine (5.7-fold) and pentamidine (1.5-fold). Cross-resistance correlates with the maximum interatomic distance between the amidine groups of these drugs and suggests that the diamidines and melaminophenyl arsenicals are recognised by the same transport system.
Alan H Fairlamb - One of the best experts on this subject based on the ideXlab platform.
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characterisation of melarsen resistant trypanosoma brucei brucei with respect to cross resistance to other drugs and trypanothione metabolism
Molecular and Biochemical Parasitology, 1992Co-Authors: Alan H Fairlamb, Mark Cunningham, Nicola S Carter, Keith SmithAbstract:An arsenical resistant cloned line of Trypanosoma brucei brucei was derived from a parent sensitive clone by repeated selection in vivo with the pentavalent melaminophenyl arsenical, sodium melarsen. The melarsen-resistant line was tested in vivo in mice against a range of trypanocidal compounds and found to be cross-resistant to the trivalent arsenicals, melarsen oxide, melarsoprol and trimelarsen (33, 67 and 122-fold, respectively). A similar pattern of cross-resistance was found in vitro using a spectrophotometric lysis assay (greater than 200-fold resistance to melarsen oxide and greater than 20-fold resistance to both trimelarsen and melarsoprol). Both lines were equally sensitive to lysis by the lipophilic analogue phenylarsine oxide in vitro, suggesting that the melamine moiety is involved in the resistance mechanism. Although trypanothione has been reported to be the primary target for trivalent arsenical drugs [1], levels of trypanothione and glutathione were not significantly different between the resistant and sensitive lines. Statistically significant differences were found in the levels of trypanothione reductase (50% lower in the resistant clone) and dihydrolipoamide dehydrogenase (38% higher in the resistant clone). However, the Km for trypanothione disulphide, the Ki for the competitive inhibitor Mel T (the melarsen oxide adduct with trypanothione) and the pseudo-first order inactivation rates with melarsen oxide were the same for trypanothione reductase purified from both clones. The melarsen-resistant line also showed varying degrees of cross-resistance to the diamidines: Stilbamidine (38-fold), berenil (31.5-fold), propamidine (5.7-fold) and pentamidine (1.5-fold). Cross-resistance correlates with the maximum interatomic distance between the amidine groups of these drugs and suggests that the diamidines and melaminophenyl arsenicals are recognised by the same transport system.