A randomized controlled trial of artemotil (beta-arteether) in Zambian children with cerebral malaria.

The efficacy and safety of intramuscular artemotil (ARTECEF) was compared to intravenous quinine in African children with cerebral malaria. This prospective block randomized open-label study was conducted at two centers in Zambia. Subjects were children aged 0 to 10 years of age with cerebral malaria and a Blantyre Coma Score of 2 or less. Ninety two children were studied; 48 received artemotil and 44 quinine. No significant differences in survival, coma resolution time, neurologic sequelae, parasite clearance time, and fever resolution time were seen between the two regimens. Rates for negative malaria smears one month after therapy were similar in both groups. Artemotil was a well-tolerated drug in the 48 patients in this study. It appears to be at least therapeutically equivalent to quinine for the treatment of pediatric cerebral malaria. It has the advantage of being able to be given intramuscularly once daily for only five days.

Progress in the research of artemisinin-related antimalarials: an update.

Artemisinin, a sesquiterpene lactone endoperoxide isolated from Artemisia annua L., and a number of its semisynthetic derivatives have shown to possess antimalarial properties. They are all effective against Plasmodium parasites that are resistant to the newest and commonly used antimalarial drugs. This article gives a survey of the literature dealing with artemisinin-related antimalarial issues that have appeared from the end of 1989 up to the beginning of 1994. A broad range of medical and pharmaceutical disciplines is covered, including phytochemical aspects like the selection of high-producing plants, analytical procedures, and plant biotechnology. Furthermore, the organic synthesis of artemisinin derivatives is discussed, as well as their mechanism of action and antimalarial activity, metabolism and pharmacokinetics, clinical studies, side-effects and toxicology, and biological activities other than antimalarial activity.

Comparison of in vivo and in vitro antimalarial activity of artemisinin, dihydroartemisinin and sodium artesunate in the Plasmodium berghei-rodent model.

The in vitro and in vivo antimalarial activity of artemisinin, artesunate and dihydroartemisinin has been compared using the Plasmodium berghei-rodent model. Drugs were added to synchronized short-term in vitro cultures of the erythrocytic stages and inhibition of parasite development was determined by measuring DNA synthesis by flow cytometry. Dihydroartemisinin was the most effective drug. IC50 values of artemisinin, artesunate and dihydroartemisinin were 1.9, 1.1 and 0.3 x 10(-8) M, respectively, when drugs were present during the complete 24 h developmental cycle. IC50 values increased significantly when drugs were added to old trophozoites, indicating that the older stages are less sensitive. To determine the in vivo antimalarial activity, mice with a parasitaemia between 1% and 3% were injected intramuscularly on 3 consecutive days with a single dose of the drugs dissolved in Miglyol 812. Again dihydroartemisinin was the most effective drug in vivo, showing a cure rate of 47% at 10 mg/kg bodyweight, while with both other drugs the recrudescence rate was 100% at the same dosage. This study showed that the P. berghei-rodent model is a useful tool for accurate comparisons of the in vivo and in vitro antimalarial activity of drugs.

Artemisinin, Related Sesquiterpenes, and Essential Oil in Artemisia annua During a Vegetation Period in Vietnam.

The active principle of ARTEMISIA ANNUA L., artemisinin, is currently being developed to a registered antimalarial drug. For production purposes, plants with a high artemisinin content are required. We followed the development of the artemisinin content and of the biosynthetically related sesquiterpenes artemisinic acid, arteannuin B, and artemisitene in A. ANNUA plants, during a vegetation period in Vietnam, where this species is indigenous. In addition, the essential oil content and composition were studied. Samples of leaves, buds, flowers, or post-bloom flowers and fruits were taken at different stages: vegetative (5, 6, and 8 months old), at mass formation of buds (9 months), at full bloom (10 months), and post-bloom (10S months). The highest artemisinin content (0.86% dry wt) was present in the leaves of 5 months-old plants. At this stage also the highest leaf yield was found. Subsequently, the artemisinin content gradually dropped. At the age of 5 months the highest artemisinic acid and arteannuin B contents, 0.16 and 0.08% dry wt, respectively, were found as well. Artemisitene was present at all stages of development, ranging from 0.002 to 0.09% dry wt. With 1.9% v/w, the essential oil content was maximal just before flowering and was composed of 55% monoterpenes and 45% sesquiterpenes. At all other stages (0.4 - 1.0% v/w oil) this ratio was ca. 30%/70%. The main components of the oil were camphor and germacrene-D.

Endod: safety evaluation of a plant molluscicide.

Toxicity tests, in accordance with the Minimal Data Requirements (Tier 1) of the OECD Guidelines for Pre-Market Chemicals, were conducted on a standard extract (Endod-S) from the unripe berries of Phytolacca dodecandra, a potent botanical molluscicide of potential importance in the control of schistosomiasis. In acute mammalian toxicity tests, except for the eye irritation toxicity test which indicated severe irritancy, all test results were classified as either nontoxic or slightly toxic. Eye protection is therefore recommended during berry crushing and handling of dry powders. Ecotoxicity tests indicated that Endod is no more toxic than currently recommended synthetic molluscicides; however, environmental fate and additional local ecotoxicity tests are recommended for nontarget aquatic organisms present in the endemic situations of field trials. Given these toxicological data and recognizing the need for an affordable, locally cultivated, botanical molluscicide, it is concluded that field trials of Endod in schistosomiasis control are now justifiable.

Artemisia annua L.: a source of novel antimalarial drugs.

Artemisia annua L. contains artemisinin, an endoperoxide sesquiterpene lactone, mainly in its leaves and inflorescences. This compound and a series of derivatives have attracted attention because of their potential value as antimalarial drugs. In this review a survey of the currently available literature data is given. It includes phytochemical aspects, such as constituents of A. annua, the artemisinin content during the development of the plant and its biosynthesis, isolation, analysis and stability. Total chemical synthesis of artemisinin is referred to, as well as structure-activity relationships of derivatives and simplified analogues. Pharmacological studies are summarized, including the mechanism of action, interaction of the antimalarial activity with other drugs, possible occurrence of resistance to artemisinin, clinical results, toxicological aspects, metabolism and pharmacokinetics. Finally, plant cell biotechnology is mentioned as a possible means to obtain plants and cell cultures with higher artemisinin contents, allowing an industrial production of pharmaceuticals containing this novel drug.

Plasmodium berghei: the antimalarial action of artemisinin and sodium artelinate in vivo and in vitro, studied by flow cytometry.

Sodium artelinate, a new water-soluble and relatively stable derivative of artemisinin, and its parent compound were tested for their antimalarial action. Experiments were done in vitro with synchronous cultures of Plasmodium berghei. The inhibition of growth by different concentrations of sodium artelinate and artemisinin was determined using flow cytometry. In vivo testing was done by subcutaneous injection of each drug in mice infected with P. berghei. Sodium artelinate, being stable in aqueous solution, was also administered orally to infected mice by its addition to their drinking water. Comparison of the parent compound and the derivative showed that sodium artelinate was slightly less active than artemisinin both in culture and in vivo. However, after oral administration of sodium artelinate, parasites were cleared from the blood with one-half to one-tenth of the dose used in the experiments with subcutaneous injection. The number of mice which were cured by oral administration of sodium artelinate was greater than after subcutaneous injection, even with a total oral dose lower than the injected dose.