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Biomedical subjects

S L Croft

Publications and source records attributed to S L Croft.

At least 73 records · Page 4Linked to original sources
PubMed1996

In vivo 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 trypanocidal activities in human and veterinary trypanosomes of African origin. One agent, CGP 40215A, a bicyclic analog of MGBG which also resembles the diamidines diminazene (Berenil) and pentamidine, was curative of infections by 19 isolates of Trypanosoma brucei subspecies as well as a Trypanosoma congolense isolate. Several of these isolates were resistant to standard trypanocides. Curative doses were < or = 25 mg/kg of body weight/day for 3 days in these acute laboratory model infections. In addition, CGP 40215A also cured a model central nervous system infection in combination with the ornithine decarboxylase inhibitor DL-alpha-difluoromethylornithine (DFMO; Ornidyl, eflornithine). Curative combinations were 14 days of oral 2% DFMO (approximately 5 g/kg/day) plus 5, 10, or 25 mg/kg/day for 3 or 7 days given by intraperitoneal injection or with a miniosmotic pump. Combinations were most effective if CGP 40215A was given in the second half or at the end of the DFMO regimen. MGBG has modest activity as an inhibitor of trypanosome S-adenosylmethionine decarboxylase (50% inhibitory concentration [IC50]. 130 microM), while CGP 40215A was a more active inhibitor (IC50, 20 microM). Preincubation of trypanosomes with CGP 40215A for 1 h caused a reduction in spermidine content (36%) and an increase in putrescine content (20%), indicating that one possible mechanism of its action may be inhibition of polyamine biosynthesis.

Adenosylmethionine Decarboxylase↗
PubMed1995

Ribosomes of Leishmania are a target for the aminoglycosides.

Ribosomes of Leishmania, a parasitic protozoan (member of the order of Kinetoplastidae), were purified on a sucrose density gradient. Two different types of ribosomes were isolated from the promastigotes: cytoplasmic (88S and 91S from L. tropica and L. donovani, respectively) and mitochondrial (75S in both species). Both types of ribosome dissociated into their subunits at low Mg2+ concentration (1-2 mM) as follows: 67S and 49S for the 91S cytoplasmic ribosomes of L. donovani and 61S and 43S for the 88S cytoplasmic ribosome of L. tropica; 55S and 34S for L. tropica and 60S and 39S for L. donovani mitochondrial ribosomes, respectively. Paromomycin (aminosidine), an aminoglycoside aminocyclitol antibiotic, interacted with the ribosomes to promote the association of the subunits. Under similar experimental conditions, spermidine and pentamidine were inactive.

Animals↗
PubMed1995

Pharmacokinetics of antimony in patients treated with sodium stibogluconate for cutaneous leishmaniasis.

The pharmacokinetics of Sb was examined in 29 patients with cutaneous leishmaniasis following the intramuscular administration of a dose of sodium stibogluconate equivalent to 600 mg of Sb. Blood was sampled at different time intervals from each patient and Sb was measured in whole blood by electrothermal atomic absorption spectrophotometry after an appropriate dilution with Triton X-100. The 24-hr urine was also collected and analyzed similarly. The blood concentration-time data conformed to the one-compartment open model with mean and (SEM) of the apparent first-order rate constants for absorption (ka) and elimination (kd) of 1.71 (0.15) and 0.391 (0.016) hr-1, respectively. The maximum concentration of Sb achieved was 8.77 (0.39) mg/L and the peak time was 1.34 (0.09) hr. The total body clearance (TBC) and the volume of distribution (Vd) were 17.67 (1.38) L/hr and 45.7 (2.6) L, respectively, assuming a complete absorption. The fraction of dose of Sb excreted in the urine was 0.80 (0.07) and the renal clearance was 12.7 (1.16) L/hr. The frequency distribution pattern of the area-under-the-curve (AUC) appears to be bimodal and separates patients into those with low exposure to Sb (AUC = 11.7-29.04 mg.hr/L) (i.e., rapid eliminators) and those with high exposure to Sb (AUC = 31.5-49.1 mg.hr/L) (i.e., slow eliminators). This may explain the variability observed in the response to treatment of leishmaniasis with sodium stibogluconate.

Absorption↗
PubMed1995

The sensitivity of Leishmania species to aminosidine.

The aminoglycoside, aminosidine exhibited ED50S of between 1 and 5 microM against the amastigotes of Leishmania major and Leishmania tropica in mouse peritoneal macrophages whereas other strains causing New World cutaneous leishmaniasis such as Leishmania braziliensis were more refractory. Aminosidine was also active against all but one of the Leishmania donovani strains tested and when combined with sodium stibogluconate, the drug showed marked potentiation against the amastigotes of L. donovani in vitro and an additive effect in experimentally infected BALB/c mice.

Animals↗
PubMed1995

Skin uptake, distribution, and elimination of antimony following administration of sodium stibogluconate to patients with cutaneous leishmaniasis.

We examined in this study the pharmacokinetics of Sb in the affected skin and normal skin of patients treated with sodium stibogluconate for cutaneous leishmaniasis and compared the results with those for the blood. The procedure was fully explained, and a written consent was obtained from each of nine patients. After a dose of sodium stibogluconate equivalent to 600 mg of Sb was administered intramuscularly, small skin biopsies were collected under local anesthesia at different time intervals from the circumferences of the lesions and simultaneously from normal skin. Antimony was measured in these biopsies after suitable ashing and processing by flameless atomic absorption spectrophotometry. The means (with standard errors of the means in parentheses) of the peak concentration, time to peak concentration, area under the curve, half-life, and mean residence time in lesions were 5.02 (1.43) micrograms/g, 2.1 (0.4) h, 32.8 (6.1) micrograms.h/g, 6.88 (0.54) h, and 10.4 (1.2) h, respectively, and those in normal skin were 6.56 (2.01) micrograms/g, 2.6 (0.8) h, 44.0 (15.8) micrograms.h/g, 5.44 (0.83) h, and 8.08 (1.34) h, respectively. There was no significant difference in any of these parameters between lesions and normal skin, whereas the differences in peak concentration, half-life, and mean residence time between lesions and whole blood were significant (P < or = 0.05). The penetration of Sb into skin, either affected or normal, as measured by the skin/blood area under the curve ratio appears to be complete, but the disposition is slow compared with that from the blood.

Adult↗
PubMed1994

Antileishmanial actions of tricyclic neuroleptics appear to lack structural specificity.

There is continuing interest in the antimicrobial effects of tricyclic neuroleptics and antidepressants, particularly against trypanosomatid protozoa, but few studies have attempted to dissociate antiparasitic actions from effects on the central nervous system. In this report, we have measured the antileishmanial potency of a range of structural analogues in this drug group, and conclude that no one structural determinant is critical for activity. Instead, potency may be predicted from an overall determination of the lipophilic and steric components of the structure by a simple combination of two descriptive parameters, valence connectivity and an interactive term.

Animals↗
PubMed1994

The activity and ultrastructural localization of primaquine-loaded poly (d,l-lactide) nanoparticles in Leishmania donovani infected mice.

The activity of primaquine (PQ) was compared to that of PQ-loaded Poly (D,L-Lactide) (PLA) nanoparticles against Leishmania donovani. The association of PQ with PLA nanoparticles increased the antileishmanial in vitro and in vivo effects of intravenously administered drug while its toxicity was reduced. The effectiveness of PQ-loaded PLA nanoparticles was 3.3 times as high as that of free drug in the suppression of amastigotes in the liver of BALB/c mice. A total dose of 30 mg PQ bound/kg (600 mg PLA/kg) was well tolerated and no sign of acute toxicity was observed. A similar dose of free drug resulted in 15% weight loss. No significant leishmanicidal activity was observed for unloaded PLA nanoparticles. Ultrastructural studies showed the uptake of drug-loaded nanoparticles by Leishmania-infected Kupffer cells. Nanoparticles were identified closed to amastigotes.

Animals↗
PubMed1993

Proton NMR lipid profile of Leishmania donovani promastigotes.

The proton nuclear magnetic resonance (NMR) lipid profile of Leishmania donovani was obtained in the one-dimensional and two-dimensional modes. Partial assignments of lipid classes and individual lipids were obtained purely from the proton NMR spectrum of the mixture. A more complete assignment and quantitative analysis was achieved by prior separation of the lipids by high pressure liquid chromatography (HPLC) followed by proton NMR analysis of the fractions. This work showed that proton NMR spectroscopy could facilitate lipid analysis and classification of various parasitic protozoa and serve as a basis for rapid studies of comparative lipid metabolism in parasites.

Animals↗
PubMed1992

An in vitro model for screening antileishmanial drugs: the human leukaemia monocyte cell line, THP-1.

Standard anti-leishmanial drugs were tested for their ability to inhibit the growth of intracellular amastigotes of Leishmania aethiopica, L. donovani and L. infantum in the human leukemia monocyte THP-1 cell line. Sodium stibogluconate and meglumine antimoniate were active against L. donovani with ED50 values of 8.9 micrograms SbV/ml and 2.9 micrograms SbV/ml, respectively. L. aethiopica was less sensitive to sodium stibogluconate with an ED50 value of 25.3 micrograms SbV/ml while pentamidine had an ED50 value of 0.6 microM. Both L. donovani (ED50, 9.3 microM), and L. aethiopica (ED50, 6.4 microM), were sensitive to aminosidine sulphate. An L. infantum isolate, clinically resistant to meglumine antimoniate treatment, had an ED50 of 22.2 micrograms SbV/ml. The toxic level of drugs on host cells was determined by colorimetric Methyl Tetrazolium (MTT) assay prior to activity tests. The results obtained with the THP-1 in vitro drug screening model were similar to those obtained in the mouse peritoneal macrophage model.

Animals↗
PubMed1992

Chemotherapy and immunity in opportunistic parasitic infections in AIDS.

Parasitic diseases are endemic in parts of the tropics, but there is no convincing evidence that their prevalence or incidence is increasing due to the HIV epidemic. Available scientific data on parasitic infections in patients with the Acquired Immunodeficiency Syndrome (AIDS) suggests a predominance of Pneumocystis carinii, Toxoplasma gondii and Cryptosporidium spp. For reasons which are unclear, parasitic infections such as Plasmodium falciparum, Strongyloides stercoralis and Entamoeba histolytica, where cell-mediated immune responses are also thought to be significant, do not appear to be opportunists of importance. It is being increasingly recognized that chemotherapy for parasitic diseases has a host-dependent component, although scientific data on this subject remain scanty. The management of opportunistic parasitic infections in patients infected with HIV is dogged by failures and relapses, aptly illustrating the notion of the relationship between chemotherapy and the immune response. This review discusses the immunity and chemotherapy of opportunistic parasite infections in patients infected with the Human Immunodeficiency Virus (HIV).

AIDS-Related Opportunistic Infections↗
PubMed1992

The activity of hydroxynaphthoquinones against Leishmania donovani.

The hydroxynaphthoquinones, buparvaquone, 250C80 and 56W82, showed high activity in vitro against Leishmania donovani amastigotes in mouse peritoneal macrophages, with ED50 values of 0.05, 2.95 and 13.82 microM, respectively. Fourteen other hydroxynaphthoquinones were tested, of which only 566C80 and 608C86 showed significant activity against amastigotes. Buparvaquone, 250C80 and 56W82 were also highly-active against cultured promastigotes. In a BALB/c mouse model, treatment with 100 mg/kg/day for five days with buparvaquone, 250C80 and 566C80 (atovaquone) reduced liver amastigote numbers by 60%, 22% and 30.5%, respectively.

Animals↗
PubMed1992

The activity of platinum, iridium and rhodium drug complexes against Leishmania donovani.

The activities of twenty seven Platinum, Rhodium and Iridium drug complexes were determined against Leishmania donovani amastigotes in mouse peritoneal macrophages in vitro. Eight compounds showed antileishmanial activity of which only three, Rh(III)-mepacrine, Ir(III) pyrrolidine dithiocarbamate and Ir(III) diethyl dithiocarbamate had ED50 values of less than 1 microM. The two Iridium complexes produced, respectively, a 50% and 39% suppression of L. donovani amastigotes in the liver of BALB/c mice following the subcutaneous administration of 200 mg/kg for 5 consecutive days. Ultrastructural studies suggest that the amastigote kinetoplast-mitochondrion complex is the primary site of action of the Ir and Rh complexes.

Animals↗
PubMed1991

Liposomal amphotericin B in drug-resistant visceral leishmaniasis.

The treatment of visceral leishmaniasis (VL) may be complicated by drug toxicity or intolerance, and by drug resistance. Amphotericin B (AmB) is effective, but its use is limited by toxicity: renal impairment, anaemia, fever, malaise, and hypokalaemia are common. Liposomes have been proposed as an effective way to target drugs at macrophages, which are the cells infected in visceral leishmaniasis. In animals AmB incorporated into liposomes is highly effective against experimental leishmaniasis, with low toxicity. This report is of the successful treatment of a patient with multiply drug-resistant visceral leishmaniasis with a commercially prepared formulation of liposomal amphotericin B (L-AmB) ('AmBisome', Vestar, San Dimas, California, USA). We also report, for comparison, a patient treated with conventional AmB, and preliminary studies in mice comparing the two agents.

Amphotericin B↗
PubMed1991

Liposomal amphotericin B in the treatment of visceral leishmaniasis.

A case of visceral leishmaniasis unresponsive to several course of treatment with standard drugs, was successfully cured by a 21 day course (50 mg/day) of liposomal amphotericin B (AmBisome, Vestar Inc.). The efficacy of the AmBisome formulation is supported by experimental studies on Leishmania donovani infected BALB/c mice where ED50 values of AmBisome and conventional amphotericin B were 0.15-0.25 and 0.95-4.9 mg/kg, respectively. A lack of toxicity of the AmBisome formulation was noted in both studies.

Adult↗
PubMed1991

Transmission and scanning EM-immunogold labeling of Leishmania major lipophosphoglycan in the sandfly Phlebotomus papatasi.

Previous studies using immunostaining and light microscopy demonstrated expression of Leishmania major lipophosphoglycan (LPG) on parasites developing in the sandfly gut from 2 days post infection. By days 4 to 7 post infection, there appeared to be large amounts of parasite-free LPG deposited on/in the microvilli and epithelial cells lining the thoracic midgut, while forward migration of parasites and the morphological changes which accompany metacyclogenesis were associated with developmental modification of the LPG molecules. Studies presented here examine this process with much greater precision using electron microscopy and immunogold labeling techniques to study the different developmental forms (nectomonads, haptomonads, paramastigotes, and metacyclics) of promastigotes in the sandfly gut. Results obtained using LPG-specific monoclonal antibodies (WIC79.3, 45D3 and the metacyclic-specific 3F12) show (1) gold labeling over the cell surface, within the flagellar pocket, and extending along the entire length of the flagellum of electron-dense nectomonads observed in the abdominal and thoracic midgut regions on days 4 and 7 post infection, and of electron-lucid haptomonads in the foregut, (2) dense labeling around the flagellar tips, by which nectomonad forms bind to the midgut microvilli, but not on the microvilli themselves or within the epithelial cells lining the midgut, (3) significant metacyclic-specific (3F12) labeling on nectomonad forms in the lumen of the midgut and attached to the microvilli, and (4) dense labeling on the cell surface of electron-lucid paramastigotes in the esophagus and in the filamentous matrix surrounding paramastigote and metacyclic forms in the esophagus and pharynx. These results are discussed in the light of the proposed roles for LPG in parasite attachment to, and survival in, the sandfly gut.

Animals↗
PubMed1989

Hydrazide antidepressants possess novel antileishmanial activity in vitro and in vivo.

The hydrazide monoamine oxidase inhibitor antidepressants possess a novel antiparasitic action against visceral and cutaneous strains of Leishmania. In vitro, phenelzine was the most active compound tested, while in vivo, nialamide was more potent, and was also effective when applied topically to cutaneous lesions. Despite the coincidence of tricyclic antidepressants also possessing antileishmanial activity, the evidence suggests that the antiparasitic action of the hydrazides is unrelated to either monoamine oxidase inhibition or CNS effects.

Animals↗