Intracellular Bacteria and Protozoa - Intracellular Delivery: Fundamentals and Applications - page 778

The eight-aminoquinolone primaquine is orally used in the treatment
(prophylactic or therapeutic) of all types of malaria infection. It remains as the only
drug that destroys late hepatic stages and latent tissue forms of P. vivax and P. ovale
and it is effective against gametocytes in only one dose. The main disadvantages
are the dose-limiting severe toxicities and side-effects (hemolytic anemia, methe-
moglobinemia and hemeolysis in patients with G6PD deficiency) and limited oral
availability.
The alkaloid quinine is used as blood schizonticidal and weak gametocide
against P. vivax and P. malariae. Quinine is less effective and more toxic as a blood
schizonticidal agent than chloroquine but it is especially useful in areas where high
level of resistance to chloroquine, mefloquine, and sulfa drug combinations with
pyrimethamine.
Artemsinin is a sesquiterpene lactone isolated from the plant Artemisia annua,
with an endoperoxide bridge, that is is thought to be responsible for their action and
is used against all forms of multi-drug resistant P. falciparum under the control of
WHO. The semi-synthetic artemisinin derivatives artesunate (hemisuccinate), arte-
mether (methyl ether) and arteether (ethyl ether) are easier to use than the parent
compound and are converted rapidly once in the body to the active compound dihy-
droartemesinin. However the therapeutic potential of derivatives is considerably
hampered due to: (i) short half-life usually between 3 h and 5 h; (ii) poor aqueous
solubility, and thus low oral bioavailability (40%); (iii) risk of degradation in acidic
conditions; (iv) associated risk of toxicity and (v) the i.m. injections currently avail-
able in the market are associated with low patient compliance and inconsistent
assimilation (Akinlolu and Shokunbi 2010 ). The mainstay of cerebral malaria
therapy is either quinine or artemisinin.
Halofrantine (phenanthrene methanol) is used as blood schizonticide effective
against all plasmodium parasites. Cytotoxic complexes are formed with ferritopor-
phyrin XI that cause plasmodial membrane damage. Despite being effective against
drug resistant parasites, halofantrine is not commonly used due to its high cost,
variable bioavailability and potentially high levels of cardiotoxicity.

6.2 Preclinical Delivery Systems

6.2.1 Non-targeted Systems

Recently Santos-Magalhães and Furtado Mosqueira have thoroughly reviewed the
latest preclinical nanomedical developments against malaria (Santos-Magalhães
and Furtado Mosqueira 2010 ). Most of the approaches however, were based on
changing antimalarial's pharmacokinetics by drugs loading in liposomes,
nanocapsules and lipid nanoparticles. A minoritary fraction of articles were focused
on targeting to infected erythrocytes or hepatocytes and subsequent cytoplasmic
delivery.