amphotericin-b and 8-aminoquinoline

The control of Leishmania infection relies primarily on chemotherapy till date. Resistance to pentavalent antimonials, which have been the recommended drugs to treat cutaneous and visceral leishmaniasis, is now widespread in Indian subcontinents. New drug formulations like amphotericin B, its lipid formulations, and miltefosine have shown great efficacy to treat leishmaniasis but their high cost and therapeutic complications limit their usefulness. In addition, irregular and inappropriate uses of these second line drugs in endemic regions like state of Bihar, India threaten resistance development in the parasite. In context to the limited drug options and unavailability of either preventive or prophylactic candidates, there is a pressing need to develop true antileishmanial drugs to reduce the disease burden of this debilitating endemic disease. Notwithstanding significant progress of leishmanial research during last few decades, identification and characterization of novel drugs and drug targets are far from satisfactory. This review will initially describe current drug regimens and later will provide an overview on few important biochemical and enzymatic machineries that could be utilized as putative drug targets for generation of true antileishmanial drugs.

Topics: Aminoquinolines; Amphotericin B; Antigens, Protozoan; Antimony Sodium Gluconate; Antiprotozoal Agents; Caspase Inhibitors; Cyclin-Dependent Kinases; Drug Discovery; Enzyme Inhibitors; Folic Acid Antagonists; Humans; Leishmaniasis; Macrophages; Microbodies; Mitogen-Activated Protein Kinase Kinases; Paromomycin; Pentamidine; Phosphorylcholine; Polyamines; Protease Inhibitors; Sterols; Sulfhydryl Compounds; Topoisomerase Inhibitors

Indian visceral leishmaniasis (VL) is a parasitic disease caused by a haemoflagellete Leishmania donovani and transmitted by the bite of sand fly Phlebotomus argentipes. It affects various age groups. In India about 1,00,000 cases of VL are estimated to occur annually; of these, the State of Bihar accounts for over than 90 per cent of the cases. Diagnosis of VL typically relies on microscopic examination of tissue smears but serology and molecular methods are better alternatives currently. Notwithstanding the growing incidence of resistance, pentavalent antimony complex has been the mainstay for the treatment of VL during the last several decades. The second line drugs such as amphotericin B, lipid formulations of amphotericin B, paromomycin and recently developed miltefosine are the other alternatives. In spite of significant development in various areas of Leishmania research, there is a pressing need for the technological advancement in the understanding of immune response, drug resistance and the pathogenesis of leishmaniasis that could be translated into field applicable and affordable methods for diagnosis, treatment, and control of the disease.

Topics: Aminoquinolines; Amphotericin B; Animals; Antimony; Antiprotozoal Agents; Drug Resistance; Enzyme-Linked Immunosorbent Assay; Humans; India; Leishmania; Leishmaniasis, Visceral; Lipids; Paromomycin; Public Health; Sensitivity and Specificity

This randomized, open-label study of patients in India with visceral leishmaniasis (VL) investigated the effect of food on sitamaquine and desethyl-sitamaquine pharmacokinetics. Patients were randomized to receive oral sitamaquine, 2 mg/kg/day, once a day for 21 days across four cohorts (n = 41) (fasted/fed, fed/fasted, fed/fed, and fasted/fasted) over two periods (days 1-10 and 11-21), or intravenous amphotericin B (AmB), 1 mg/kg every other day for 30 days (n = 20). Mean day 21 pharmacokinetics across the four cohorts were sitamaquine, area under curve (AUC)((0-τ)) = 6,627-8,903 ng.hr/mL, AUC((0-16)) = 4,859-6,633 ng.hr/mL, maximum plasma concentration (C(max)) = 401-570 ng/mL, apparent terminal half-life (t(1/2)) = 18.3-22.8 hr, time to reach C(max) (t(max)) = 3.5-6 hr; and desethyl-sitamaquine, AUC((0-τ)) = 2,307-3,163 ng.hr/mL, C(max) = 109-154 ng/mL, t(1/2) = 23.0-27.9 hr, t(max) = 2-10 hr, with no significant food effect. On-therapy adverse events were observed for sitamaquine in 4 (10%) of 41 patients and for AmB in 17 (85%) of 20 patients. The final clinical cure (day 180) was 85% (95% confidence interval = 70.8-94.4%) for sitamaquine and 95% (95% confidence interval = 75.1-99.9) for AmB. Sitamaquine can be taken regardless of food intake, was generally well tolerated, and showed potential efficacy in patients with visceral leishmaniasis.

Topics: Administration, Oral; Adolescent; Adult; Aminoquinolines; Amphotericin B; Antiprotozoal Agents; Area Under Curve; Cohort Studies; Cross-Over Studies; Fasting; Female; Food; Food-Drug Interactions; Half-Life; Humans; India; Leishmaniasis, Visceral; Male; Middle Aged; Prospective Studies; Young Adult

Leishmaniasis is a neglected disease that affects poorest population mainly in developing countries, representing one of the major causes of mortality and morbidity. Therefore, efforts to find new chemotherapeutics for leishmaniasis remain a priority. Previous reports demonstrated the in vitro and in vivo antileishmanial activity of nitazoxanide, an antiprotozoan agent used in the treatment of infectious diarrhea. The present work was carried out to determine the effect of nitazoxanide in combination with current antileishmanial drugs. Mouse peritoneal macrophages were infected with Leishmania (Leishmania) infantum amastigotes in order to calculate the 50% and 90% inhibitory concentration values. Drug interactions were assessed with fixed ratio isobologram method and fractional inhibitory concentrations (FIC50 and FIC90); sum of FIC (ΣFIC50 and ΣFIC90) and overall mean ΣFIC (xΣFIC50 and xΣFIC90) were calculated for each combination. The nature of interactions was classified according to the xΣFIC50 and xΣFIC90. The combination between nitazoxanide and amphotericin B, Glucantime(®), miltefosine and sitamaquine showed xΣFIC50 values of 1.13, 0.83, 1.06 and 0.94, respectively, indicating additive interaction. Considering the in vitro activity of nitazoxanide and the obtained results, further in vivo studies may be considered to evaluate possible drug interactions in visceral leishmaniasis.

Topics: Aminoquinolines; Amphotericin B; Animals; Antiprotozoal Agents; Drug Combinations; Leishmania infantum; Leishmaniasis, Visceral; Macrophages, Peritoneal; Meglumine; Meglumine Antimoniate; Mice; Nitro Compounds; Organometallic Compounds; Parasitic Sensitivity Tests; Phosphorylcholine; Thiazoles

Three new series of 8-aminoquinolines with modifications in the side-chain by conjugation with amino acids, dipeptides and pseudodipeptides have been synthesized. The synthesized compounds were tested for in vitro antimalarial activity against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains, in vitro cytotoxicity in mammalian kidney cells (Vero), in vitro antileishmanial activity against Leishmania donovani, in vitro antimicrobial activity and in vitro inhibition of β-haematin formation. The promising compounds were also evaluated for in vivo blood-schizontocidal antimalarial activity against Plasmodium berghei infected mice. The analogues 55 and 101 produced highest antimalarial activities, in vitro. Analogues 52 and 59 exhibited promising antileishmanial and broad spectrum of antifungal activities, respectively.

Topics: Amino Acids; Aminoquinolines; Animals; Anti-Infective Agents; Chemistry Techniques, Synthetic; Chlorocebus aethiops; Dipeptides; Fungi; Hemeproteins; Leishmania donovani; Mice; Peptidomimetics; Plasmodium falciparum; Vero Cells

We report the synthesis, in vitro antiprotozoal (against Plasmodium and Leishmania), antimicrobial, cytotoxicity (Vero and MetHb-producing properties), and in vivo antimalarial activities of two series of 8-quinolinamines. N1-{4-[2-(tert-Butyl)-6-methoxy-8-quinolylamino]pentyl}-(2S/2R)-2-aminosubstitutedamides (21-33) and N1-[4-(4-ethyl-6-methoxy-5-pentyloxy-8-quinolylamino)pentyl]-(2S/2R)-2-aminosubstitutedamides (51-63) were synthesized in six steps from 6-methoxy-8-nitroquinoline and 4-methoxy-2-nitro-5-pentyloxyaniline, respectively. Several analogs displayed promising antimalarial activity in vitro against Plasmodium falciparum D6 (chloroquine-sensitive) and W2 (chloroquine-resistant) clones with high selectivity indices versus mammalian cells. The most promising analogs (21-24) also displayed potent antimalarial activity in vivo in a Plasmodium berghei-infected mouse model. Most interestingly, many analogs exhibited promising in vitro antileishmanial activity against Leishmania donovani promastigotes, and antimicrobial activities against a panel of pathogenic bacteria and fungi. Several analogs, notably 21-24, 26-32, and 60, showed less MetHb formation compared to primaquine indicating the potential of these compounds in 8-quinolinamine-based antimalarial drug development.

Topics: Aminoquinolines; Animals; Anti-Bacterial Agents; Antifungal Agents; Antimalarials; Antineoplastic Agents; Antiparasitic Agents; Bacteria; Chlorocebus aethiops; Erythrocytes; Fungi; Humans; Indicators and Reagents; L-Lactate Dehydrogenase; Leishmania donovani; Magnetic Resonance Spectroscopy; Methemoglobin; Methicillin Resistance; Mice; Microbial Sensitivity Tests; Plasmodium berghei; Plasmodium falciparum; Structure-Activity Relationship; Vero Cells

Topics: Aminoquinolines; Amphotericin B; Antiprotozoal Agents; Humans; Leishmaniasis, Visceral; Paromomycin

Throughout the world, pentavalent antimonial compounds (Sb(v)) have been the mainstay of antileishmanial therapy for more than 50 years. Sb(v) has been highly effective in the treatment of Indian visceral leishmaniasis (VL: kala-azar) at a low dose (10 mg/kg) for short durations (6-10 days). But in the early 1980s reports of its ineffectiveness emerged, and the dose of Sb(v) was eventually raised to 20 mg/kg for 30-40 days. This regimen cures most patients with VL except in India, where the proportion of patients unresponsive to Sb(v) has steadily increased. In hyperendemic districts of north Bihar, 50-65% patients fail treatment with Sb(v). Important reasons are rampant use of subtherapeutic doses, incomplete duration of treatment and substandard drugs. In vitro experiments have established emergence of Sb(v) resistant strains of Leishmania donovani, as isolates from unresponsive patients require 3-5 times more Sb(v) to reach similarly effectiveness against the parasite as in Sb(v) responders. Anthroponotic transmission in India has been an important factor in rapid increase in the Sb(v) refractoriness. Pentamidine was the first drug to be used and cured 99% of these refractory patients, but over time even with double the amount of initial doses, it cures only 69-78% patients now and its use has largely been abandoned in India. Despite several disadvantages, amphotericin B is the only drug available for use in these areas and should be used as first-line drug instead of Sb(v). The new oral antileishmanial drug miltefosine is likely to be the first-line drug in future. Unfortunately, development of newer antileishmanial drugs is rare; two promising drugs, aminosidine and sitamaquine, may be developed for use in the treatment of VL. Lipid associated amphotericin B has an excellent safety and efficacy profile, but remains out of reach for most patients because of its high cost.

Topics: Aminoquinolines; Amphotericin B; Antimony; Antiprotozoal Agents; Dose-Response Relationship, Drug; Drug Resistance; Geography; History, 20th Century; History, 21st Century; Humans; India; Leishmaniasis, Visceral; Paromomycin; Pentamidine; Phosphorylcholine; Treatment Outcome

We have compared the in vitro activity of six agents against macrophage-contained Leishmania tropica amastigotes determined by the conventional Giemsa staining procedure, with the activity determined by the semiautomated assessment of incorporation of radiolabeled uracil into the nucleic acid of the organisms. Although the mean 50% effective dose of Pentostam by Giemsa staining (4.1 micrograms/ml) was somewhat higher than that by uracil incorporation (2.8 micrograms/ml), the ED50S for the other two clinical agents (pentamidine, 0.035 versus 0.037 micrograms/ml; amphotericin B, 0.67 versus 0.70 micrograms/ml) and for three promising experimental agents (ketoconazole, 11.3 versus 11.3 micrograms/ml; the 8-aminoquinoline WR 6026, 1.6 versus 1.5 micrograms/ml formycin B, 0.018 versus 0.017 micrograms/ml) were virtually identical. The radiolabeling technique has several advantages over the Giemsa staining procedure. These include the need for relatively few macrophages, rapid and objective data generation, and viability of the test organism being measured. The successful application of the radiolabeling technique to at least six different chemical classes of compounds suggests that it would be useful for the routine assessment of antileishmanial activity in vitro.

Topics: Aminoquinolines; Amphotericin B; Antimony Sodium Gluconate; Antiprotozoal Agents; Automation; Azure Stains; Drug Evaluation, Preclinical; Formycins; Humans; In Vitro Techniques; Ketoconazole; Leishmania tropica; Macrophages; Pentamidine; Tritium; Uracil

The mechanism of action of antileishmanial compounds is poorly understood. Ultrastructural changes in Leishmania tropica within human macrophages exposed in vitro to Pentostam, pentamidine, amphotericin B, WR 6026, ketoconazole, and Formycin B were examined in these experiments. In Pentostam-treated cultures, some organisms exhibited diminished definition of mitochondrial and other membranes, while other organisms had completely disintegrated. Pentostam-exposed macrophages demonstrated loss of membrane definition in the absence of further alterations; it is therefore hypothesized that impaired macrophage membrane function may contribute towards the effect of this drug against macrophage-contained organisms. Leishmania parasites in pentamidine-treated cultures initially demonstrated swollen kinetoplasts and fragmentation of the kinetoplast DNA core. The initial observed effect of the other four drugs on the parasites was cytoplasmic condensation. These ultrastructural studies suggest that all five non-antimonial drugs may have different mechanisms of action than antimony (Pentostam) against Leishmania.

Topics: Aminoquinolines; Amphotericin B; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Cell Membrane; Formycins; Humans; Intracellular Membranes; Ketoconazole; Leishmania; Macrophages; Organoids; Pentamidine