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PubMed1974

Susceptibility of an insect Leptomonas and Crithidia fasciculata to several established antitrypanosomatid agents.

Growth inhibition of the lower trypanosomatids Crithidia fasciculata and a Leptomonas from a hemipteron by several established trypanocides and leishmanicides were compared in four complex and one defined media. The Leptomonas was more susceptible than C. fasciculata in all media, especially to phenanthridines (ethidium, prothidium, isometamidium) and diamidines (pentamidine, diminazene diaceturate [Berenil], hydroxystilbamidine, stilbamidine); concentrations of these drugs required for 50% inhibition of the Leptomonas were <5 mug/ml. In contrast, C. fasciculata was uninhibited by <20 mug of diamidines per ml and was three- to sixfold less susceptible than the Leptomonas to isometamidium and prothidium. Both trypanosomatids were susceptible to nucleoside antibiotics, e.g., nucleocidin. Neither was inhibited by suramin, melarsen, melarsen oxide, or tryparsamide. The Leptomonas was more susceptible to standard trypanocides than five other insect trypanosomatids in a complex medium; it was the only one inhibited by <20 mug of stilbamidine and hydroxystilbamidine per ml.

Animals↗

PubMed1975

Interaction between aromatic diamidines and nucleic acids: possible implications for chemotherapy.

Interaction between aromatic diamidines (pentamidine, propamidine, and stilbamidine) and nucleic acids were studied to elucidate the mechanism underlying renal toxicity included by pentamidine in patients. Pentamidine, propamidine, and stilbamidine precipitated with RNA and DNA of all species and types. Furthermore, the diamidines interacted and precipitated with all nucleoside triphosphates and nucleoside diphosphates, but not with nucleoside monophosphates, nucleosides, or free bases. Nucleoside diphosphate is the minimum unit necessary for interaction with the diamidines. This interaction between diamidines and nucleotides or nucleic acids may be implicated in the etiology of renal damage and skin reactions associated with these drugs.

Adenosine Triphosphate↗

PubMed1989

In vitro action of platinum (II) and platinum (IV) complexes on Trypanosoma cruzi and Leishmania donovani.

The in vitro activities of 22 neutral Pt(II) complexes, 4 Pt(IV) complex salts, and one Pt(II) complex salt on epimastigote forms of Trypanosoma cruzi and promastigote forms of Leishmania donovani were studied. Only 2 out of the 18 complexes with cis-Pt(DDH)Xn structure completely inhibited the growth of the epimastigote forms of T. cruzi and the promastigote of L. donovani. Against T. cruzi the cis-Pt(L)n(Cl)2 complexes showed no activities, but the complex in which the (L) ligand was stilbamidine did show a limited activity against L. donovani. Of the Pt(IV)complex salts, [Pt X6]H2(L) were very active against the epimastigote forms of T. cruzi. However, the Pt(II) complex salt [cis-Pt Cl4]H2 (pentamidine) showed no activity. The actions of the Pt(IV) complex salts on the promastigote forms of L. donovani were different and only those salts in which the (L) ligand was pentamidine or stilbamidine induced parasite growth inhibition. The one Pt(II) salt tested showed no antiparasitic activity. At the same time, the known antiparasitic activities of the nifurtimox and pentamidine molecules were confirmed.

Animals↗

PubMed1993

Aromatic diamidines are reversible inhibitors of porcine kidney diamine oxidase.

The inhibitory ability of aromatic diamidines has been studied on porcine kidney diamine oxidase. The reversibility of drug-protein interactions has been tested by means of exhaustive dialysis experiments, showing in all cases a reversible binding pattern. Ki values obtained by means of Lineweaver-Burk plots were: stilbamidine 12 microM, 2-OH-stilbamide 8.5 microM, phenamidine 4 microM, propamidine 8 microM, dibromopropamidine 4.9 microM and amicarbalide 12 microM.

Acquired Immunodeficiency Syndrome↗

PubMed1993

Intracranial injection of Fluoro-Gold results in the degeneration of local but not retrogradely labeled neurons.

Small volumes of either Fluoro-Gold (hydroxy-stilbamidine) or physiological saline were pressure injected into the striatum of adult rats. This paradigm is essentially the same as that used by neuroscientists who inject small quantities of Fluoro-Gold into brain structures to reveal neuronal connections. Using a modified de Olmos' cupric-silver technique, virtually no degeneration could be detected as the result of saline injection at any time point examined. However, comparable injections of Fluoro-Gold resulted in conspicuous cell body and terminal degeneration within the striatum 1-10 days post injection. Terminal degeneration within the substantia nigra pars reticulata could also be seen 2-10 days after injection. Examination of cells of the compacta region revealed conspicuous retrograde uptake of Fluoro-Gold, although none of these cells exhibited any evidence of neuronal degeneration at any postoperative time examined.

Animals↗

PubMedDate not supplied

Chemotherapy for the systemic mycoses: the prelude to ketoconazole.

Successful chemotherapy of the systemic mycoses now covers a span of more than 75 years and dates to the first reported use of potassium iodide for treatment of sporotrichosis. The second drug with efficacy was stilbamidine, and its currently available successor, hydroxystilbamidine isethionate, still has a role in therapy of some patients with nonprogressive blastomycosis of the skin. The introduction in 1957 of amphotericin B marked the first time there was an effective agent for such diseases as cryptococcosis, histoplasmosis, candidosis, and with lesser success, for coccidioidomycosis, mucormycosis, and aspergillosis. However, amphotericin B is nephrotoxic, depresses bone marrow (especially erythropoeisis), and, if patients are not monitored and controlled closely, the drug produces hypokalemic muscle weakness and cardiotoxicity. Flucytosine has a narrower spectrum of activity (cryptococcosis, candidosis, cladosporiosis, and chromomycosis) but a preferable route of administration (oral). Newer agents presently available are miconazole and clotrimazole; the latter is for topical use only.

Amphotericin B↗

PubMed1984

The solvation contribution to the binding energy of DNA with non-intercalating antibiotics.

The influence of the solvent on the binding energies to DNA of six non-intercalating antibiotics - netropsin, distamycin-3, distamycin-2, SN 18071, berenil and stilbamidine - is evaluated by combining the effect of the first hydration shell with that of bulk water. The first effect is computed by a methodology based on a spherical/point dipole model of water and limited to electrostatic interaction energies. Hydration shells are obtained which are energy optimized with respect to both water-solute and water-water interactions for the complexes and for the isolated DNA oligomers and ligands. The method allows even very large complexes to be studied in reasonable computation times. The second effect is introduced via a cavity treatment. It is shown that if the vacuum interaction energies already predict correctly the preference of the ligands for the minor groove of AT sequences of B-DNA, the introduction of the solvation effect is indispensable for reproducing the order of affinity of the ligands and for bringing the values of the complexation energies into close agreement with experimental data.

Anti-Bacterial Agents↗

PubMed1959

Drug resistance in trapanososmes: cross-resitance analyses.

Eight strains of Trypanosoma rhodesiense, made resistant respectively to atoxyl, butarsen, acriflavine, stilbamidine, Surfen C, suramin, and pontamine sky blue 5BX, have been examined for cross-resistance to representatives of nine structurally dissimilar groups of trypanocide. On the basis of their predominant ionic form at blood pH, these groups are considered in three main classes: (a) feebly ionized (neutral aromatic arsenicals), (b) ionized as cations (melaminyl arsenicals and antimonials, acridine derivatives, diguanidines and diamidines, 6-aminoquinoline and 6-aminocinnoline derivatives, phenanthridinium derivatives, triphenylmethane dyes), and (c) ionized as anions (carboxylated aromatic arsenicals and sulphonated naphthylamine derivatives). The results are discussed in relation to those of other workers and to possible modes of trypanocidal drug action. Cross-resistance behaviour is not wholly explicable on an ionic basis; the results suggest that stereospecific structural changes associated with initial drug uptake occur in resistant trypanosomes.

Aminoquinolines↗

PubMed1995

Trypanosoma brucei brucei: antitrypanosomal evaluation of stilbamidinium hexachloroiridiate on the murine CNS model and iridium serum kinetics in infected sheep.

Stilbamidinium hexachloroiridiate was found trypanocidal in vitro against Trypanosoma brucei brucei IPP at 600 microM after a 1 h incubation period and 30 microM after 24 h. This activity was confirmed in mice with a subcutaneous treatment at 20 mg/kg in a single dose. It was then evaluated on T.b. brucei murine CNS model. At the early stage, a subcutaneous treatment at 2 mg/kg/day x 5 cured 50% mice where-as one single dose at 10 mg/kg was completely inactive. Higher doses failed to cure the mice. Nevertheless, hexachloroiridiate salt of stilbamidine was 3.3 fold less toxic than dihydrochloride salt. Although the compound appeared inactive at the late stage of the murine trypanosomiasis, the difference of toxicity justified its evaluation on the early stage of sheep trypanosomiasis. The compound was trypanocidal at 2 mg/kg in a single dose when administered 8 days after infection. The study of iridium serum kinetic showed that stilbamidinium hexachloroiridiate was distributed rapidly according to a monocompartmental model. Moreover, iridium persisted in serum for a long time. The compound in aqueous suspension with 1% carboxymethylcellulose acted therefore as a controlled release system with a bioavailability allowing its trypanocidal action at the early stage.

Animals↗

PubMed1992

Characterisation of melarsen-resistant Trypanosoma brucei brucei with respect to cross-resistance to other drugs and trypanothione metabolism.

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.

Animals↗

PubMed1995

Characterisation of pentamidine-resistant Trypanosoma brucei brucei.

Following selection in vitro by exposure to increasing concentrations of the aromatic diamidine pentamidine, a Trypanosoma brucei brucei clone has been characterised in vivo and in vitro. The resistant clone, designated T.b. brucei S427/118/PR32.6, was found to be less virulent than the parental clone T.b. bruci S427/118, with an intraperitoneal injection of 2.5 x 10(6) resistant organisms required to produce a course of disease equivalent to 1 x 10(4) sensitive trypanosomes. This lowered virulence is not associated with an increased susceptibility to the host's immune system, and is not due to the in vitro culturing process. The pentamidine-resistant clone was found to be 26- and 4.5-fold resistant to pentamidine in vitro and in vivo, respectively. Although not cross-resistant in vivo to any other aromatic diamidines (stilbamidine, berenil and propamidine), a 2.4-fold increase in resistance to the melaminophenylarsine melarsoprol was observed. While pentamidine completely inhibited uptake of 1 microM [3H]adenosine in the presence of 1 mM inosine, suggesting that pentamidine is transported by the inosine-insensitive P2 transporter, the pentamidine-resistant clone appeared to have a fully functional P2-adenosine transport system. Both resistant and parental cloned lines accumulated approx. 6 nmol pentamidine (10(8) cells)-1 over the course of 3 h, representing an internal concentration of 0.7-1.0 mM. Thus, unlike previously characterised drug-resistant trypanosomes, T.b. brucei PR32.6 is not deficient in drug accumulation, suggesting that other resistance mechanisms are likely to be involved.

Adenosine↗

PubMed1980

Synthesis and antitrypanosomal activity of some bis(4-guanylphenyl) five- and six-membered ring heterocycles.

2,5-Bis(4-guanylphenyl)-1,3-oxazole, 2,5-bis(4-guanylphenyl)-1,3,4-oxadiazole and -1,3,4-thiadiazole, and 3,6-bis(4-guanylphenyl)pyridazine and several of their "cyclic guanyl" analogues have been synthesized. 2,5-Bis(4-guanylphenyl)-1,3-oxazole and -1,3,4-thiadiazole showed good activity, whithout acute toxicity, against Trypanosoma rhodesiense in mice, producing cures at a 3 mg/kg dosage level. This activity is comparable to stilbamidine, hydroxystilbamidine, and pentamidine in this test. In contrast, 2,5-bis(4-guanylphenyl)-1,3,4-oxadiazole shows a sharp reduction in activity in our test system. Generally, the cyclic guanyl analogues exhibit low orders of activity, and toxicity begins to appear at moderate dosage levels. All guanyl and cyclic guanyl compounds were synthesized from bisnitrile precursors by way of imidate ester hydrochlorides in a classical Pinner-type approach.

Animals↗

PubMed1977

Synthesis and antiprotozoal activity of 2,5-bis(4-guanylphenyl)furans.

Eighteen substituted 2,5-bis(4-guanylphenyl)furans and related analogues, including "masked" amidines in which the guanyl function is incorporated into a heterocyclic ring, have been synthesized and their antimalarial and antitrypanosomal activity has been evaluated. None of the compounds exhibited high orders of antimalarial activity; however, 11 were very active against Trypanosoma rhodesiense in mice. Six compounds, including 2,5-bis(4-guanylphenyl)furan (4) and its 3-chloro (32), 3,4-dichloro (31), 3-methyl (25), 3,4-dimethyl (20), and 3-chloro-4-methyl (38) derivatives, produced cures in mice at submilligram dosage levels; the 3,4-dimethyl (20) analogue exhibited a prolonged curative effect providing protection for 30 days after a single dose against a challenge by T. rhodesiense. These six compounds are somewhat more active in this screen than stilbamidine, hydroxystilbamidine, and pentamidine. The "masked" amidines generally exhibited lower antitrypanosomal activity than their true guanyl counterparts. Compound 4 was synthesized from 1,4-di-p-bromophenyl-1,4-butanedione by cyclodehydrative furanization to 2,5-bis(4-bromophenyl)furan (2) which was allowed to react with Cu2(CN)2 to produce the corresponding bis-nitrile 3. The latter compound was ultimately converted by way of an imidate ester into 4. Similarly, the 3- and/or 4-substituted derivatives of 2 were employed to prepare the other members of the series.

Animals↗

PubMed1962

Trypanocidal action of p-biguanidoacetophenone amidinohydrazone.

p-Biguanidoacetophenone amidinohydrazone, given in single doses, can cure mice infected with an old laboratory strain of Trypanosoma rhodesiense, but it has only slight action on more recently isolated strains. Trypanosomes which are resistant to stilbamidine are resistant to this compound also. Apparently its trypanocidal action is similar to that of the diamidine series of trypanocidal compounds.

Acetophenones↗

PubMed1976

Pentamidine transport and sensitivity in brucei-group trypanosomes.

Sensitivity to pentamidine of bloodstream forms and culture forms of Trypanosoma brucei brucei, strains of this subspecies, and strains of T. brucei rhodesiense characteristically differs in vitro. Analyses of transport parameters for pentamidine uptake in these organisms show differences that correspond with drug sensitivity. Long slender bloodstream forms of T. b. brucei have a high affinity for the drug and high rates of uptake at indicated by Km and Vmax values for [3H]pentamidine transport. Although pentamidine and stilbamidine resistance is associated with dyskinetoplasty, this condition does not itself confer resistance to pentamidine nor does it affect pentamidine transport. However, drug-resistant strains show lower rates for pentamidine transport as does T. b. rhodesiense, which is characteristically less sensitive to the drug. Of all the forms and strains studied, procyclic trypomastigotes were least sensitive to pentamidine and had a remarkable ability to exclude the drug.

Amidines↗

PubMed2001

Uptake of pentamidine in Trypanosoma brucei brucei is mediated by three distinct transporters: implications for cross-resistance with arsenicals.

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.

Animals↗

PubMed1975

Drug-resistant Leptomonas: cross-resistance in trypanocide-resistant clones.

A Leptomonas of insect origin was highly susceptible to several standard trypanocides and leishmanicides in vitro. Resistance was induced to some of these drugs; clones were isolated from each strain. Cross-resistance patterns of the clones were derived for diamidines, quinapyramine (Antrycide), acriflavin, phenanthridines, and other drugs active against trypanosomes and leishmanias. Clones tested included two each that were resistant to acriflavin, Antrycide, diminazene aceturate (Berenil), and pentamidine and one that was resistant to stilbamidine. Appreciable cross-resistance was evident for all clones. Differences were observed between clones from the same parent strain. Collateral susceptibility towards isometamidium and oxophenarsine was detected in most clone-derived populations. In clones passaged without drug to test for drug fastness, acriflavin and pentamidine clones lost resistance within 10 transfers, whereas Berenil and Antrycide clones retained considerable resistance after 20 to 30 subcultures without drug. Considerations of differences in life cycles suggest that the clone collection may be useful in screening for agents effective against leishmanias and stercorarian trypanosomes rather than against salivary trypanosomes.

Clone Cells↗

PubMed1997

Differential effects of NGF and BDNF on axotomy-induced changes in GABA(A)-receptor-mediated conductance and sodium currents in cutaneous afferent neurons.

The effects of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) on injury-induced changes in the electrophysiological properties of adult rat cutaneous afferent dorsal root ganglion (DRG) neurons were examined. Whole cell patch-clamp techniques were used to study gamma-aminobutyric acid-A (GABA(A))-receptor-mediated conductance, voltage-dependent sodium currents, and action potential waveform in cutaneous afferent neurons (35-60 microm diam) cultured from control and axotomized animals. Cutaneous afferent neurons were identified by retrograde labeling with hydroxy-stilbamidine (Fluoro-gold, a fluorescent retrograde axonal tracer); the sciatic nerve was transected 1 wk after Fluoro-gold injection and L4/L5 DRG neurons were cultured 2-3 wk after axotomy. NGF, BDNF, or Ringer (vehicle) solution was delivered in vivo directly to the transected sciatic nerve stump in axotomized rats via an osmotic pump. Recordings were obtained from neurons 5-24 h after culture. Axotomized neurons from rats treated with vehicle solution displayed a twofold increase in GABA-induced conductance and a prominent reduction in the proportion of neurons expressing action potentials that had inflections on the falling phase. The expression of kinetically slow tetrodotoxin (TTX)-resistant sodium current was markedly reduced and an increased expression of kinetically fast TTX-sensitive current was observed in neurons from vehicle-treated, axotomized rats. Treatment with NGF (0.25 microg/microl at 12 microl/day for 14 days) in axotomized animals resulted in an increase in the proportion of neurons expressing TTX-resistant, slow sodium currents and inflected action potentials, but had no effect on GABA-induced conductance. Treatment with BDNF (0.5 microg/microl at 12 microl/day for 14 days) attenuated the axotomy-induced increase in GABA(A)-receptor-mediated conductance while minimally affecting action potential waveform. The observed neurotrophin effects occurred independently of cell size changes. These findings indicate a differential regulation of GABA(A) receptor and sodium channel properties in axotomized rat cutaneous afferent neurons by specific neurotrophic factors.

Animals↗