Antimalarials tolerability

Antimalarial drug choice takes into account tolerability and plasmodial resistance. 

Tolerability. The first available antimalarial, quinine, has the smallest therapeutic margin. All newer agents are rather well tolerated. 

Clinical Use. Atovaquone (Mepron) is used primarily to treat the protozoon that causes toxoplasmosis and the fungus that causes pneumocystis pneumonia in immunocompromised patients.6 This drug is not typically the primary treatment for pneumocystis, but is often reserved for patients who cannot tolerate more traditional treatments using sulfamethoxazole and trimethoprim (see Chapter 34) or pentamidine (see later). Atovaquone can also be used to prevent and treat resistant cases of malaria, and the antimalarial effects of this drug seem especially useful when combined with proguanil.48... 

Halofantrine (Hf) is a new phenanthrenemethanol antimalarial that shares many physicochemical similarities with cyclosporine and has been the subject of a number of investigations in our laboratory. Hf is orally active, well tolerated, and is finding increasing use in the treatment of malaria associated with multidrug resitant strains of Plasmodium falciparum. However, Hf is extremely lipophilic (log P 8) and poorly water soluble (<10 p,g/mL), and the bioavailability of Hf after oral administration of Hf.HCl tablets is low and variable. 

There has been a meta-analysis of 15 trials from Africa, Europe, and Asia of the use of varying doses of artesunate plus lumefantrine compared with several alternative antimalarial drugs in 1869 patients conducted by the manufacturers Novartis into its clinical safety and tolerability in the treatment of uncomplicated malaria (13). The most common adverse events were gastrointestinal—nausea (6.3%), abdominal pain (12%), vomiting (2.4%), anorexia (13%)—or central nervous—headache (21%) or dizziness (16%). There were 20 serious adverse events with artesunate plus lumefantrine, but only one (hemolytic anemia) was possibly due to artesunate plus lumefantrine. There was no QT prolongation associated with artesunate plus lumefantrine. 

At its introduction in 1926, an antimalarial drug, pamaquine, was associated with the appearance of severe and mysterious ailments. Most patients tolerated the drug well, but a few developed severe symptoms within a few days after therapy was started. The urine turned black, jaundice developed, and the hemoglobin content of the blood dropped sharply. In some cases, massive destruction of red blood cells caused death. 

Dosage and duration of therapy depend on patient response, tolerance of side effects, and development of retinal toxicity, which is a potentially irreversible adverse reaction associated with long-term therapy, especially with chloroquine. Current recommended doses of antimalarials in SLE are hydroxychloroquine 200-400 mg/day and chloroquine 250-500 mg/day. After 1 or 2 years of treatment, gradual tapering of dosage can be attempted. Some patients may require only one or two tablets per week to suppress cutaneous manifestations. ... 

Quinine is one of the least toxic alkaloids, but there is wide variation in tolerance to it, and allergy is not unknown (63). Nonfatal cases of poisoning may be caused from its use as an antimalarial (155), but fatalities are usually due to its use as an abortifacient (156, 157). The toxic dose is difficult to assess and may be anywhere in the region from 2 to 20 gm. Deafness and blindness, which may be permanent, are symptoms commonly seen. Quinine was the most common cause of suicide in Bulgaria in the 1930 s (158). 

Amodiaquine hydrochloride is an antimalarial of low toxicity and is three to four times as active as quinine as a suppressive drug against Plasmodium vivax and Plasmodium falciparum infections (44,45,46). In therapeutic doses amodiaquine hydrochloride is generally well tolerated but may occasionally give rise to side-effects, including nausea, vomiting. 

These studies culminated in the selection of cycloguanil pamoate (Camolar , CI-501) (XIX) [72] for expanded studies [5]. Cycloguanil pamoate has been subjected to extensive antimalarial and tolerance studies in experimental animals... 

Compared with the plethoric studies on antiplasmodial activity against P. falciparum in vitro, in vivo antimalarial assays dedicated to quassinoids are scarce and hardly comparable. Nevertheless, the excellent antimalarial activities highlighted in those studies should open the way to complementary studies of their pharmacokinetics and toxicity. Association with other antimalarials should also be investigated in order to define new therapeutic schemes and to lower the administered doses, increasing drugs tolerability. 

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