amphotericin-b and Parasitemia

Human trypansomiasis due to infection by animal trypanosomes is rarely reported from India.. We describe clinical presentation of a 2-month-old boyfrom a rat infested house in rural Gujarat who was diagnosed to be havinginfection with the rodent parasite Trypanosoma lewisi.. The fever and parasitemia resolved on treatment with liposomal amphotericin B, Ceftriaxone and Amikacin, and there was no recurrence of parasitemia over a 2 month follow-up.. The case highlights the need for increased awareness and heightened surveillance for this rare zoonotic infection.

Topics: Amphotericin B; Animals; Antiprotozoal Agents; Fever of Unknown Origin; Humans; India; Infant; Parasitemia; Rats; Trypanosoma lewisi; Trypanosomiasis; Zoonoses

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

Babesia gibsoni is a causative pathogen of canine babesiosis, which is commonly treated with anti-babesial drugs; however, the development of novel, more effective anti-babesial drugs is necessary because the currently used drugs cannot remove the parasites from dogs. Therefore we investigated the anti-babesial effect of amphotericin B (AmB), a membrane-active polyene macrolide antibiotic. The interaction of such compounds with sterols in bilayer cell membranes can lead to cell damage and ultimately cell lysis. AmB exhibits in vitro activity against B. gibsoni in normal canine erythrocytes within 12h. We also studied liposomal AmB (L-AmB), a liposomal formulation of AmB that required a longer incubation period to reduce the number of parasites. However, L-AmB completely inhibited the invasion of free parasites into erythrocytes. These results indicated that free parasites failed to invade erythrocytes in the presence of L-AmB. Both AmB and L-AmB induced mild hemolysis of erythrocytes. Moreover, the methemoglobin level and the turbidity index of erythrocytes were significantly increased when erythrocytes were incubated with AmB, suggesting that AmB induced oxidative damage in erythrocytes. Finally, the anti-babesial activity of AmB in vivo was observed. When experimentally B. gibsoni-infected dogs were administered 0.5 and 1mg/kg AmB by the intravenous route, the number of parasites decreased; however, recurrence of parasitemia was observed, indicating that AmB did not eliminate parasites completely. Blood urea nitrogen and creatinine of dogs were abnormally elevated after the administration of 1mg/kg AmB. These results indicate that AmB has in vivo activity against B. gibsoni; however, it does not eliminate parasites from infected dogs and affects kidney function at a high dose.

Topics: Amphotericin B; Animals; Anti-Bacterial Agents; Babesia; Babesiosis; Dog Diseases; Dogs; Erythrocytes; Female; Male; Parasitemia

The present work aimed to investigate the curative effect of benznidazole (BZL) in combination with other patented drugs [nifurtimox (NFX), posaconazole (POS) or AmBisome(®) (AMB)] in mice acutely or chronically infected with either a BZL-susceptible (Tulahuen) or a BZL-partially-resistant (Y) strain of Trypanosoma cruzi. To appreciate the eventual advantage of such combinations, infected mice were treated for short durations (non-curative) of each individual treatment. Cure rates were determined by investigating blood parasites (microscopic examination) and parasite DNA (quantitative PCR) after submitting treated mice to immune suppression with cyclophosphamide. The results mainly suggest that shorter durations of treatment combining BZL and POS or NFX might cure mice acutely or chronically infected with the Tulahuen strain, whereas the combination of BZL with AMB does not have such an effect. Moreover, the association BZL+POS does not improve the curative effect of POS (all used for shorter durations) in infection with the Y strain. Shortening the duration of treatment whilst keeping a complete curative effect deserves interest in limiting adverse reactions due to dose-cumulative toxic effects of long treatment. Genotyping of the T. cruzi strain(s) infecting patients might also allow a better adaptation of individual therapeutic schedules, improving both the efficiency and safety of trypanocidal treatment. This preliminary experimental study should encourage further investigations to find the best combination of adequate drug concentrations and timing of treatment.

Topics: Amphotericin B; Animals; Chagas Disease; Disease Models, Animal; DNA, Protozoan; Drug Therapy, Combination; Female; Mice; Mice, Inbred BALB C; Nifurtimox; Nitroimidazoles; Parasite Load; Parasitemia; Real-Time Polymerase Chain Reaction; Treatment Outcome; Triazoles; Trypanocidal Agents; Trypanosoma cruzi

Arylimidamides (AIAs) represent a new class of molecules that exhibit potent antileishmanial activity (50% inhibitory concentration [IC(50)], <1 microM) against both Leishmania donovani axenic amastigotes and intracellular Leishmania, the causative agent for human visceral leishmaniasis (VL). A systematic lead discovery program was employed to characterize in vitro and in vivo antileishmanial activities, pharmacokinetics, mutagenicities, and toxicities of two novel AIAs, DB745 and DB766. They were exceptionally active (IC(50) < or = 0.12 microM) against intracellular L. donovani, Leishmania amazonensis, and Leishmania major and did not exhibit mutagenicity in an Ames screen. DB745 and DB766, given orally, produced a dose-dependent inhibition of liver parasitemia in two efficacy models, L. donovani-infected mice and hamsters. Most notably, DB766 (100 mg/kg of body weight/day for 5 days) reduced liver parasitemia in mice and hamsters by 71% and 89%, respectively. Marked reduction of parasitemia in the spleen (79%) and bone marrow (92%) of hamsters was also observed. Furthermore, these compounds distributed to target tissues (liver and spleen) and had a moderate oral bioavailability (up to 25%), a large volume of distribution, and an elimination half-life ranging from 1 to 2 days in mice. In a repeat-dose toxicity study of mice, there was no indication of liver or kidney toxicity for DB766 from serum chemistries, although mild hepatic cell eosinophilia, hypertrophy, and fatty changes were noted. These results demonstrated that arylimidamides are a promising class of molecules that possess good antileishmanial activity and desirable pharmacokinetics and should be considered for further preclinical development as an oral treatment for VL.

Topics: Amidines; Animals; Antiprotozoal Agents; Biological Availability; Cricetinae; Disease Models, Animal; Drug Discovery; Female; Furans; Humans; In Vitro Techniques; Leishmania donovani; Leishmania major; Leishmania mexicana; Leishmaniasis, Visceral; Liver; Mesocricetus; Mice; Mice, Inbred BALB C; Microsomes, Liver; Mutagenicity Tests; Parasitemia; Parasitic Sensitivity Tests; Spleen; Tissue Distribution

The aim of the study was to describe a new evolutionary form of visceral leishmaniasis observed in immunocompromised patients.. We carried out long-term clinical and biological follow-up of 10 HIV-1/Leishmania-coinfected patients presenting numerous secondary visceral leishmaniasis episodes despite treatment, with the follow-up time ranging from 0.5 to 10 years.. Analysis of polymerase chain reaction (PCR) and blood culture results demonstrated continuous multiplication and circulation of parasites despite treatment, both during asymptomatic periods and during secondary visceral leishmaniasis episodes. This condition may be termed 'chronic' because of the presence of relapses over a period of several years and 'active' because of the continuous blood circulation of the parasite.. We wish to define 'active chronic visceral leishmaniasis' as a novel nosological entity observed in HIV-1/Leishmania-coinfected patients.

Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Chronic Disease; Follow-Up Studies; HIV-1; Humans; Immunocompromised Host; Leishmania infantum; Leishmaniasis, Visceral; Parasitemia; Polymerase Chain Reaction; Recurrence; Treatment Failure

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

Visceral leishmaniasis is a deadly parasitic disease caused by obligate intramacrophage protozoans of the Leishmania genus. The World Health Organization estimates the annual death toll to be 50,000, with 500,000 new cases each year. Without treatment, visceral leishmaniasis is inevitably fatal. For the last 70 years, the first line of defense has been pentavalent antimonials; however, increased resistance has brought amphotericin B to the forefront of treatment options. Unfortunately, the difficult route of drug administration, toxicity issues, and cost prevent amphotericin B from reaching the infected population, and mortality continues to rise. Our reformulation of amphotericin B for oral administration has resulted in a highly efficacious antileishmanial treatment that significantly reduces or eradicates liver parasitemia in a murine model of visceral leishmaniasis. This formulation has overcome amphotericin B's significant physicochemical barriers to absorption and holds promise for the development of a self-administered oral therapy for the treatment of visceral leishmaniasis.

Topics: Administration, Oral; Amphotericin B; Animals; Antiprotozoal Agents; Chemistry, Pharmaceutical; Dose-Response Relationship, Drug; Leishmaniasis, Visceral; Liver; Mice; Mice, Inbred BALB C; Parasitemia; Phosphorylcholine

Quantification of Leishmania infantum DNA in blood samples by an ultrasensitive quantitative polymerase chain reaction (QPCR) detected parasitemias in different clinical presentations. We observed a large range of parasitemias, more than 9 log values, and could determine the threshold between asymptomatic carriage and disease in the Mediterranean area (approximately one parasite/mL of blood). Based on kinetoplast DNA amplification, this assay had a sensitivity of 0.001 parasite DNA equivalents/mL and detected asymptomatic carriage of Leishmania. It detected parasite DNA in 58% of healthy subjects, while an immunoblot detected specific antibodies in only 16%. For initial diagnosis of disease, this quantitative PCR with blood samples constitutes a non-invasive alternative to bone marrow aspiration. Its main applications are monitoring of drug therapy and follow-up of immunodeficient patients for biologic confirmation of relapses.

Topics: Amphotericin B; Animals; DNA, Protozoan; Follow-Up Studies; Leishmania infantum; Leishmaniasis, Visceral; Parasitemia; Polymerase Chain Reaction; Recurrence; Reference Values; Sensitivity and Specificity

Visceral leishmaniasis (VL) is endemic in areas bordering the Mediterranean Sea (Spain, Italy, France, Greece, Morocco, Tunisia) where it is caused by Leishmania infantum and is transmitted by the bite of a hematophagous sandfly belonging to Phlebotomus spp.; the dog constitutes the main reservoir of infection. Two cases of VL in immunocompetent children are described. Both patients lived in endemic areas for leishmaniasis (Sicily) and at admission were febrile, pale and had splenomegaly. In both patients anti-leishmania antibodies were present and a definitive diagnosis was confirmed by demonstration of leishmania parasites by microscopy or polymerase chain reaction (PCR) in the bone marrow aspirates. The use of PCR performed on peripheral blood has been reported to be highly sensitive for the diagnosis and follow-up of children with VL. One patient was treated with N-dimethylglucamine, Glucantim, the other one with liposomal Amphotericin B (AmBisome). Both had symptomatic relapses 3 months later, and recovered following re-treatment with AmBisome administered intravenously at a dosage of 3 mg/Kg for ten consecutive days. The patients were monitored for one year after treatment was completed.

Topics: Amphotericin B; Antiprotozoal Agents; Bone Marrow; Female; Humans; Immunocompetence; Infant; Leishmaniasis, Visceral; Liposomes; Male; Meglumine; Meglumine Antimoniate; Organometallic Compounds; Parasitemia; Recurrence