amphotericin-b and Malaria

The use of liposomes as drug carriers in treatment of various diseases has been explored extensively for more than 20 years. 'Conventional' liposomes, when administered in vivo by a variety of routes, rapidly accumulate in the mononuclear phagocyte system (MPS). The inherent tendency of the liposomes to concentrate in MPS can be exploited in enhancing the non-specific host defence against infections by entrapping in them the macrophage modulators, and as carriers of antibiotics in treatment of intracellular infections that reside in MPS. This must further be enhanced by grafting on the liposome surface the ligands, e.g. tuftsin, that not only binds specifically to the MPS cells but also enhances their natural killer activity. Keeping this in view, we designed and developed tuftsin-bearing liposomes as drug carriers for the treatment of macrophage-based infections and outline these studies in this overview.

Topics: Amphotericin B; Animals; Drug Carriers; Drug Delivery Systems; Humans; Leishmaniasis; Liposomes; Macrophages; Malaria; Mycoses; Tuberculosis; Tuftsin

Attachment of antibodies to the surface of liposomes was performed to confer specificity for a certain cell or organ expressing the targeted antigenic determinant. These so-called immunoliposomes are expected to be applied as targeted drug carriers. In this article, the literature concerning in vivo studies of the targeting of immunoliposomes to various sites in the body is reviewed. The anatomical, physiological, and pathological constraints and current progress are described. Moreover, perspectives on the therapeutic feasibility of this drug targeting system are discussed.

Topics: Amphotericin B; Animals; Antibodies, Monoclonal; Antineoplastic Agents; Biological Availability; Candidiasis; Chloroquine; Clinical Trials as Topic; Drug Carriers; Drug Compounding; Drug Evaluation, Preclinical; Humans; Immunoconjugates; Injections, Intravenous; Liposomes; Lung; Lymph Nodes; Malaria; Mice; Neoplasms; Peritoneal Cavity; Plasmodium berghei; Rats; Tissue Distribution

Topics: Amphotericin B; Anthelmintics; Bithionol; Cestode Infections; Chloroquine; Humans; Intestinal Diseases, Parasitic; Leishmaniasis; Malaria; Metronidazole; Nematode Infections; Quinacrine; Tetracycline; Thiabendazole

A preliminary in vitro screening of compounds belonging to various chemical families from our library revealed the thieno[3,2-d]pyrimidin-4(3H)-one scaffold displayed a promising profile against Plasmodium falciparum. Then, 120 new derivatives were synthesized and evaluated in vitro; compared to drug references, 40 showed good activity toward chloroquine sensitive (IC50 35-344 nM) and resistant (IC50 45-800 nM) P. falciparum strains. They were neither cytotoxic (CC50 15-50 μM) toward HepG2 and CHO cells, nor mutagenic. Structure-activity relationships were defined. The lead-compound also appeared active against the Plasmodium liver stages (Plasmodium yoelii IC50 = 35 nM) and a preliminary in vivo evaluation indicated the in vitro activity was preserved (45% reduction in parasitemia compared to untreated infected mice). A mechanistic study demonstrated these molecules do not involve any of the pathways described for commercial drugs and exert a specific activity on the ring and trophozoite stages.

Topics: Animals; Antimalarials; Cell Proliferation; CHO Cells; Cricetinae; Cricetulus; Drug Discovery; Erythrocytes; Hep G2 Cells; Humans; Liver; Malaria; Male; Mice; Parasitemia; Plasmodium falciparum; Pyrimidines; Structure-Activity Relationship; Trophozoites

New antimalarial agents that exhibit multistage activities against drug-resistant strains of malaria parasites represent good starting points for developing next-generation antimalarial therapies. To facilitate the progression of such agents into the development phase, we developed an image-based parasitological screening method for defining drug effects on different asexual life cycle stages of Plasmodium falciparum. High-throughput screening of a newly assembled diversity-oriented synthetic library using this approach led to the identification of carbohybrid-based 2-aminopyrimidine compounds with fast-acting growth inhibitory activities against three laboratory strains of multidrug-resistant P. falciparum. Our structure-activity relationship study led to the identification of two derivatives (8aA and 11aA) as the most promising antimalarial candidates (mean EC50 of 0.130 and 0.096 μM against all three P. falciparum strains, selectivity indices >600, microsomal stabilities >80%, and mouse malaria ED50 values of 0.32 and 0.12 mg/kg/day, respectively), targeting all major blood stages of multidrug-resistant P. falciparum parasites.

Topics: Animals; Antimalarials; Area Under Curve; Cell Line, Tumor; Cell Survival; Drug Discovery; Drug Evaluation, Preclinical; Hep G2 Cells; Host-Parasite Interactions; Humans; Life Cycle Stages; Malaria; Male; Metabolic Clearance Rate; Mice; Mice, Inbred BALB C; Models, Chemical; Molecular Structure; Plasmodium chabaudi; Plasmodium falciparum; Pyrimidines; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship

Treatment of diseases such as African sleeping sickness and leishmaniasis often depends on relatively expensive or toxic drugs, and resistance to current chemotherapeutics is an issue in treating these diseases and malaria. In this study, a new semi-synthetic berberine analogue, 5,6-didehydro-8,8-diethyl-13-oxodihydroberberine chloride (1), showed nanomolar level potency against in vitro models of leishmaniasis, malaria, and trypanosomiasis as well as activity in an in vivo visceral leishmaniasis model. Since the synthetic starting material, berberine hemisulfate, is inexpensive, 8,8-dialkyl-substituted analogues of berberine may lead to a new class of affordable antiprotozoal compounds.

Topics: Animals; Antiprotozoal Agents; Berberine; Chlorocebus aethiops; Disease Models, Animal; Inhibitory Concentration 50; Leishmania; Leishmaniasis; Malaria; Mice; Models, Molecular; Parasites; Plasmodium falciparum; Protozoan Infections; Trypanosoma brucei brucei; Trypanosomiasis; Vero Cells

Histone deacetylase inhibitors (HDACi) are endowed with plethora of biological functions including anti-proliferative, anti-inflammatory, anti-parasitic, and cognition-enhancing activities. Parsing the structure-activity relationship (SAR) for each disease condition is vital for long-term therapeutic applications of HDACi. We report in the present study specific cap group substitution patterns and spacer-group chain lengths that enhance the antimalarial and antileishmanial activity of aryltriazolylhydroxamates-based HDACi. We identified many compounds that are several folds selectively cytotoxic to the plasmodium parasites compared to standard HDACi. Also, a few of these compounds have antileishmanial activity that rivals that of miltefosine, the only currently available oral agent against visceral leishmaniasis. The anti-parasite properties of several of these compounds tracked well with their anti-HDAC activities. The results presented here provide further evidence on the suitability of HDAC inhibition as a viable therapeutic option to curb infections caused by apicomplexan protozoans and trypanosomatids.

Topics: Antimalarials; Antiprotozoal Agents; Histone Deacetylase Inhibitors; Histone Deacetylases; Leishmania donovani; Leishmaniasis; Malaria; Plasmodium falciparum; Structure-Activity Relationship; Triazoles

Premature death of Plasmodium-infected erythrocytes is considered to favourably influence the clinical course of malaria. Amphotericin B has previously been shown to trigger suicidal erythrocyte death or eryptosis, which is characterized by cell membrane scrambling leading to phosphatidylserine exposure at the cell surface. Phosphatidylserine-exposing cells are rapidly cleared from circulating blood. The present study thus tested whether amphotericin B exerts a direct effect on Plasmodium falciparum and influences eryptosis of infected erythrocytes, parasitemia and host survival in murine malaria. To this end, human erythrocytes were infected in vitro with Plasmodium falciparum and mice were infected with Plasmodium berghei ANKA by in vivo intraperitoneal injection of parasitized murine erythrocytes (1x10(6)). Half of the infected mice received amphotericin B (1.5 mg/kg b.w. i.v.) from the 8(th) day of infection. Amphotericin B (> or = 1 microM) compromised the intracellular development of the parasite in human erythrocytes as evident from in vitro growth and DNA amplification assays. Amphotericin B further augmented the eryptosis of infected human erythrocytes. The administration of amphotericin B to infected mice tended to delay the increase of parasitemia and significantly delayed host death. All nontreated mice died from malaria within 27 days. In contrast, some 50% of amphotericin B-treated mice survived for more than 27 days after infection. In conclusion, amphotericin B augmented the suicidal death of infected erythrocytes and delayed the lethal course of malaria in Plasmodium berghei infected mice.

Topics: Amphotericin B; Animals; Antiprotozoal Agents; Apoptosis; Erythrocytes; Humans; Malaria; Mice; Parasitemia; Plasmodium berghei

Topics: Adult; Amphotericin B; Ancylostomiasis; Humans; Infusions, Parenteral; Leishmaniasis; Leishmaniasis, Mucocutaneous; Malaria; Male; Middle Aged; Plasmodium falciparum

We have previously reported the antimalarial activity of imidazoles and amphotericin B against chloroquine-resistant Plasmodium falciparum. We now report the enhancement of imidazole activity in an atmosphere with 17-18% oxygen (the candle jar) vs. 3% or 0.3% oxygen. Based on both morphologic and radiometric testing, smaller amounts of the imidazoles were required to inhibit parasite growth by 50% in the candle jar vs. 3% or 0.3% oxygen. The use of older (more oxidant-sensitive) red cells also enhanced the antimalarial activity of ketoconazole. Neither increased concentrations of oxygen nor the use of older red cells affected the activity of amphotericin B. These results suggest that the imidazoles may exert their antimalarial effect by increasing the oxidant stress on the red cell-parasite complex.

Topics: Amphotericin B; Drug Synergism; Imidazoles; Malaria; Oxygen; Plasmodium falciparum