ArticlePDF Available

Unexpected pharmacological and toxicological effects of tafenoquine

  • The Quinism Foundation
Occupational Medicine 2015;65:417
© The Author 2015. Published by Oxford University Press on behalf of the Society of Occupational Medicine.
All rights reserved. For Permissions, please email:
Unexpected pharmacological and
toxicological effects of tafenoquine
Dear Sir,
I read with interest the recent case report by Cannon
etal. [1], describing a case of occupational asthma result-
ing from exposure to the 8-aminoquinoline tafenoquine,
a transmission-blocking antimalarial currently in late
stage development [2,3].
Their report, the rst describing the asthmagenicity of
the drug, is particularly unexpected given historical lit-
erature from the 1950s and 1960s describing seemingly
successful investigations into the use of quinolines as bron-
chodilators in the treatment of bronchial asthma [4,5].
More recent reports have also suggested that the quino-
lines may be effective anti-inammatory agents [6,7].
Broader use of the 8-aminoquinolines has historically
been limited owing to ndings of idiosyncratic neurotoxic-
ity [8,9], with a fatal human case marked by widespread
neuronal degeneration within the brainstem [10]. The new
nding of unexpected and idiosyncratic asthmagenicity
suggests a need to more thoroughly dene the potentially
complex pharmacology and toxicology of tafenoquine prior
to the drug’s more widespread use, particularly among
asymptomatic populations in planned antimalarial mass
drug administration. Pharmacogenetic investigations, par-
ticularly of common polymorphisms in drug metabolizing
and transport enzyme genes [3], may provide insight into
the drug’s unexpected effects and should be considered
both in future pre-licensing studies and in occupational
medicine investigations of idiosyncratic toxicity.
Conicts of interest
The author has been retained as consultant and expert
witness in criminal and civil cases involving claims of
antimalarial toxicity. The author has no other nancial or
other conicts of interest to report.
Remington L.Nevin
Department of MentalHealth,
Johns Hopkins Bloomberg School of PublicHealth,
624 N.Broadway, Room782, Baltimore, MD 21205,USA
e-mail: r
1. Cannon J, Fitzgerald B, Seed M, Agius R, Jiwany A,
Cullinan P. Occupational asthma from tafenoquine in the
pharmaceutical industry: implications for QSAR. Occup
Med (Lond) 2015;65:256–258.
2. Renslo AR. Antimalarial drug discovery: From qui-
nine to the dream of eradication. ACS Med Chem Lett
3. Marcsisin SR, Sousa JC, Reichard GA et al. Tafenoquine
and NPC-1161B require CYP 2D metabolism for anti-
malarial activity: implications for the 8-aminoquinoline
class of anti-malarial compounds. Malar J 2014;13:2.
4. Geschickter CF. Quinoline therapy in asthma: a report of
500 cases. South Med J 1955;48:497–509.
5. Young RC Jr, Murray AJ, Carr C, Harden KA.
Phthalamaquin: its effect in the treatment of bronchial
asthma as determined by studies of ventilatory function. J
Natl Med Assoc 1965;57:189–193.
6. Mukherjee S, Pal M. Quinolines: a new hope against
inammation. Drug Discov Today 2013;18:389–398.
7. Mukherjee S, Pal M. Medicinal chemistr y of quinolines as
emerging anti-inammatory agents: an overview. Cur r Med
Chem 2013;20:4386–4410.
8. Schmidt IG, Schmidt LH. Neurotoxicity of the 8-amino-
quinolines. III. The effects of pentaquine, isopentaquine,
primaquine, and pamaquine on the central nervous sys-
tem of the rhesus monkey. J Neuropathol Exp Neurol
9. Sipe JC, Vick NA, Schulman S, Fernandez C. Plasmocid
encephalopathy in the rhesus monkey: a study of
selective vulnerability. J Neuropathol Exp Neurol
10. Loken AC, Haymaker W. Pamaquine poisoning in man,
with a clinicopathologic study of one case. Am J Trop Med
Hyg 1949;29:341–352.
ResearchGate has not been able to resolve any citations for this publication.
Full-text available
Tafenoquine (TQ) is an 8-aminoquinoline (8AQ) that has been tested in several Phase II and Phase III clinical studies and is currently in late stage development as an anti-malarial prophylactic agent. NPC-1161B is a promising 8AQ in late preclinical development. It has recently been reported that the 8AQ drug primaquine requires metabolic activation by CYP 2D6 for efficacy in humans and in mice, highlighting the importance of pharmacogenomics in the target population when administering primaquine. A logical follow-up study was to determine whether CYP 2D activation is required for other compounds in the 8AQ structural class. In the present study, the anti-malarial activities of NPC-1161B and TQ were assessed against luciferase expressing Plasmodium berghei in CYP 2D knock-out mice in comparison with normal C57BL/6 mice (WT) and with humanized/CYP 2D6 knock-in mice by monitoring luminescence with an in vivo imaging system. These experiments were designed to determine the direct effects of CYP 2D metabolic activation on the anti-malarial efficacy of NPC-1161B and TQ. NPC-1161B and TQ exhibited no anti-malarial activity in CYP 2D knock-out mice when dosed at their ED100 values (1 mg/kg and 3 mg/kg, respectively) established in WT mice. TQ anti-malarial activity was partially restored in humanized/CYP 2D6 knock-in mice when tested at two times its ED100. The results reported here strongly suggest that metabolism of NPC-1161B and TQ by the CYP 2D enzyme class is essential for their anti-malarial activity. Furthermore, these results may provide a possible explanation for therapeutic failures for patients who do not respond to 8AQ treatment for relapsing malaria. Because CYP 2D6 is highly polymorphic, variable expression of this enzyme in humans represents a significant pharmacogenomic liability for 8AQs which require CYP 2D metabolic activation for efficacy, particularly for large-scale prophylaxis and eradication campaigns.
Full-text available
Quinoline-based small molecules have been explored and being developed as anti-inflammatory agents targeting several pharmacological targets namely Phosphodiesterase 4 (PDE4), Transient Receptor Potential Vanilloid 1 (TRPV1), TNF-α converting enzyme (TACE) and Cyclooxygenase (COX). Efforts on Structure Activity Relationship (SAR) studies revealed that the pharmacological activities and target specificities of these quinoline derivatives were mainly dependent on the nature and position of substituent(s) present on the quinoline ring. For example, quinolines having carboxamide moiety displayed TRPV1 antagonism whereas that with carboxylic acid showed COX-inhibition. Similarly, quinolines possessing aniline moiety at C-4, aryl group at C-8 and oxazole ring at C-5 showed PDE4 inhibition. These quinoline derivatives were synthesized by using various synthetic approaches like Pd-mediated C-C (e.g. Suzuki, Sonogashira type coupling etc.) or C-N (the Buchwald-Hartwig type coupling) or C-S bond formation, AlCl3 induced C-C bond formation, traditional amide bond formation or amination, formation of ether linkage or additional heterocyclic rings. All these efforts resulted in the discovery of several quinoline-based anti-inflammatory agents for the potential treatment of acute as well as chronic inflammatory diseases.
We report occupational asthma and rhinitis in a formulation pharmacist, employed in the development of tafenoquine. Tafenoquine is a new anti-malarial drug in development; the pure drug substance has an asthma hazard index of zero and previously was not known to be a respiratory sensitizing agent. The implications of this finding for the refinement of quantitative structural analysis of asthmagenic chemicals are discussed. © The Author 2015. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email:
The search for antimalarial remedies predates modern medicine and the concept of small molecule chemotherapy, yet has played a central role in the development of both. This history is reviewed in the context of the current renaissance in antimalarial drug discovery, which is seeing modern drug discovery approaches applied to the problem for the first time. Great strides have been made in the past decade, but further innovations from the drug discovery community will be required if the ultimate dream of eradication is to be achieved.
Although countless numbers of anti-inflammatory drugs have been discovered and developed to treat diseases associated with acute and chronic inflammation, many anti-inflammatories cause adverse side effects. The quinoline framework has emerged as a new template for the design and identification of novel anti-inflammatory agents. These agents are classified based on the number of substituents present on the quinoline ring or compounds containing a quinoline ring fused to other heterocycles. This review focuses on the discovery of various quinoline derivatives as inhibitors of cyclooxygenase (COX), phosphodiesterase 4 (PDE4) and tumour necrosis factor-α converting enzyme (TACE), along with transient receptor potential vanilloid 1 (TRPV1) antagonists.
The effects of plasmocid (8 diethylaminopropylamino 6 methoxyquinoline) on the central nervous system of rhesus monkeys were studied by electron and correlative light microscopy. Light microscopic studies showed neuronal vacuolar lesions distributed selectively in the diencephalon and brain stem. In the affected nuclei, principally III, IV, VI and VIII, the brunt of the damage was consistently borne by large multipolar neurons. The cerebral and cerebellar cortices were normal. Electron microscopy showed the earliest effects to be an abnormality of neuronal mitochondria, which were enormously increased in number with incompletely formed transverse inner cristae. Later stages of degeneration showed dissolution of mitochondrial contents so that only their outer membranes remained. Neuroglia were morphologically normal, as were synapses in contact with the altered neurons. Neurons in the most advanced stage of degeneration exhibited complete destruction of cytoplasmic contents and disruption of the cell membrane with crenated nuclei remaining. The ultrastructural data confirm the highly selective vulnerability of brain stem nuclei to plasmocid and suggest that the primary effect of the drug is on neuronal mitochondria.