TreatmentUpdate60; Volume 7, No. 6 - June 1995
Sean Hosein

Malaria kills between 1 and 2 million people each year. Although there are several antimalarial drugs available, the parasite that causes malaria is becoming increasingly resistant to them. In Asia, where malaria is a serious problem, researchers are continually trying to find and test new antimalarial compounds.

* TARRAGON AND SAGEBRUSH

In the past, practitioners of traditional Chinese medicine used the bark sweet wormwood (A. annua) to treat hemorrhoids and about 1700 years ago they documented its ability to "reduce fevers". More importantly, about 400 years ago, Chinese doctors documented its antimalarial activity. In the 1970s, Chinese researchers 'rediscovered' the antimalarial activity of A. annua and extracted the chemical QHS (quinghaosu or artemisinin). The weed A. annua is 'related' to plants such as sagebrush and tarragon. Plant scientists think that A. annua came from Asia. The weed can be found along the bank of the Potomac river in Washington, DC. The concentration of QHS in A. annua is low and researchers have only been able to extract about "2% of dry plant weight". A. annua growing in Sichuan province, China, is supposed to have the highest concentration of QHS.

* QHS

Pure QHS or artemisinin looks like "fine, colourless needles" and does not dissolve in water but can be mixed with oil forming a 'suspension'. Chinese researchers have made drugs 'related' to QHS and they are:

- artemether - arteeher - artelinic acid

* QHS AND MALARIA

QHS and related compounds, used in China and Vietnam since the late 1970s, are potential treatments for malaria and up to 1 million humans with malaria have received QHS or its 'relatives'. Some researchers think that QHS causes the release of highly active molecules called 'free radicals', which damage the parasite that causes malaria.

* EFFECTIVENESS AGAINST MALARIA

Several forms of QHS have been tested and the total dose given over 3 to 5 days is:

- tablets: 3g (50 mg/kg) or - injection (same dose) into muscle (QHS in oil or water).

Most subjects with malaria recovered within 2 days. Relapse was more likely among subjects who received tablets than among those who received injections. In other studies, QHS-treated subjects recovered faster than others given chloroquine, quinine or mefloquine. In one study, 21% of subjects receiving QHS relapsed 1 month after treatment, while no relapse occurred among subjects given quinine during that time.

QHS has also been made into suppositories and tested in at least 600 subjects. Giving adults 2800 mg over 3 days (50 mg/kg) produced "the best results". In trials comparing QHS or related compounds to standard therapy, preliminary results indicated that fewer subjects on QHS died.

* TOXICITY

In experiments with animals, QHS and related drugs "are considerably less toxic than [standard therapy]." Large doses of artemisinin compounds do cause side effects in 'large animals'. Symptoms of toxicity in dogs include "loss of spinal and pain responses, restlessness, tremors and incoordination...[problems breathing and standing], convulsions and [death]."

According to one team of reviewers, there "have been remarkably few adverse effects in [humans]" caused by QHS or related drugs. In summarizing test results, they noted that "there has been no evidence of significant toxicity in over 4,000 [human] subjects entered into clinical studies." One research team warns that "for now, it is best to avoid use of [QHS] compounds in pregnant women with uncomplicated malaria...".

* VERY RARE SIDE EFFECTS

1 of 82 subjects receiving artesunate and 3 of 39 [subjects] receiving artemether temporarily had a first-degree heart block". This seemed to have no further toxicity or cause any damage to subjects. Some subjects receiving more than 4 mg/kg of artemether had decreased red blood cell counts 4 days after receiving the drug. One week later they returned to normal. One subject who received "120 mg/kg" of artemesinin suppositories had temporarily increased blood levels of liver enzymes. In phase III studies in China, 6% of subjects using artemisinin suppositories had gastrointestinal problems such as nausea/vomiting, intestinal pain and diarrhea. As many as 25% of subjects using QHS and related compounds have temporary bouts of fever.

* FUTURE USE

The cost of developing QHS compounds to meet standards set by the US Food and Drug Administration (FDA) is high. As well, some researchers suggest that pharmaceutical companies do not make huge profits on "antimalarials and do not have an incentive to develop them".

* AVAILABILITY

In some Asian countries--China and Vietnam--QHS containing compounds are sold for the treatment of malaria in the form of tablets, suppositories or mixed with oil for injection. Some researchers think that longer courses of treatment--between 5 and 7 days--may provide better results than shorter courses. In our next article we report on the potential of QHS as a treatment for PCP/toxo.

REFERENCES:

1. Klayman Dl. Quinghaosu (artemisinin): an antimalarial drug from China. Science 1985;228:1049-1055.

2. Hien TT and White NJ. Quinghaosu. Lancet 1993;341:603- 608.

3. Wesche DL, DeCoster MA, Tortella FC and Brewer TG. Neurotoxicity of artemisinin analogues in vitro. Antimicrobial Agents and Chemotherapy 1994;38(8):1813-1819.

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