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Biomedical subjects

S L Croft

Publications and source records attributed to S L Croft.

At least 55 records · Page 3Linked to original sources
PubMed1999

Cytotoxicity of (2,2':6',2''-terpyridine)platinum(II) complexes to Leishmania donovani, Trypanosoma cruzi, and Trypanosoma brucei.

A range of (2,2':6',2''-terpyridine)platinum(II) complexes are shown to possess antiprotozoal activity in vitro against Leishmania donovani, Trypanosoma cruzi, and Trypanosoma brucei,the causative organisms of tropical diseases leishmaniasis and trypanosomiasis. The best compounds caused 100% and 78% inhibition of growth of the intracellular amastigote forms of L. donovani and T. cruzi, respectively, at a concentration of 1 microM and 100% inhibition of growth of the bloodstream trypomastigote forms of T. brucei at a concentration of 0.03 microM. The results obtained with complexes in which the fourth ligand to platinum(II) is capable of being substituted with a substitution inert hydroxyethanethiolate complex are compared. The ammine complexes show high antiprotozoal activity suggesting that the trans influence of the 2,2':6',2''-terpyridine ligand has a profound effect on the ease of displacement of the fourth ligand in (2,2':6',2'' -terpyridine)platinum(II) complexes, although nonbonded interaction between the ammine ligand and the 6 and 6' ' hydrogens probably also weakens the ligation to Pt(II).

Animals↗
PubMed1999

Activity of extracts and naphthoquinones from Kigelia pinnata against Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense.

Dichloromethane extracts of the root bark and stem bark of Kigelia pinnata collected from Zimbabwe exhibited antitrypanosomal activity against Trypanosoma brucei brucei in vitro. Activity-guided fractionation led to the isolation of four naphthoquinones from both the root and stem bark of the plant. The compounds were identified as 2-(1-hydroxyethyl)-naphtho[2,3-b]furan-4,9-quinone (1), isopinnatal (2), kigelinol (3), and isokigelinol (4). Subsequently, the compounds were assessed for antitrypanosomal activity against T. brucei brucei and T. brucei rhodesiense bloodstream form trypomastigotes in vitro. Compound 1 with a furanonaphthoquinone structure was found to possess pronounced activity against both parasites with IC50 values of 0.12 and 0.045 microM, respectively, although it was less active than the standard drug pentamidine. Compounds 2, 3, and 4 also exhibited activity against the parasites, although to a lesser extent. The activities of the compounds were further assessed by comparison with the cytotoxic activities obtained against KB cell lines.

Animals↗
PubMed1999

Activity of a heat-induced reformulation of amphotericin B deoxycholate (fungizone) against Leishmania donovani.

The heat treatment of amphotericin B deoxycholate (Fungizone), which was previously shown to induce superaggregation and decrease the toxicity of the drug to mammalian cells, increased its activity against Leishmania donovani in BALB/c mice, whereas it reduced its toxicity. Heat treatment preserved the activity of Fungizone against L. donovani HU3-infected mouse peritoneal macrophages.

Amphotericin B↗
PubMed1999

TbRab2p, a marker for the endoplasmic reticulum of Trypanosoma brucei, localises to the ERGIC in mammalian cells.

The Rab family of small GTPases is a subset of the Ras superfamily. Rabs regulate the flux through individual steps of the intracellular membrane trafficking pathway, such as ER-to-Golgi transport, probably by controlling SNARE complex assembly. In Trypanosoma brucei a number of Rab proteins have been isolated by EST analysis; here we characterise one of these, TbRab2p (originally designated Trab1p), which is a member of the Ypt1p subfamily of Rab proteins. Recombinant TbRab2p is capable of hydrolysing GTP and is post-translationally modified in vitro by addition of a geranylgeranyl prenyl group, properties of an authentic Rab GTPase. Antibodies against recombinant TbRab2p show that in trypanosomes TbRab2p is localised primarily to the endoplasmic reticulum (ER) and colocalises with BiP in wild-type trypanosomes. Over expression of TbRab2p in procyclic form T. brucei results in a cell population having a 40-fold increase in TbRab2p expression. In these cells biosynthesis of procyclin, a secretory pathway glycoprotein, is decreased, accompanied by an increase in general protein biosynthesis, suggesting that excess TbRab2p affects ER function. Heterologous expression of TbRab2p in COS cells resulted in targeting to the pre-Golgi transport intermediate (ERGIC), indicating that the targeting information is conserved between mammals and trypanosomes. Clustal and phylogenetic analyses support assignment of TbRab2p as a Rab2 homologue. In addition, over expression of TbRab2p in trypanosomes results in membrane reorganisation and formation of opaque vesicular structures visible by phase contrast microscopy, consistent with accumulation of ER-derived vesicular structures in cells highly overexpressing TbRab2p. Ultrastructural examination by electron microscopy confirmed the presence of a tubulo-vesicular membrane bound compartment in close proximity to the cis-Golgi, probably equivalent to the ERGIC. TbRab2p is therefore a new ER/ERGIC marker for T. brucei.

Amino Acid Sequence↗
PubMed1999

In vitro and in vivo activity of amphotericin B-lipid formulations against experimental Trypanosoma cruzi infections.

The activities of four amphotericin B formulations, Fungizone, AmBisome, Amphocil, and Abelcet, were compared in vitro and in vivo against Trypanosoma cruzi infections. In vitro, Fungizone and Amphocil were highly active against T. cruzi Y strain amastigotes in macrophages with 50% effective dose (ED50) values of 0.027-0.028 microg/ml, which were 7-fold and 42-fold more active than AmBisome and Abelcet, respectively. In vitro activities of all formulations against T. cruzi amastigotes in Vero cells were similar, with ED50 values in the range of 2.0-4.2 microg/ml. Acute infections of the T. cruzi Y strain in BALB/c mice were suppressed in all animals by a single 25 mg/kg dose of the liposomal formulation AmBisome. At the same dose, the two other lipid formulations, Amphocil and Abelcet, increased the survival rate but did not suppress infection in all animals.

Administration, Oral↗
PubMed1998

Down-regulation of Leishmania donovani trypanothione reductase by heterologous expression of a trans-dominant mutant homologue: effect on parasite intracellular survival.

A trans-dominant mutational strategy was used to down-regulate trypanothione reductase (TR) activity levels in Leishmania donovani, the causative agent of visceral leishmaniasis in humans. TR, regarded as an ideal drug target against trypanosomatid infections, is a homodimeric flavoprotein oxidoreductase unique to these organisms that plays a central role in the enzymatic regeneration of the thiol pool. Extrachromosomal, heterologous expression of a trans-dominant mutant version of the Trypanosoma cruzi enzyme in L. donovani resulted in the formation of inactive cross-species heterodimers and in a dramatic decrease of endogenous TR activity levels. Recombinant cells depleted of up to 85% of TR activity were significantly impaired in their ability to regenerate dihydrotrypanothione from trypanothione disulfide following oxidation with diamide. Nonetheless trans-dominant mutant recombinants were still capable of maintaining a reduced intracellular environment during cell growth in culture and were able to metabolize hydrogen peroxide at wild-type rates in vitro. Importantly, however, cells expressing the trans-dominant mutant enzyme displayed a decreased ability to survive inside activated macrophages in a murine model of Leishmania infection. The apparent inability of Leishmania to modulate the expression of active TR homodimers in response to the expression of trans-dominant mutant protein suggests that specific inhibitors of this enzyme should be useful anti-leishmanial agents.

Animals↗
PubMed1998

Phenothiazine inhibitors of trypanothione reductase as potential antitrypanosomal and antileishmanial drugs.

Given the role of trypanothione in the redox defenses of pathogenic trypanosomal and leishmanial parasites, in contrast to glutathione for their mammalian hosts, selective inhibitors of trypanothione reductase are potential drug leads against trypanosomiasis and leishmaniasis. In the present study, the rational drug design approach was used to discover tricyclic neuroleptic molecular frameworks as lead structures for the development of inhibitors, selective for trypanothione reductase over host glutathione reductase. From a homology-modeled structure for trypanothione reductase, replaced in the later stages of the study by the X-ray coordinates for the enzyme from Crithidia fasciculata, a series of inhibitors based on phenothiazine was designed. These were shown to be reversible inhibitors of trypanothione reductase from Trypanosoma cruzi, linearly competitive with trypanothione as substrate and noncompetitive with NADPH, consistent with ping-pong bi bi kinetics. Analogues, synthesized to define structure-activity relationships for the active site, included N-acylpromazines, 2-substituted phenothiazines, and trisubstituted promazines. Analysis of Ki and I50 data, on the basis of calculated log P and molar refractivity values, provided evidence of a specially favored fit of small 2-substituents (especially 2-chloro and 2-trifluoromethyl), with a remote hydrophobic patch on the enzyme accessible for larger, hydrophobic 2-substituents. There was also evidence of an additional hydrophobic enzymic region available to suitable N-substituents of the promazine nucleus. Ki data also indicated that the phenothiazine nucleus can adopt more than one inhibitory orientation in its binding site. Selected compounds were tested for in vitro activity against Trypanosoma brucei, T. cruzi, and Leishmania donovani, with selective activities in the micromolar range being determined for a number of them.

Animals↗
PubMed1998

Failure of buparvaquone (Butalex) in the treatment of canine visceral leishmaniosis.

Buparvaquone (Butalex), a therapeutic for theileriosis, has been shown to have anti-leishmanial activity in vitro. Seven dogs with symptomatic, parasitologically positive, canine visceral leishmaniosis were treated with Butalex at 5 mg kg(-1) body weight using four doses over 12 days. Two animals showed minor clinical improvement (growth of healthy hair) but all remained parasitologically positive and disease progression was not halted.

Animals↗
PubMed1997

Structure-activity relationships for the antileishmanial and antitrypanosomal activities of 1'-substituted 9-anilinoacridines.

Members of the class of 9-anilinoacridine topoisomerase II inhibitors bearing lipophilic electron-donating 1'-anilino substituents are active against both the promastigote and amastigote forms of the parasite Leishmania major. A series of analogues of the known 1'-NHhexyl lead compound were prepared and evaluated against L. major in macrophage culture to further develop structure-activity relationships (SAR). Toxicity toward mammalian cells was measured in a human leukemia cell line, and the ratio of the two IC50 values (IC50(J)/IC50(L)) was used as a measure of the in vitro therapeutic index (IVTI). A 3,6-diNMe2 substitution pattern on the acridine greatly increased toxicity to L. major without altering mammalian toxicity, increasing IVTIs over that of the lead compound. The 2-OMe, 6-Cl acridine substitution pattern used in the antimalarial drug mepacrine also resulted in potent antileishmanial activity and high IVTIs. Earlier suggestions of the utility of 2'-OR groups in lowering mammalian cytotoxicity were not borne out in this wider study. A series of very lipophilic 1'-NRR (symmetric dialkylamino)-substituted analogues showed relatively high antileishmanial potency, but no clear trend was apparent across the series, and none were superior to the 1'-NH(CH2)5Me subclass. Subsets of the most active 1'-N(R)(CH2)5Me- and 1'-N(alkyl)2-substituted compounds against L. major were also evaluated against Leishmania donovani, Trypanosoma cruzi, and Trypanosoma brucei, but no consistent SAR could be discerned in these physiologically diverse test systems. The present study has confirmed earlier conclusions that lipophilic electron-donating groups at the 1'-position of 9-anilinoacridines provide high activity against L. major, but the SAR patterns observed do not carry over to the other parasites studied.

Amsacrine↗
PubMed1997

Activity of liposomal amphotericin B against experimental cutaneous leishmaniasis.

The polyene antibiotic amphotericin B is currently a second-line treatment for visceral leishmaniasis (VL) and mucocutaneous leishmaniasis. Lipid-amphotericin B formulations with lower toxicity than the parent drug that were developed for the treatment of systemic mycoses have proved to be an effective treatment for VL, especially AmBisome, a small unilamellar negatively charged liposome. In vitro, free amphotericin B was three to six times more active than the liposomal formulation AmBisome against both Leishmania major promastigotes in culture and amastigotes in murine macrophages. In a BALB/c L. major model of cutaneous infection, liposomal amphotericin B administered once a day on six alternate days by the intravenous route produced a dose-response effect between 6.25 and 50 mg/kg. Liposomal amphotericin B administered subcutaneously close to a lesion had no significant activity. Free drug was ineffective at nontoxic doses. The results suggest that liposomal amphotericin B may be useful in the treatment of cutaneous leishmaniasis.

Amphotericin B↗
PubMed1997

Intestinal microsporidiosis.

Intestinal microsporidiosis is caused by the protozoan parasites Enterocytozoon bieneusi and Encephalitozoon intestinalis. The disease has been described within the past decade and is found predominantly in acquired immunodeficiency syndrome (AIDS) patients in association with diarrhea. There have been rare reports of infections in immunocompetent patients. Both species of microsporidia invade and multiply within the enterocytes of the small intestine; Encephalitozoon intestinalis also causes a disseminated infection. Electron microscopy has been the mainstay of diagnosis, but improved noninvasive methods of detecting spores in feces are in development. The biology and pathogenicity of the parasites and the pathology and treatment of the disease are poorly understood.

AIDS-Related Opportunistic Infections↗
PubMed1997

The current status of antiparasite chemotherapy.

Currently used antiparasitic drugs, including benzimidazoles, nitroimidazoles, avermectins, polyene ionophores, hydroxynaphthoquinones and sesquiterpene lactones, were identified through the empirical route to drug discovery. The modern rational approach to drug design is focused upon the structure and function of biochemical and molecular targets. The requisite pharmacological properties for new anti-parasite drugs should not be ignored in this process.

Animals↗
PubMed1996

Hepatic extracellular matrix in BALB/c mice infected with Leishmania donovani.

The development of the extracellular matrix (ECM) in the liver of the BALB/c mouse infected with Leishmania donovani was observed by histology, immunocytochemistry and electron microscopy at 1, 2, 4, 8, 14 and 20 weeks after infection. Collagen III and proteoglycan were detected in granulomas and in the portal spaces from 4 to 20 weeks after infection. Laminin was not detected in granulomas but was observed in the basement membrane of new small blood vessels in the granulation tissue around the portal spaces from 8 to 20 weeks after infection. The ECM components in the space of Disse showed no changes in distribution throughout the entire period of study. Systemic fibrosis in the hepatic lobule was not evident in the BALB/c mice. This mouse strain does not appear to be an appropriate model to study the role of ECM in chronic visceral leishmaniasis.

Animals↗
PubMed1996

Activity of pyronaridine and mepacrine against twelve strains of Plasmodium falciparum in vitro.

Pyronaridine, an acridine derivative, has been found effective in China for the treatment of drug-resistant falciparum malaria. The activities of pyronaridine and mepacrine were compared with those of standard antimalarial drugs in vitro against chloroquine-sensitive (CS) and chloroquine-resistant (CR) Plasmodium falciparum isolates to investigate cross resistance. The 50% inhibitory concentrations (IC(50)) against the resistant isolates were 2.8-fold higher than the sensitive isolates for pyronaridine (CS = 7.3 nM; CR = 20.5 nM) and 3.2-fold higher for mepacrine (CS = 13.3 nM; CR = 42.6 nM). These same isolates showed an 11-fold difference in sensitivity to chloroquine with mean IC(50) values of 21 nM for sensitive and 239 nM for resistant parasites. A significant correlation was observed between parasite sensitivity (IC(50)) to pyronaridine and the drugs, mepacrine, amodiaquine and chloroquine. However, the high level of activity seen with pyronaridine, even against the CR isolates, should encourage further field trials with this drug.

Amodiaquine↗
PubMed1996

The activities of four anticancer alkyllysophospholipids against Leishmania donovani, Trypanosoma cruzi and Trypanosoma brucei.

The in-vitro activities of four anticancer alkyllysophospholipids, ET-18-OCH3 (edelfosine), hexadecylphosphocholine (miltefosine), ilmofosine and SRI 62-834, were determined with ED50 values for Leishmania donovani and Trypanosoma cruzi amastigotes between 0.2 and 5.0 microM and for Trypanosoma brucei trypomastigotes between 7.0 and 50.8 microM. In BALB/c mice miltefosine and ilmofosine were the most active compounds with ED50 values of 2.9 and 14.5 mg/kg x 5 doses against L. donovani and a suppressive effect on T. cruzi infections at 30 mg/kg x 5 doses.

Animals↗
PubMed1996

In vitro trypanocidal activities of new S-adenosylmethionine decarboxylase inhibitors.

A series of novel aromatic derivatives based on the structure of methylglyoxal bis(guanylhydrazone) (MGBG) was examined for in vitro antitrypanosomal activities and cytotoxicities for human cells. One-third of the compounds tested showed trypanocidal activity at concentrations below 0.5 microM after an incubation period of 72 h. Structure-activity analysis revealed that bicyclic compounds with homocyclic rings and unmodified termini were the most active compounds. Results obtained in three laboratories employing different methods and trypanosome populations consistently ranked compound CGP 40215A highest. This compound had a 50% inhibitory concentration of 0.0045 microM for Trypanosoma brucei rhodesiense, was also active against other trypanosome species, including a multidrug-resistant Trypanosoma brucei brucei, and was significantly less toxic than other compounds tested for a human adenocarcinoma cell line, with a 50% inhibitory concentration of 1.14 mM. The effect of CGP 40215A was time and dose dependent, and low concentrations of the compound required exposure times of > 2 days to exert trypanocidal activity. Compounds were inactive against Leishmania donovani and Trypanosoma cruzi amastigotes in murine macrophages in vitro.

Adenocarcinoma↗