The Treatment of Acute Malaria with Single Oral Doses of Amodiaquin, Chloroquine, Hydroxychloroquine and Pyrimethamine 1

Hoekenga, Mark T.

doi:10.4269/ajtmh.1954.3.833

Cited by 20 publications

(10 citation statements)

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“…The pH gradient of the lysosome is actively driven by a V-Type ATPase H + pump [ 18 ], and its inhibition with concanamycin A (CMA) prevented dye retention in the lysosome. As well, hydroxychloroquine (HCQ), originally used for treatment of malaria [ 19 ] and extensively studied as a lysosomotropic detergent [ 20 ] showed decreased dye retention (positive control) (Additional file 3 figure S3A). SV119 and PB28, with high affinity to sigma-2 receptors, displayed leakeage of lysosomal dyes by acridine orange,and leakage by all compounds was confirmed with LysoTracker Green (Additional file 3 figure S3B).…”

Section: Resultsmentioning

confidence: 99%

Lysosomal Membrane Permeabilization is an Early Event in Sigma-2 Receptor Ligand Mediated Cell Death in Pancreatic Cancer

Hornick

Vangveravong

Spitzer

et al. 2012

J Exp Clin Cancer Res

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BackgroundSigma-2 receptor ligands have been studied for treatment of pancreatic cancer because they are preferentially internalized by proliferating cells and induce apoptosis. This mechanism of apoptosis is poorly understood, with varying reports of caspase-3 dependence. We evaluated multiple sigma-2 receptor ligands in this study, each shown to decrease tumor burden in preclinical models of human pancreatic cancer.ResultsFluorescently labeled sigma-2 receptor ligands of two classes (derivatives of SW43 and PB282) localize to cell membrane components in Bxpc3 and Aspc1 pancreatic cancer cells and accumulate in lysosomes. We found that interactions in the lysosome are critical for cell death following sigma-2 ligand treatment because selective inhibition of a protective lysosomal membrane glycoprotein, LAMP1, with shRNA greatly reduced the viability of cells following treatment. Sigma-2 ligands induced lysosomal membrane permeabilization (LMP) and protease translocation triggering downstream effectors of apoptosis. Subsequently, cellular oxidative stress was greatly increased following treatment with SW43, and the hydrophilic antioxidant N-acetylcysteine (NAC) gave greater protection against this than a lipophilic antioxidant, α-tocopherol (α-toco). Conversely, PB282-mediated cytotoxicity relied less on cellular oxidation, even though α-toco did provide protection from this ligand. In addition, we found that caspase-3 induction was not as significantly inhibited by cathepsin inhibitors as by antioxidants. Both NAC and α-toco protected against caspase-3 induction following PB282 treatment, while only NAC offered protection following SW43 treatment. The caspase-3 inhibitor DEVD-FMK offered significant protection from PB282, but not SW43.ConclusionsSigma-2 ligand SW43 commits pancreatic cancer cells to death by a caspase-independent process involving LMP and oxidative stress which is protected from by NAC. PB282 however undergoes a caspase-dependent death following LMP protected by DEVD-FMK and α-toco, which is also known to stabilize the mitochondrial membrane during apoptotic stimuli. These differences in mechanism are likely dependent on the structural class of the compounds versus the inherent sigma-2 binding affinity. As resistance of pancreatic cancers to specific apoptotic stimuli from chemotherapy is better appreciated, and patient-tailored treatments become more available, ligands with high sigma-2 receptor affinity should be chosen based on sensitivities to apoptotic pathways.

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Section: Resultsmentioning

confidence: 99%

Lysosomal Membrane Permeabilization is an Early Event in Sigma-2 Receptor Ligand Mediated Cell Death in Pancreatic Cancer

Hornick

Vangveravong

Spitzer

et al. 2012

J Exp Clin Cancer Res

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“…These compounds served as an excellent internal validation of our screening assay, as we were blinded to the identities of the compounds. The known antimalarial therapeutics we identified were all active at 100 n m and included: quinine (13), quinidine and hydroquinidine (14), chloroquine and hydroxychloroquine (15), amodiaquine (16), cinchonine (17), cinchonidine (18), mefloquine (19), atovaquone (20), pyrimethamine (15), dihydroartemisinin (21), and quinacrine (22). Six more members of the MicroSource Collection inhibited P. falciparum growth at a concentration of 100 n m .…”

Section: Resultsmentioning

confidence: 99%

Searching for New Antimalarial Therapeutics amongst Known Drugs

et al. 2006

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The need to discover and develop new antimalarial therapeutics is severe. The annual mortality attributed to malaria, currently approximately 2.5 million, is increasing due primarily to widespread resistance to currently used drugs. One strategy to identify new treatment alternatives for malaria is to examine libraries of diverse compounds for the possible identification of novel scaffolds. Beginning with libraries of drug or drug-like compounds is an ideal starting point because, in the case of approved drugs, substantial pharmacokinetic and toxicologic data should be available for each compound series. We have employed a high throughput screen of the MicroSource Spectrum and Killer collections, a library of known drugs, bioactive compounds, and natural products. Our screening assay identifies compounds that inhibit growth of Plasmodium falciparum cultured in human erythrocytes. We have identified 36 novel inhibitors of P. falciparum, of which 19 are therapeutics, and five of these drugs exhibit effective 50% inhibitory concentrations within similar ranges to therapeutic serum concentrations for their currently indicated uses: propafenone, thioridazine, chlorprothixene, perhexiline and azlocillin. The findings we report here indicate that this is an effective strategy to identify novel scaffolds and therefore aid in antimalarial drug discovery efforts.

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“…There have been several reports, most recently reference, 45 on the efficacy of this drug for treating pregnant women with SLE and regarding the apparent absence of fetal toxicity. The more than half century of experience with this drug for treating malaria 46 and SLE; 47 its established profile with respect to adverse effects, toxicities, and drug interactions; and the absence of hemorrhagic risks are some of the factors that would favor its being evaluated for treatment of APS in prospective randomized clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Hydroxychloroquine protects the annexin A5 anticoagulant shield from disruption by antiphospholipid antibodies: evidence for a novel effect for an old antimalarial drug

Rand

Quinn

et al. 2010

Blood

231

141

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Annexin A5 (AnxA5) is a potent anticoagulant protein that crystallizes over phospholipid bilayers (PLBs), blocking their availability for coagulation reactions. Antiphospholipid antibodies disrupt AnxA5 binding, thereby accelerating coagulation reactions. This disruption may contribute to thrombosis and miscarriages in the antiphospholipid syndrome (APS). We investigated whether the antimalarial drug, hydroxychloroquine (HCQ), might affect this prothrombotic mechanism. Binding of AnxA5 to PLBs was measured with labeled AnxA5 and also imaged with atomic force microscopy. Immunoglobulin G levels, AnxA5, and plasma coagulation times were measured on cultured human umbilical vein endothelial cells and a syncytialized trophoblast cell line. AnxA5 anticoagulant activities of APS patient plasmas were also determined. HCQ reversed the effect of antiphospholipid antibodies on AnxA5 and restored AnxA5 binding to PLBs, an effect corroborated by atomic force microscopy. Similar reversals of antiphospholipid-induced abnormalities were measured on the surfaces of human umbilical vein endothelial cells and syncytialized trophoblast cell lines, wherein HCQ reduced the binding of antiphospholipid antibodies, increased cell-surface AnxA5 concentrations, and prolonged plasma coagulation to control levels. In addition, HCQ increased the AnxA5 anticoagulant activities of APS patient plasmas. In conclusion, HCQ reversed antiphospholipid-mediated disruptions of AnxA5 on PLBs and cultured cells, and in APS patient plasmas. These results support the concept of novel therapeutic approaches that address specific APS disease mechanisms.

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The Treatment of Acute Malaria with Single Oral Doses of Amodiaquin, Chloroquine, Hydroxychloroquine and Pyrimethamine 1

Cited by 20 publications

References 0 publications

Lysosomal Membrane Permeabilization is an Early Event in Sigma-2 Receptor Ligand Mediated Cell Death in Pancreatic Cancer

Lysosomal Membrane Permeabilization is an Early Event in Sigma-2 Receptor Ligand Mediated Cell Death in Pancreatic Cancer

Searching for New Antimalarial Therapeutics amongst Known Drugs

Hydroxychloroquine protects the annexin A5 anticoagulant shield from disruption by antiphospholipid antibodies: evidence for a novel effect for an old antimalarial drug

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