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Article: Oxidative stress and inflammation in Parkinson's disease: is there a causal link?

Hald, Andreas / Lotharius, Julie

2005 Volume 193, Issue 2, Page(s) 279–290

Abstract: Parkinson's disease (PD) is a neurodegenerative disorder characterized by a dramatic loss of dopaminergic neurons in the substantia nigra (SN). Among the many pathogenic mechanisms thought to contribute to the demise of these cells, dopamine-dependent ... ...

Abstract	Parkinson's disease (PD) is a neurodegenerative disorder characterized by a dramatic loss of dopaminergic neurons in the substantia nigra (SN). Among the many pathogenic mechanisms thought to contribute to the demise of these cells, dopamine-dependent oxidative stress has classically taken center stage due to extensive experimental evidence showing that dopamine-derived reactive oxygen species and oxidized dopamine metabolites are toxic to nigral neurons. In recent years, however, the involvement of neuro-inflammatory processes in nigral degeneration has gained increasing attention. Not only have activated microglia and increased levels of inflammatory mediators been detected in the striatum of deceased PD patients, but a large body of animal studies points to a contributory role of inflammation in dopaminergic cell loss. Recently, postmortem examination of human subjects exposed to the parkinsonism-inducing toxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), revealed the presence of activated microglia decades after drug exposure, suggesting that even a brief pathogenic insult can induce an ongoing inflammatory response. Perhaps not surprisingly, non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce the risk of developing PD. In the past few years, various pathways have come to light that could link dopamine-dependent oxidative stress and microglial activation, finally ascribing a pathogenic trigger to the chronic inflammatory response characteristic of PD.
MeSH term(s)	Animals ; Anti-Inflammatory Agents/therapeutic use ; Disease Models, Animal ; Dopamine/metabolism ; Encephalitis/drug therapy ; Encephalitis/etiology ; Encephalitis/pathology ; Humans ; Microglia/physiology ; Mitochondria/physiology ; Models, Neurological ; Oxidative Stress/physiology ; Parkinson Disease/drug therapy ; Parkinson Disease/pathology ; Parkinson Disease/physiopathology
Chemical Substances	Anti-Inflammatory Agents ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2005-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	207148-4
ISSN	1090-2430 ; 0014-4886
ISSN (online)	1090-2430
ISSN	0014-4886
DOI	10.1016/j.expneurol.2005.01.013
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Article ; Online: Challenges in antimalarial drug discovery.

Burrows, Jeremy N / Leroy, Didier / Lotharius, Julie / Waterson, David

Future medicinal chemistry

2011 Volume 3, Issue 11, Page(s) 1401–1412

Abstract: Malaria is one of the most devastating diseases in the world, affecting almost 225 million people a year, and causing over 780,000 deaths, most of which are children under the age of 5 years. Following the recent call for the eradication of the disease, ... ...

Abstract	Malaria is one of the most devastating diseases in the world, affecting almost 225 million people a year, and causing over 780,000 deaths, most of which are children under the age of 5 years. Following the recent call for the eradication of the disease, supported by the WHO, there has been increasing investment into antimalarial drug-discovery projects. These activities are aimed at generating the next generation of molecules focused on the treatment and transmission-blocking of Plasmodium falciparum and Plasmodium vivax endo- and exo-erythrocytic stages of the parasite. This article summarizes the current top-level thinking regarding the prosecution of such endeavors and the disease-specific considerations in project planning.
MeSH term(s)	Animals ; Antimalarials/chemical synthesis ; Antimalarials/chemistry ; Antimalarials/therapeutic use ; Chemistry, Pharmaceutical ; Drug Discovery/methods ; Drug Discovery/organization & administration ; Drug Discovery/trends ; Humans ; Malaria/blood ; Malaria/drug therapy ; Malaria/transmission ; Structure-Activity Relationship
Chemical Substances	Antimalarials
Language	English
Publishing date	2011-09
Publishing country	England
Document type	Journal Article ; Review
ISSN	1756-8927
ISSN (online)	1756-8927
DOI	10.4155/fmc.11.91
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Article: Pathogenesis of Parkinson's disease: dopamine, vesicles and alpha-synuclein.

Lotharius, Julie / Brundin, Patrik

Nature reviews. Neuroscience

2002 Volume 3, Issue 12, Page(s) 932–942

MeSH term(s)	Animals ; Dopamine/genetics ; Dopamine/metabolism ; Humans ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Parkinson Disease/etiology ; Parkinson Disease/genetics ; Parkinson Disease/metabolism ; Parkinson Disease/pathology ; Synaptic Vesicles/genetics ; Synaptic Vesicles/metabolism ; Synaptic Vesicles/pathology ; Synucleins ; alpha-Synuclein
Chemical Substances	Nerve Tissue Proteins ; SNCA protein, human ; Synucleins ; alpha-Synuclein ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2002-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2034150-7
ISSN	1471-0048 ; 1471-003X ; 1471-0048
ISSN (online)	1471-0048
ISSN	1471-003X ; 1471-0048
DOI	10.1038/nrn983
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Article: Impaired dopamine storage resulting from alpha-synuclein mutations may contribute to the pathogenesis of Parkinson's disease.

Lotharius, Julie / Brundin, Patrik

Human molecular genetics

2002 Volume 11, Issue 20, Page(s) 2395–2407

Abstract: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the inability to initiate, execute and control movement. Neuropathologically, there is a striking loss of dopamine-producing neurons in the substantia nigra pars ... ...

Abstract	Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the inability to initiate, execute and control movement. Neuropathologically, there is a striking loss of dopamine-producing neurons in the substantia nigra pars compacta, accompanied by depletion of dopamine in the striatum. Most forms of PD are sporadic, though in some cases familial inheritance is observed. In the late 1990s, two mutations in the alpha-synuclein gene were linked to rare, autosomal dominant forms of PD. Previously cloned from cholinergic vesicles of the Torpedo electric ray, alpha-synuclein is highly enriched in presynaptic nerve terminals and appears to be involved in synapse maintenance and plasticity. It is expressed ubiquitously in the brain, raising the important question of why dopaminergic neurons are primarily targeted in persons carrying mutations in alpha-synuclein. In this article, we review the current literature on alpha-synuclein and suggest a possible role for this protein in vesicle recycling via its regulation of phospholipase D2, its fatty acid-binding properties, or both. Exogenous application of dopamine, as well as redistribution of vesicular dopamine to the cytoplasm, can be toxic to dopaminergic neurons. Thus, impaired neurotransmitter storage arising from mutations in alpha-synuclein could lead to cytoplasmic accumulation of dopamine. The breakdown of this labile neurotransmitter in the cytoplasm could, in turn, promote oxidative stress and metabolic dysfunction, both of which have been observed in nigral tissue from PD patients.
MeSH term(s)	Animals ; Cytosol/metabolism ; Dopamine/metabolism ; Dopamine/physiology ; Fatty Acids/metabolism ; Homeostasis/physiology ; Humans ; Mutation ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Nerve Tissue Proteins/physiology ; Parkinson Disease/genetics ; Phospholipase D/metabolism ; Protein Binding ; Synaptic Vesicles/metabolism ; Synucleins ; Torpedo ; alpha-Synuclein
Chemical Substances	Fatty Acids ; Nerve Tissue Proteins ; SNCA protein, human ; Synucleins ; alpha-Synuclein ; phospholipase D2 (EC 3.1.4.-) ; Phospholipase D (EC 3.1.4.4) ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2002-10-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/11.20.2395
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Zs.A 3469: Show issues

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Article: Inflammation in Parkinson's disease: causative or epiphenomenal?

Hald, Andreas / Van Beek, Johan / Lotharius, Julie

Sub-cellular biochemistry

2007 Volume 42, Page(s) 249–279

Abstract: Parkinson's disease (PD) is a neurodegenerative disorder characterized by a dramatic loss of dopaminergic neurons in the substantia nigra (SN). Several pathogenic mechanisms have been implicated in the demise of these cells, including dopamine-dependent ... ...

Abstract	Parkinson's disease (PD) is a neurodegenerative disorder characterized by a dramatic loss of dopaminergic neurons in the substantia nigra (SN). Several pathogenic mechanisms have been implicated in the demise of these cells, including dopamine-dependent oxidative stress, mitochondrial dysfunction, excitotoxicity, and proteasomal impairment. In recent years, the involvement of neuroinflammatory processes in nigral degeneration has gained increasing attention. Not only have activated microglia and increased levels of inflammatory mediators been detected in the striatum of PD patients, but a large body of animal studies points to a contributory role of inflammation in dopaminergic cell loss. For example, post-mortem examination of human subjects exposed to the parkinsonism-inducing toxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, revealed the presence of activated microglia decades after drug exposure, suggesting that even a brief pathogenic insult can induce an ongoing inflammatory response. Perhaps not surprisingly, nonsteroidal anti-inflammatory drugs have been shown to reduce the risk of developing PD. In the past few years, various pathways have come to light that could link neurodegeneration and microglial activation, finally ascribing a pathogenic trigger to the chronic inflammatory response characteristic of PD.
MeSH term(s)	1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; Chronic Disease ; Dopamine/metabolism ; Humans ; Inflammation/chemically induced ; Inflammation/drug therapy ; Inflammation/metabolism ; MPTP Poisoning/drug therapy ; MPTP Poisoning/metabolism ; MPTP Poisoning/pathology ; Microglia/metabolism ; Microglia/pathology ; Oxidative Stress/drug effects ; Risk Factors ; Substantia Nigra/metabolism ; Substantia Nigra/pathology
Chemical Substances	Anti-Inflammatory Agents, Non-Steroidal ; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (9P21XSP91P) ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2007
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ISSN	0306-0225 ; 0096-8757
ISSN	0306-0225 ; 0096-8757
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Article ; Online: A randomized, double-blind, placebo-controlled study to investigate the safety, tolerability, and pharmacokinetics of single enantiomer (+)-mefloquine compared with racemic mefloquine in healthy persons.

Tansley, Robert / Lotharius, Julie / Priestley, Anthony / Bull, Fiona / Duparc, Stephan / Möhrle, Jörg

The American journal of tropical medicine and hygiene

2010 Volume 83, Issue 6, Page(s) 1195–1201

Abstract: Racemic mefloquine is a highly effective antimalarial whose clinical utility has been compromised by its association with neuropsychiatric and gastrointestinal side effects. It is hypothesized that the cause of the side effects may reside in the (-) ... ...

Abstract	Racemic mefloquine is a highly effective antimalarial whose clinical utility has been compromised by its association with neuropsychiatric and gastrointestinal side effects. It is hypothesized that the cause of the side effects may reside in the (-) enantiomer. We sought to compare the safety, tolerability and pharmacokinetic profile of (+)-mefloquine with racemic mefloquine in a randomized, ascending-dose, double-blind, active and placebo-controlled, parallel cohort study in healthy male and female adult volunteers. Although differing in its manifestations, both study drugs displayed a substantially worse tolerability profile compared with placebo. The systemic clearance was slower for (-)-mefloquine than (+)-mefloquine. Thus, (+)-mefloquine has a different safety and tolerability profile compared with racemic mefloquine but its global safety profile is not superior and replacement of the currently used antimalarial drug with (+)-mefloquine is not warranted.
MeSH term(s)	Adult ; Antimalarials/administration & dosage ; Antimalarials/adverse effects ; Antimalarials/chemistry ; Antimalarials/pharmacokinetics ; Dizziness/chemically induced ; Dose-Response Relationship, Drug ; Double-Blind Method ; Drug Administration Schedule ; Female ; Humans ; Male ; Mefloquine/administration & dosage ; Mefloquine/adverse effects ; Mefloquine/chemistry ; Mefloquine/pharmacokinetics ; Nausea/chemically induced ; Sex Characteristics ; Vomiting/chemically induced
Chemical Substances	Antimalarials ; Mefloquine (TML814419R)
Language	English
Publishing date	2010-11-24
Publishing country	United States
Document type	Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	2942-7
ISSN	1476-1645 ; 0002-9637
ISSN (online)	1476-1645
ISSN	0002-9637
DOI	10.4269/ajtmh.2010.10-0228
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Article: Vesicular monoamine transporter 2 regulates the sensitivity of rat dopaminergic neurons to disturbed cytosolic dopamine levels.

Vergo, Sandra / Johansen, Jens Leander / Leist, Marcel / Lotharius, Julie

Brain research

2007 Volume 1185, Page(s) 18–32

Abstract: An abnormal accumulation of cytosolic dopamine resulting in reactive oxygen species and dopamine-quinone products may play an important role in the rather selective degeneration of substantia nigra pars compacta (SNc) dopaminergic neurons in Parkinson's ... ...

Abstract	An abnormal accumulation of cytosolic dopamine resulting in reactive oxygen species and dopamine-quinone products may play an important role in the rather selective degeneration of substantia nigra pars compacta (SNc) dopaminergic neurons in Parkinson's disease. The neuronal-specific vesicular monoamine transporter (VMAT2), responsible for uptake of dopamine into vesicles, has been shown to play a central role both in intracellular dopamine homeostasis and sequestration of dopaminergic neurotoxins. Direct or indirect enhancement of VMAT2 activity could therefore have neuroprotective effects by decreasing cytosolic dopamine levels. Here, we demonstrate that transfection of VMAT2 in the dopaminergic cell line, PC12, increases intracellular dopamine content, augments potassium-induced dopamine release and attenuates cell death induced by the cytosolic dopamine enhancer, methamphetamine, suggesting an enhancement in vesicular dopamine storage. In rat ventral mesencephalic cultures highly enriched for dopaminergic neurons, lentiviral delivery of recombinant VMAT2 using a neuronal-specific promoter also resulted in elevated intracellular dopamine content and neurotransmitter release after depolarization. The opposite was seen after downregulation of VMAT2 using virally delivered shRNAs. Furthermore, using this VMAT2 knockdown model, we are the first to report a direct link between enhanced cytoplasmic dopamine levels, measured following mild permeabilization of the plasma membrane using digitonin, and neurite degeneration in primary dopaminergic neurons. In conclusion, our data support the hypothesis that an increase in vesicular sequestration of dopamine by modulation of VMAT2 activity could restore neuronal function and enhance dopaminergic cell survival in conditions of dysregulated dopamine homeostasis such as Parkinson's disease.
MeSH term(s)	Adrenergic Uptake Inhibitors/pharmacology ; Analysis of Variance ; Animals ; Cell Proliferation ; Cytosol/drug effects ; Cytosol/metabolism ; Dopamine/metabolism ; Drug Interactions ; Green Fluorescent Proteins/genetics ; Green Fluorescent Proteins/metabolism ; L-Lactate Dehydrogenase/metabolism ; Methamphetamine/pharmacology ; PC12 Cells/cytology ; Potassium Chloride/pharmacology ; Rats ; Reserpine/pharmacology ; Tetrazolium Salts ; Thiazoles ; Time Factors ; Transfection ; Tyrosine 3-Monooxygenase/metabolism ; Vesicular Monoamine Transport Proteins/physiology
Chemical Substances	Adrenergic Uptake Inhibitors ; Slc18a2 protein, rat ; Tetrazolium Salts ; Thiazoles ; Vesicular Monoamine Transport Proteins ; enhanced green fluorescent protein ; Green Fluorescent Proteins (147336-22-9) ; Methamphetamine (44RAL3456C) ; Potassium Chloride (660YQ98I10) ; Reserpine (8B1QWR724A) ; L-Lactate Dehydrogenase (EC 1.1.1.27) ; Tyrosine 3-Monooxygenase (EC 1.14.16.2) ; thiazolyl blue (EUY85H477I) ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2007-12-14
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1200-2
ISSN	1872-6240 ; 0006-8993
ISSN (online)	1872-6240
ISSN	0006-8993
DOI	10.1016/j.brainres.2007.09.028
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Article: Specific modulation of astrocyte inflammation by inhibition of mixed lineage kinases with CEP-1347.

Falsig, Jeppe / Pörzgen, Peter / Lotharius, Julie / Leist, Marcel

Journal of immunology (Baltimore, Md. : 1950)

2004 Volume 173, Issue 4, Page(s) 2762–2770

Abstract: Inflammatory conversion of murine astrocytes correlates with the activation of various MAPK, and inhibition of terminal MAPKs like JNK or p38 dampens the inflammatory reaction. Mixed lineage kinases (MLKs), a family of MAPK kinase kinases, may therefore ... ...

Abstract	Inflammatory conversion of murine astrocytes correlates with the activation of various MAPK, and inhibition of terminal MAPKs like JNK or p38 dampens the inflammatory reaction. Mixed lineage kinases (MLKs), a family of MAPK kinase kinases, may therefore be involved in astrocyte inflammation. In this study, we explored the effect of the MLK inhibitors CEP-1347 and CEP-11004 on the activation of murine astrocytes by either TNF plus IL-1 or by a complete cytokine mix containing additional IFN-gamma. The compounds blocked NO-, PG-, and IL-6 release with a median inhibitory concentration of approximately 100 nM. This activity correlated with a block of the JNK and the p38 pathways activated in complete cytokine mix-treated astrocytes. Although CEP-1347 did not affect the activation of NF-kappaB, it blocked the expression of cyclooxygenase-2 and inducible NO synthase at the transcriptional level. Quantitative transcript profiling of 17 inflammation-linked genes revealed a specific modulation pattern of astrocyte activation by MLK inhibition, for instance, characterized by up-regulation of the anti-stress factors inhibitor of apoptosis protein-2 and activated transcription factor 4, no effect on manganese superoxide dismutase and caspase-11, and down-regulation of major inflammatory players like TNF, GM-CSF, urokinase-type plasminogen activator, and IL-6. In conclusion, MLK inhibitors like CEP-1347 are highly potent astrocyte immune modulators with a novel spectrum of activity.
MeSH term(s)	Animals ; Astrocytes/drug effects ; Astrocytes/enzymology ; Astrocytes/immunology ; Blotting, Western ; Carbazoles/pharmacology ; Cells, Cultured ; Cyclooxygenase 2 ; Dose-Response Relationship, Drug ; Enzyme Activation/drug effects ; Enzyme Activation/immunology ; Enzyme Inhibitors/pharmacology ; Gene Expression/drug effects ; Immunoassay ; In Situ Hybridization ; Indoles/pharmacology ; Inflammation/immunology ; Interleukin-6/metabolism ; Isoenzymes/drug effects ; Isoenzymes/metabolism ; JNK Mitogen-Activated Protein Kinases ; MAP Kinase Kinase 4 ; MAP Kinase Kinase Kinases/drug effects ; MAP Kinase Kinase Kinases/immunology ; Mice ; Mitogen-Activated Protein Kinase Kinases/drug effects ; Mitogen-Activated Protein Kinase Kinases/metabolism ; NF-kappa B/drug effects ; NF-kappa B/metabolism ; Nitric Oxide/metabolism ; Nitric Oxide Synthase/drug effects ; Nitric Oxide Synthase/metabolism ; Nitric Oxide Synthase Type II ; Polymerase Chain Reaction ; Prostaglandin-Endoperoxide Synthases/drug effects ; Prostaglandin-Endoperoxide Synthases/metabolism ; Prostaglandins/metabolism ; Transcription, Genetic/drug effects
Chemical Substances	CEP-11004 ; Carbazoles ; Enzyme Inhibitors ; Indoles ; Interleukin-6 ; Isoenzymes ; NF-kappa B ; Prostaglandins ; 3,9-bis((ethylthio)methyl)-K-252a (156177-65-0) ; Nitric Oxide (31C4KY9ESH) ; Nitric Oxide Synthase (EC 1.14.13.39) ; Nitric Oxide Synthase Type II (EC 1.14.13.39) ; Nos2 protein, mouse (EC 1.14.13.39) ; Cyclooxygenase 2 (EC 1.14.99.1) ; Prostaglandin-Endoperoxide Synthases (EC 1.14.99.1) ; JNK Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; MAP Kinase Kinase Kinases (EC 2.7.11.25) ; MAP Kinase Kinase 4 (EC 2.7.12.2) ; Mitogen-Activated Protein Kinase Kinases (EC 2.7.12.2)
Language	English
Publishing date	2004-08-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.173.4.2762
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Article: Fria radikaler och sjuka proteiner--bovarna bakom Parkinsons sjukdom?

Smith, Ruben / Lotharius, Julie / Brundin, Patrik

Lakartidningen

2003 Volume 100, Issue 15, Page(s) 1324–6, 1329–30

Abstract: Parkinson's disease is one of the most common neurodegenerative diseases, and affects approximately 1% of the population over 65 years of age. Many different insults appear to be involved in the etiology of the disease, among them environmental toxins ... ...

Title translation	Free radicals and ailing proteins--the culprits behind Parkinson disease?.
Abstract	Parkinson's disease is one of the most common neurodegenerative diseases, and affects approximately 1% of the population over 65 years of age. Many different insults appear to be involved in the etiology of the disease, among them environmental toxins and mitochondrial dysfunction. During the past five years, mutations in five different genes have been linked to rare, familial forms of Parkinson's disease. One of the mutated proteins, alpha-synuclein is normally implicated in synaptic plasticity and vesicle function. Dysfunction of this protein might lead to increased cytoplasmic dopamine levels. Since cytoplasmic dopamine is readily prone to autooxidation and enzymatic degradation--processes which generate reactive oxygen species--failure to properly store dopamine into vesicles might lead to oxidative stress. Indeed, nigral tissue from idiopathic Parkinson's disease patients shows signs of oxidative damage. In this article we propose that dopamine-induced oxidative stress might be a common final pathway in the pathogenesis of the disease.
MeSH term(s)	Aged ; Dopamine/metabolism ; Free Radicals/metabolism ; Humans ; Mutation ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Neurons/metabolism ; Oxidative Stress ; Parkinson Disease/etiology ; Parkinson Disease/genetics ; Parkinson Disease/metabolism
Chemical Substances	Free Radicals ; Nerve Tissue Proteins ; Dopamine (VTD58H1Z2X)
Language	Swedish
Publishing date	2003-04-10
Publishing country	Sweden
Document type	English Abstract ; Journal Article ; Review
ZDB-ID	391010-6
ISSN	1652-7518 ; 0023-7205
ISSN (online)	1652-7518
ISSN	0023-7205
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Article ; Online: Safety, tolerability, pharmacokinetics, and activity of the novel long-acting antimalarial DSM265: a two-part first-in-human phase 1a/1b randomised study.

McCarthy, James S / Lotharius, Julie / Rückle, Thomas / Chalon, Stephan / Phillips, Margaret A / Elliott, Suzanne / Sekuloski, Silvana / Griffin, Paul / Ng, Caroline L / Fidock, David A / Marquart, Louise / Williams, Noelle S / Gobeau, Nathalie / Bebrevska, Lidiya / Rosario, Maria / Marsh, Kennan / Möhrle, Jörg J

The Lancet. Infectious diseases

2017 Volume 17, Issue 6, Page(s) 626–635

Abstract: ... enrolled between April 12, 2013, and July 14, 2015 (DSM265, n=55; placebo, n=18). In part 2, nine ...

Abstract	Background: DSM265 is a novel antimalarial that inhibits plasmodial dihydroorotate dehydrogenase, an enzyme essential for pyrimidine biosynthesis. We investigated the safety, tolerability, and pharmacokinetics of DSM265, and tested its antimalarial activity. Methods: Healthy participants aged 18-55 years were enrolled in a two-part study: part 1, a single ascending dose (25-1200 mg), double-blind, randomised, placebo-controlled study, and part 2, an open-label, randomised, active-comparator controlled study, in which participants were inoculated with Plasmodium falciparum induced blood-stage malaria (IBSM) and treated with DSM265 (150 mg) or mefloquine (10 mg/kg). Primary endpoints were DSM265 safety, tolerability, and pharmacokinetics. Randomisation lists were created using a validated, automated system. Both parts were registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12613000522718 (part 1) and number ACTRN12613000527763 (part 2). Findings: In part 1, 73 participants were enrolled between April 12, 2013, and July 14, 2015 (DSM265, n=55; placebo, n=18). In part 2, nine participants were enrolled between Sept 30 and Nov 25, 2013 (150 mg DSM265, n=7; 10 mg/kg mefloquine, n=2). In part 1, 117 adverse events were reported; no drug-related serious or severe events were reported. The most common drug-related adverse event was headache. The mean DSM265 peak plasma concentration (C Interpretation: The good safety profile, long elimination half-life, and antimalarial effect of DSM265 supports its development as a partner drug in a single-dose antimalarial combination treatment. Funding: Wellcome Trust, UK Department for International Development, Global Health Innovative Technology Fund, Bill & Melinda Gates Foundation.
MeSH term(s)	Adolescent ; Adult ; Antimalarials/administration & dosage ; Antimalarials/pharmacokinetics ; Antimalarials/therapeutic use ; Australia ; Dihydroorotate Dehydrogenase ; Double-Blind Method ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacokinetics ; Half-Life ; Humans ; Malaria, Falciparum/drug therapy ; Mefloquine/therapeutic use ; Middle Aged ; New Zealand ; Oxidoreductases Acting on CH-CH Group Donors ; Plasmodium falciparum ; Pyrimidines/administration & dosage ; Pyrimidines/pharmacokinetics ; Pyrimidines/therapeutic use ; Triazoles/administration & dosage ; Triazoles/pharmacokinetics ; Triazoles/therapeutic use
Chemical Substances	Antimalarials ; Dihydroorotate Dehydrogenase ; Enzyme Inhibitors ; Pyrimidines ; Triazoles ; DSM265 (0Q42P4YI6B) ; Oxidoreductases Acting on CH-CH Group Donors (EC 1.3.-) ; Mefloquine (TML814419R)
Language	English
Publishing date	2017-03-28
Publishing country	United States
Document type	Clinical Trial, Phase I ; Journal Article ; Randomized Controlled Trial
ZDB-ID	2061641-7
ISSN	1474-4457 ; 1473-3099
ISSN (online)	1474-4457
ISSN	1473-3099
DOI	10.1016/S1473-3099(17)30171-8
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Zs.A 5743: Show issues

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