Invited reviewPrimaquine revisited six decades after its discovery
Graphical abstract
On the occasion of its recent 60th anniversary primaquine is the focus of the present review and several aspects related to this drug are revisited.
Section snippets
Historical synopsis
Tropical diseases, normally confined to underdeveloped regions of the globe, have been traditionally neglected by the pharmaceutical industries and, consequently, seldom considered as hot matter capable of drawing the attention of top scientists, from chemists to physicians. This attitude was changed by force of historical events in some periods, such as the first half of the 20th century, when world-wide belligerency required western soldiers, fighting in tropical regions, to be protected
Parasitic resistance
The establishment that parasitic resistance is occurring requires the demonstration that parasites are able to survive in vivo in the presence of an adequate therapeutic concentration of the drug system [117]. Several anti-malarial drugs are referenced as affected by the problem of resistance by Plasmodia, among which chloroquine is known to present severe resistance problems from both the deadliest P. falciparum and the second most concerning P. vivax strains [118], [119], [120].
The resistance
Relevant primaquine metabolites
PQ is rapidly absorbed in the gastrointestinal tract and concentrated in the liver, brain, heart, lungs and skeletal muscle. The mean volume of distribution is 3 L/kg. It peaks in plasma within 1–3 h, at ∼70 mg/mL, and is rapidly excreted in urine, with a plasma half-life of 4–9 h [9]. PQ is primarily metabolised to carboxyprimaquine that is not accumulated in the body. PQ is also metabolised to a number of other identified and unidentified metabolites that are detectable in urine and plasma (
PQ as scaffold for novel drugs
There have been two main routes for the direct modification of PQ, on the basis of its most representative metabolic transformations. Therefore, introduction of substituents on the quinoline ring and modification of the terminal primary amino group have been the main targets for PQ modification and only these will be referred to in some detail.
Final remarks
Primaquine may not be the anti-malarial drug with the best therapeutic profiles [121], [234], and several aspects of its biological action are yet to be discovered. However, primaquine is still the only transmission-blocking anti-malarial clinically useful and it goes on being used as the platform for developing novel anti-malarials with improved efficacy and reduced toxicity [21]. Good safety, tolerance and efficacy, along with key advantages in dosing requirements, make PQ an excellent drug
Acknowledgments
Thanks are due to FCT (Fundação para a Ciência e Tecnologia, Portugal) for funding through project PTDC/QUI/65142/2006. NV thanks FCT for Ph.D. grant SFRH/BD/17754/2004. PG and RM thank FCT for financial support to CIQUP and CECF, respectively.
References (238)
- et al.
Lancet Infect. Dis.
(2004) - et al.
Acta Trop.
(2008) - et al.
Trans. R. Soc. Trop. Med. Hyg.
(2003) - et al.
Trends Parasitol.
(2003) - et al.
Toxicology
(2007) - et al.
Int. J. Pharm.
(1996) - et al.
Int. J. Pharm.
(2003) - et al.
Int. J. Pharm.
(2005) - et al.
Int. J. Pharm.
(1995) - et al.
Int. J. Pharm.
(2008)