Proguanil antimalarial

Aromatic biguanides such as proguanil (181) have been found useful as antimalarial agents. Investigation of the metabolism of this class of drugs revealed that the active compound was in fact the triazine produced by oxidative cyclization onto the terminal alkyl group. The very rapid excretion of the active entity means that it cannot be used as such in therapy. Consequently, treatment usually consists in administration of either the metabolic precursor or, alternately, the triazine as some very insoluble salt to provide slow but continual release of drug. 

Proguanil appears to have a dual activity. Part of it is metabolized to cycloguanil, which subsequently inhibits the protozaon dihydrofolate reduc-tase/thymidylate synthase (DHFR/TS) (Fig. 4). In addition, the native form, proguanil itself, exerts a potent antimalarial activity, especially in combination with other antimalarial drugs. The target of proguanil is unknown. 

Different antimalarials selectively kill the parasite s different developmental forms. The mechanism of action is known for some of them pyrimethamine and dapsone inhibit dihydrofolate reductase (p. 273), as does chlorguanide (proguanil) via its active metabolite. The sulfonamide sulfadoxine inhibits synthesis of dihydrofolic acid (p. 272). Chlo-roquine and quinine accumulate within the acidic vacuoles of blood schizonts and inhibit polymerization of heme, the latter substance being toxic for the schizonts. 

VLa.2,6. Other antimalarials. Doxycydine (see Section ILb) is a useful and effective short-term prophylactic agent for travellers to chloroquine-resistant areas and can be used as an alternative when mefloquine or proguanil is unavailable or mefloquine is contraindicated. In combination with quinine also tetracycline is used as an antimalarial. 

Diamino-l-(4-chlorophenyl)-2,2-dimethyl-l,2-dihydro-l,3,5-triazine is the active antimalarial metabolite of the British antimalarial Paludrine (or proguanil) (210) (B-61MI22000, p. 717). 

Several drugs (for example amiodarone, androgens, glucocorticoids, phenytoin, and salicylates) interfere with the transport or metabolism of thyroid hormones and thereby alter thyroid function tests. These have been reviewed (90). In patients taking levothyroxine serum TSH rises after treatment with sertraline (91) and antimalarial prophylaxis with chloroquine and proguanil... 

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... 

Ward SA, Helby NA, Skjelbo E. The activation of the biguanide antimalarial proguanil co-segragates with the mephenytoin oxidation polymorphism—a panel study. Br J Clin Pharmacol 1991 31 689-692. 

In another major review the risk of depression, psychosis, a panic attack, or a suicide attempt during current or previous use of mefloquine was compared with the risk during the use of proguanil and/or chloroquine or doxy-cycline (513). The study population (n = 35 370) was aged 17-79 years (45% men). There was no evidence that the risk of depression was increased during or after the use of mefloquine, but psychoses and panic attacks were more frequent in current users of mefloquine than in those using other antimalarial drugs. 

ANTACIDS ANTIMALARIALS - PROGUANIL, CHLOROQUINE 1 chloroquine and proguanil levels 1 absorption Separate doses by at least 4 hours... 

CIMETIDINE ANTIMALARIALS OTHER THAN PROGUANIL t efficacy and adverse effects of antimalarials Inhibition of metabolism, some definitely via CYP3A4 Avoid co-administration... 

The adverse effects of mefloquine have been extensively reviewed both for prophylaxis (when rare neuropsychiatric adverse effects make its use controversial) and in treatment doses, when it has been linked to an increased incidence of the postmalaria neurological syndrome. A retrospective review of 5120 Itahan soldiers showed an overall chemoprophylaxis curtailment rate of less than 1%, which was not significantly different from the combination of chloroquine and proguanil (11). A semi-systematic review also suggested no significant difference in tolerabihty compared with other antimalarial drugs (12). 

It has tentatively been suggested that mefloquine can exacerbate psoriasis (as can other antimalarial drugs, such as quinidine, chloroquine, and proguanil) (38). 

Proguanil is one of the antimalarial drugs most widely used for prophylactic purposes, usually in combination with chloroquine or atovaquone in malaria prophylaxis, and with atovaquone in malaria treatment (SEDA-21, 297). A biguanide, it is rapidly absorbed in standard doses and mainly excreted by the kidneys. Its antimalarial effect is due to its metabolite cycloguanU. However, its metabolism varies individually, and this is reflected in a variable degree of efficacy (SEDA-17, 328). 

A rise in serum TSH has been described after antimalarial prophylaxis with chloroquine and proguanil in patients taking levothyroxine (SEDA-22, 469). In one case there was a marked increase in serum TSH in the same patient on two occasions after several weeks of antimalarial prophylaxis with chloroquine and proguanil, the likely mechanism being enzyme catabolism (8). 

Chlorhexidine is an antimicrobial agent first synthesized at Imperial Chemical Industries in 1954 in a research programme to produce compounds related to the biguanide antimalarial proguanil. 

During World War II, chemists at ICI, then a newcomer in pharmaceutical research, discovered antimalarials based on biguanidines, including proguanil (89) (Paludrine, 1944), prepared from 3-chloroaniline (Scheme 28), and its metabolite dihydrodiazine (90). In 1950, George Hitchings developed the diaminotriazine into what became known as pyrimethamine (Diaprim) (91) (Scheme 29)98. 

Chloroaniline (133) is the starting point for biguanidine therapeuticals including the antimalarial proguanil (Paludrine) (134). Metabolism of 134 affords dihydrodiazine (135). Another useful antimalarial is the 4-aminoquinoline known as amodiaquin (136). 

Pyrimethamine and proguanil are used as oral antimalarials.and inhibit the utilization of folate by the malarial parasite, so are valuable in chemoprophylaxis and in preventing the transmission of malaria. (See ANTIMALARIALS.) Trimethoprim is a useful antibacterial, and as an antiprotozoal in antimalarial therapy. The selectivity of these agents derives, in part, from the fact that whereas mammals can obtain folic acid from the diet, bacteria and the asexual forms of the malarial parasite must synthesize it. Also, the dihydrofolate reductase enzyme in humans is less sensitive to these drugs than that of the parasites. 

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