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Many different drug-resistant lines of rodent malaria are available as screening models. It is obligatory to screen new compounds for antimalarial activity against a series of resistant lines in order to identify a compound with potential for the treatment of multi-drug resistant (MDR) malaria infections. Instead of using a battery of resistant lines, a single MDR Plasmodium yoelii nigeriensis strain that shows a wide spectrum of drug resistance to high doses of chloroquine, mepacrine, amodiaquine, mefloquine, quinine, quinidine, halofantrine as well as tetracyclines, fluoroquinolines and erythromycin, was used to assess the blood schizontocidal efficacy of a new macrolide azithromycin and other antibiotics. The present study shows that only azithromycin has the potential to control an MDR P. y. nigeriensis infection in Swiss mice, provided the treatment with a dose of 50-100 mg/kg/day by oral route is continued for a period of 7 days. Tetracycline, oxytetracycline, doxycyline, erythromycin, ciprofloxacin and norfloxacin, although active in vitro, failed to protect the mice. Tetracycline, ciprofloxacin and norfloxacin combinations with chloroquine did not control the infection. Additionally, the antimalarial efficacy of azithromycin can be potentiated with the addition of arteether, which is an ethyl ether derivative of artemisinin. A total (100%) curative effect has been obtained with a shorter regimen of 4 days only.

Artemisinin and its derivative alpha, beta-arteether have been evaluated for activity against experimental primary amoebic meningoencephalitis. In vivo experiments have shown that amphotericin B at dose of 2.5 mg/kg for 5 days produced 100% protection. Artemisinin and alpha, beta-arteether, even when tested at a high doses (60-120 mg/kg x 5 days and 90-180 mg/x 5 days) respectively, were not curative and showed only slight protection as indicated by extension of mean survival time.

Arteether (alpha/beta) (a mixture of alpha and beta enantioners) has been reported to possess gametocytocidal activity against Plasmodium cynomolgi B when the drug is given by the intramuscular route, but it would be preferable to use oral route therapy for gametocyte carriers. This is a report of a study of the gametocytocidal action of arteether administered by the oral route. The results indicate high levels of activity at 10 mg/kg in a single dose or in two divided doses when given orally.

The water-soluble artemisinin analogue sodium beta-artelinate, a fast-acting blood schizontocide, was evaluated for gametocytocidal action against simian malaria Plasmodium cynomolgi B, and a single dose of the compound has been found to be an effective gametocytocide by both oral and intravenous routes. The compound was able to sterilize the circulating gametocytes in rhesus monkey, resulting in loss of mosquito infectivity and oocyst development in the Anopheles stephensi. However, no sporontocidal action has been observed with this compound.

Artemisinin and its derivatives, beta-arteether and sodium artesunic acid, have been evaluated for activity against experimental primary amebic meningoencephalitis and the efficacy of these compounds has been compared with that of the standard drug amphotericin B. In vivo experiments in Swiss mice have shown that amphotericin B at a dose of 2.5 mg/kg for 5 days produced 100% protection in the mice infected intranasally with Naegleria fowleri. Artemisinin, beta-arteether, and sodium artesunic acid, even when tested at high doses (60-180 mg/kg x 5 days), were not curative and showed only slight protection as indicated by extension of mean survival time.

alpha-Artelinic acid [8], a potent, stable, and water-soluble antimalarial agent, has been synthesized from artemisinin [1], the sesquiterpene lactone endoperoxide isolated from Artemisia annua. The blood schizontocidal antimalarial activity of alpha-artelinic acid evaluated against Plasmodium knowlesi is also reported.

The blood schizontocidal activity of alpha and beta arteether has been compared with that of alpha/beta arteether (a 30:70 mixture of alpha and beta isomers), which is a fast-acting blood schizontocide undergoing phase I clinical trials at the Central Drug Research Institute. Both beta and alpha/beta arteether have comparable activity and are curative at a dose of 5 mg/kg for 3 days against blood-induced Plasmodium cynomolgi B infection in the rhesus monkey; alpha arteether alone is slightly less active, with a 50% cure rate at the above dose.

The gametocytocidal efficacy of artemisinin (qinghaosu) was evaluated and scanning electron microscopical evidence is given for gametocytocidal action of a single 5-10-mg/kg dose of artemisinin against simian malarial parasite (Plasmodium cynomolgi B). No sporontocidal effect of artemisinin was observed.

A new sesquiterpene lactone alpha/beta arteether (a 30:70 mixture of enantiomers), which possesses very high blood schizontocidal activity, has been evaluated for gametocytocidal/sporontocidal action against Plasmodium cynomolgi B infection in the rhesus monkey. This paper reports gametocytocidal action of this new antimalarial drug at 2.5-5 mg/kg (single im dose) against P. cynomologi B as shown by the complete absence of mosquito infectivity. No sporontocidal action was demonstrable in the vector at a dose of up to 20-50 mg/kg im.

New quick-acting blood schizontocides are needed to contain the spread of multiple drug resistant strains of P. falciparum and for the treatment of the cerebral malaria cases. A multiple drug resistant strain of P. yoelii nigeriensis resistant to mefloquine (128 mg/kg x 6 days), quinine (300 mg/kg x 7 days) and chloroquine (64 mg/kg x 8 days) was found to be completely susceptible to arteether (a 30:70 mixture of alpha and beta enantiomers) and a dose of 5 mg/kg x 3 days by i.m. route was curative in Swiss mice. Artemisinin at 50 mg/kg x 7 days had only suppressive action against this strain.

Arteether (30:70 mixture of alpha and beta epimers) used as injectable intramuscular preparation (in neutralized ground-nut oil) had curative action at 5 mg/kg x 3 d against blood-induced Plasmodium cynomolgi B infection in rhesus monkeys, while the curative dose of artemisinin (qinghaosu) oil suspension was 10 mg/kg x 7 d or 20 mg/kg x 3 d. Parasite clearance with arteether was achieved within 24 h. Neither arteether nor artemisinin exhibited any causal prophylactic or radical curative action up to dose levels of 20 mg/kg against sporozoite-induced P. cynomolgi B infection in rhesus monkeys.

Pharmacological studies on alpha/beta arteether (a 30:70 mixture of isomers), a potential drug for the treatment of cerebral malaria, were carried out in experimental animals by giving the drug in arachis oil suspension. The compound appears to be devoid of significant pharmacological activity on the central nervous, cardiovascular and urinary systems. It lacks an anti-inflammatory response in rats up to 50 mg/kg intramuscularly but at 50-200 mg/kg it has some antianaphylactic potential.

Gametocytocidal activity of artemisinin (qinghaosu) has been demonstrated against simian malaria parasite Plasmodium cynomolgi B. Colony-bred Anopheles stephensi were allowed to feed on gametocyte-carrying rhesus monkeys and the mosquito infectivity rate and oocyst count of the infected mosquito gut were recorded on day 8-9 postinfection. Control (pretreatment) feedings of mosquito on gametocyte-carrying monkeys showed good infectivity in different batches of the mosquitoes ranging from 57.14 to 95.0%. Administration of single intramuscular injection of 5 mg/kg artemisinin (suspended in neutralised oil) resulted in complete loss of mosquito infectivity within 24 h of drug administration. This is the first report on the possible use of artemisinin to stop malaria transmission. The drug has no sporontocidal action.