Malaria: Miscellaneous products

• Tetracycline, minocycline and doxycycline are antibiotics which are active against malaria parasites, but are very slow-acting. For this reason they are never given as monotherapy, but in combination with quinine. They very much reduce the risk of relapse. Doxycycline has the advantage that it only needs to be administered once daily. It is also more potent than tetracycline itself, probably due to its high fat solubility. It is sometimes used for malaria prophylaxis in mefloquine intolerance, e.g. in Southeast Asia or South America (100 mg per day beginning 1 day before arriving in an endemic zone).

• Clindamycin (Dalacin®) is also active against plasmodia, but is a second choice drug (risk of pseudomembranous colitis due to Clostridium difficile). The dose of clindamycin is 10 mg/kg for 3-7 days. It is given together with quinine.

• Sometimes cotrimoxazole is used as third choice (together with quinine).

• Fosmidomycin is being studied at present for its anti-malaria properties. Fosmidomycin, a phosphonic acid derivative, blocks 1-deoxy-D-xylulose 5-phosphate (DOXP) reductoisomerase, a key enzyme of the DOXP pathway in the apicoplast of P falciparum, thereby inhibiting the growth. The drug is well tolerated in people. The optimal treatment schedule is still to be determined, although a dose of 1,2 gram every eight hours for a minimum of 5 days seems promising.

• Azithromycin (Zitromax®) was developed in 1988. It is a macrolide related to erythromycin. The molecule has a ring structure of 15 atoms, including 1 nitrogen (the letters ‘az’ in azithro refer to the nitrogen). In some studies a prophylactic effect was demonstrated (83% after daily ingestion of 250 mg, 64% after weekly ingestion of 1 gram). Azithromycin is stable in an acid environment (unlike erythromycin) and can easily be taken orally. High intracellular concentrations are reached, even in the white blood cells (100 times the serum concentration) and there is long-term retention in the tissues. The tissue half-life is 50-90 hours, which makes one dose per day possible.

• Atebrine. Atebrine was developed in Germany in the 1930s. It was widely used for malaria prevention during World War II (of strategic importance in the Pacific). In the USA it was named quinacrine and in England it was called mepacrine. It quite often caused stomach problems, nausea, vomiting, dizziness and yellow discoloration of the skin. High doses can cause acute toxic psychosis. Aplastic anaemia occurs in 1/20,000 cases. Psoriasis may become worse during treatment. The product has a disulfiram effect and taking alcohol during its use is not advisable. It passes the placental barrier. The use of atebrine has now been almost abandoned. It is still sometimes used to treat tinidazole-resistant Giardia.

• Pyronaridine (PO, IM, IV) is an acridine derivative, just as mepacrine. It is closely related structurally to amodiaquine. Although it was synthesised as early as 1970 in China, at present it is being regarded elsewhere as experimental. The recommended dose is 1800 mg over 5 days. Studies in Africa produced favourable results, but in Thailand there was frequent recrudescence after treatment.

• Nitroquine is being evaluated for its activity against various Plasmodium species.

• Artemisone is a semi-synthetic artemisinin-derivate ("second-generation"). Initial studies showed a lack of neurotoxicity in vitro and in vivo animal models. Artemisone is metabolized into an active metabolite. Formulation work has indicated stability problems with the present formulation. These problems have postponed clinical use until they can be overcome.

• Isoquine is an amodiaquine-like compound that has been redesigned and synthesized to remove the structural cause of toxicity of its class while retaining full antimalaria activity. This second-generation aminoquinoline retains the easy synthesis of amodiaquine from inexpensive precursors, and promises a new generation of affordable, well-tolerated, and effective antimalarials. It is possible that it will avoid cross-resistance to its chemical cousin chloroquine (and amodiaquine).

• Arteflene is a new product, still in the clinical trial phase. It is a synthetic bicyclic sesquiterpene peroxide, derived from a substance which is present in the Chinese plant Artabotrys uncinatus. The half-life is quite short (3 hours). It has an active metabolite.

• Piperaquine is a new Chinese synthetic drug belonging to the bisquinolines. The combination with dihydroartemisinin (Artekin) is very promising. Trimethoprim can also be added to this combination. Piperaquine is a highly lipid-soluble drug. Its clearance is greater in children than in adults.

• Other miscellaneous substances. Iron chelators (deferoxamine), pentoxifylline, mannitol and other products have been studied as adjuvants in malaria treatment, but have not to date proved convincing. Naphthylisoquinolines form a new group of experimental anti-malaria agents. Various studies are at present evaluating their potential. Various trioxanes and tetroxanes, highly active in vitro, are being evaluated (an oxane is a cyclic ether). Licochalcone A is a substance obtained from Chinese liquorice (Glycyrrhiza inflata) and is at present being studied for its activity against Plasmodium species. It may also be active against Leishmania sp. The bark of Enantia chloranta (Annonaceae) contains some active anti-malaria products, but toxicity studies and in-vivo studies still have to determine a possible therapeutic use. Since the severity of cerebral malaria correlates with the concentration of tumour necrosis factor, and the latter plays a role in the physiopathology, trials are currently being carried out with CytoTAb®, an anti-TNF product. Triclosan, an antibacterial agent which is sometimes used in anti-acne products, deodorants, toothpastes and mouthwash, is an inhibitor of fatty acid synthesis in P. falciparum (and also active against Toxoplasma gondii). More research is necessary to determine any clinical relevance. Non-infected red blood cells do not produce membrane lipids. When a malaria parasite finds itself in a red blood cell, however, it must synthesise membrane lipids. Phosphatidylcholine is the most important of the phospolipids among the membrane lipids. To produce this, choline is taken up from the plasma by means of a transporter. This step can be blocked by a new experimental agent (G25).

• Malarex is extracted from the Brazilian tree Peschiera fuchsiaefolia, a source of traditional remedies against fever. The active compound is the alkaloid voacamine. The efficacy of this compound is not clear at the moment.

• Falcipain is a critical protease used by the parasite to breakdown proteins in the red blood cells. A treatment based on falcipain inhibitors might be possible in the future if a non-toxic inhibitor would be identified.

Category: Medicine Notes