artelinic-acid and Malaria

It is urgent to develop new antimalarial drugs with good therapeutic effects to address the emergence of drug resistance. Here, the artelinic acid-choline derivative (AD) was synthesized by dehydration reaction and esterification reaction, aimed to avoid the emergence of drug resistance by synergistic effect of artemisinins and choline derivative, which could compete with choline for rate-limiting enzymes in the phosphatidylcholine (PC) biosynthetic pathway. AD was formulated into liposomes (ADLs) by the thin-film hydration method. Efficacy of ADLs was evaluated by Peters 4-day suppression test. The suppression percentage against Plasmodium yoelii BY265 (PyBY265) in ADLs group was higher than those of positive control groups (dihydroartemisinin liposomes, P < 0.05) and other control groups (P ⩽ 0.05) at the doses of 4.4, 8.8, 17.6 µmol (kg·d)-1, respectively. The negative conversion fraction, recrudescence fraction and survival fraction of ADLs group were superior to other control groups. Pharmacokinetics in rats after intravenous injection suggested that ADLs exhibited higher exposure levels (indexed by area under concentration-time curve) than that of AD solution, artelinic acid liposomes or artelinic acid solution (P < 0.01). Taken together, ADLs exhibited promising antimalarial efficacy and pharmacokinetic characteristics.

Topics: Animals; Antimalarials; Artemisinins; Choline; Liposomes; Malaria; Mice; Mice, Inbred ICR; Plasmodium yoelii; Rats; Rats, Sprague-Dawley

The US Army designed artelinate/lysine salt (AL) to overcome the instability of sodium artesunate in aqueous solution (AS). To select the most efficacious artemisinin treatment, direct comparison was performed in an uncomplicated non-human primate malaria model.. Splenectomized rhesus monkeys were inoculated with Plasmodium coatneyi and on day six, single equimolar loading dose of IV AL (11.8 mg kg(-1)) or IV AS (8 mg kg(-1)) were administered followed by 1/2 the first dose once daily for 2 more days. Blood smear were performed twice daily and the number of parasites were counted microscopically. Blood samples were obtained after the first dose within 6 h for pharmacokinetic (PK) and ex vivo pharmacodynamic evaluation by simultaneously measuring plasma drug concentration and anti-malarial activity against Plasmodium falciparum in vitro.. The anti-P. coatneyi in vivo activity of both compounds were comparable, but the ex vivo anti-P. falciparum potency of the IV AS regimen as administered was sevenfold higher than that of IV AL. Comparing in vivo pharmacodynamics of AL and AS, daily assessed parasite counts showed comparable 99 % parasite clearance times (PC99: 2.03, 1.84 day), parasite clearance rates (5.34, 4.13 per min) and clearance half-life (PCt1/2: 7.79, 10.1 h). This study showed strong and significant inverse correlation between PCt1/2 and t1/2 of AS + DHA, and AUC0-∞ of DHA, and correlated with Vz of AS (r(2) > 0.7, p ≤ 0.002). Lastly, following IV AL, there was a modest inverse correlation between PCt1/2 and Cmax (r(2) 0.6, p ≤ 0.04). Although all tested monkeys recrudesced subsequently, two died following AL regimen before parasite clearance. While the aetiology of those deaths could not be definitively determined, pathologic evidence favoured a sepsis-like syndrome and suggested that severe malaria was more likely than drug toxicity.. The model demonstrated that both AS and DHA contributed to the anti-malarial activity of IV AS, while IV AL activity was largely restricted to the parent drug. Parasite clearance was strongly and linearly dependent on drug exposure for both artemisinin regimens. However, IV AS had higher ex vivo potency against P. falciparum, leading to an IND filing for GMP manufactured AS in the United States.

Topics: Animals; Antimalarials; Artemisinins; Artesunate; Disease Models, Animal; Macaca mulatta; Malaria; Splenectomy; Treatment Outcome; United States

A recent therapeutic index study in rats demonstrated that i.v. artesunate (AS) is safer than artelinate (AL). The present study of acute toxicity illustrated an LD(50) of 177 mg/kg and 488 mg/kg for AL and AS, respectively, following daily i.v. injection for 3 days in Plasmodium berghei-infected rats. In uninfected rats, the LD(50) values were 116 mg/kg and 351 mg/kg after a single dose of AL and AS, respectively. This study showed vascular necrosis in 50% of the animals at 13.5 mg/kg AL and at 42.8 mg/kg AS. Animals also showed moderate signs of renal failure at 40 mg/kg AL and 240 mg/kg AS (100 times higher than the therapeutic dose). Histopathological evaluation demonstrated mild to moderate tubular necrosis in uninfected rats treated with 40 mg/kg AL and 240 mg/kg AS; interestingly, fewer pathological lesions were observed in malaria-infected rats. Renal injury was reversible in all cases by Day 8 after cessation of dosing. No neurotoxicity was seen in any case with all i.v. regimens. In conclusion, AL and AS exhibit less toxic effects in P. berghei-infected rats than in uninfected rats. Both agents caused irreversible vascular irritation, reversible nephrotoxicity and no neurotoxicity at high doses. The data indicate that AS is three times safer than AL in rats.

Topics: Acute Kidney Injury; Animals; Antimalarials; Artemisinins; Artesunate; Brain Diseases; Dose-Response Relationship, Drug; Lethal Dose 50; Malaria; Male; Necrosis; Plasmodium berghei; Random Allocation; Rats; Rats, Sprague-Dawley; Sesquiterpenes; Tail; Vascular Diseases

An economical phase-transfer method is used to prepare 10-arylaminoartemisinins from DHA and arylamines, and artemether, arteether, and artelinate from the corresponding alcohols. In vivo sc screens against Plasmodium berghei and P. yoelii in mice reveal that the p-fluorophenylamino derivative 5 g is some 13 and 70 times, respectively, more active than artesunate; this reflects the very high sc activity of 10-alkylaminoartemisinins. However, through the po route, the compounds are less active than the alkylaminoartemisinins, but still approximately equipotent with artesunate.

Topics: Animals; Antimalarials; Artemether; Artemisinins; Malaria; Mice; Molecular Structure; Parasitemia; Plasmodium berghei; Plasmodium falciparum; Plasmodium yoelii; Sesquiterpenes

To search for water soluble dihydroartemisinin derivatives with higher efficacy and longer plasma half-life than artesunic or artelinic acid, a series of new stereoisomers of 4-(p-substituted phenyl)-4(R or S)-[10(alpha or beta)-dihydroartemisininoxy]butyric acids were synthesized as new potential antimalarial agents. Two approaches were taken in the design of these new molecules in an attempt to (a) increase the lipophilicity of the molecule and (b) decrease the rate of oxidative dealkylation of the target compounds. The new compounds showed a 2-10-fold increase in in vitro antimalarial activity against D-6 and W-2 clones of Plasmodium falciparum than artemisinin or artelinic acid. R-diastereomers are, in general, more potent than the corresponding S-diastereomers. p-Chlorophenyl and p-bromophenyl derivatives showed in vivo oral antimalarial activity against P. berghei (with 3/8 cured) superior to that of artelinic acid (1/8 cured), whereas p-fluorophenyl and p-methoxyphenyl analogs demonstrated activity only comparable (1/8 cured) to that of artelinic acid at the same dosage level (64 mg/kg twice a day). The in vivo antimalarial activity of these new compounds correlates with their SD50 (50% parasitemia suppression dose). The biological results suggested that an electronic effect, besides the lipophylicity, may play a role in determining the efficacy of this class of compounds.

Topics: Animals; Antimalarials; Artemisinins; Drug Design; Female; Magnetic Resonance Spectroscopy; Malaria; Mice; Molecular Conformation; Molecular Structure; Parasitemia; Plasmodium berghei; Plasmodium falciparum; Sesquiterpenes; Solubility

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.

Topics: Administration, Oral; Animals; Antimalarials; Artemisinins; Culicidae; Injections, Intravenous; Insect Vectors; Macaca mulatta; Malaria; Plasmodium cynomolgi; Sesquiterpenes

In addition to artelinic acid, which was demonstrated previously to possess good prophylactic as well as curative antimalarial activity against Plasmodium berghei by transdermal administration, seven artemisinin derivatives in a gel formulation were assessed for their antimalarial activities in this study. Artemisinin, the parent compound of the series, showed moderate prophylactic but poor curative activity. Although methyl artelinate was more active against P. berghei than artelinic acid and sodium artelinate by subcutaneous injection, its transdermal curative and prophylactic activity was only comparable with or weaker than that of artelinic acid. Conversely, both dihydroartemisinin trimethylsilyl ether and dehydrodihydroartemisinin showed weaker antimalarial activity than artelinic acid by the subcutaneous route, yet exhibited comparable activity by transdermal administration. Artemether, a prodrug of dihydroartemisinin, is as effective as the parent dihydroartemisinin, and both compounds were the most potent agents among the compounds studied, with total prophylactic and curative doses of 30 mg/kg and 60 mg/kg, respectively. Complete absorption of dihydroartemisinin appears to occur within 5 min after application. In general, we found that the prophylactic dose is about half that of the curative dose under the protocols used in this study. This novel drug delivery system may be an easy and safe way to administer artemisinin-type antimalarials and also a good alternative dosage form for active compounds with solubility problems.

Topics: Administration, Cutaneous; Animals; Antimalarials; Artemether; Artemisinins; Gels; Malaria; Mice; Plasmodium berghei; Sesquiterpenes; Structure-Activity Relationship

The efficacy of artelinic acid and artemisinin, orally administered at 10 and 50 mg kg-1 day-1, was compared in Plasmodium berghei infected mice. Subsequently, the pharmacokinetics of artelinic acid after intravenous, intramuscular, oral and rectal administration of a 20 mg kg-1 aqueous solution to rabbits were studied in a four-way randomized cross-over experiment. After intravenous administration, artelinic acid concentrations in blood plasma were high (C0: 76 +/- 15 mg L-1), and the drug was rapidly eliminated from the central compartment, showing linear elimination kinetics with an elimination half-life of 15 +/- 3 min. A large inter-subject variation appeared in the absorption rate and the extent of absorption (2-92%) over the 120 min interval after intramuscular administration. Also, a large inter-subject variation in individual rectal bioavailability (17-100%) was shown, which was dependent on the site of absorption in the rectum. The estimated oral bioavailability was low (4.6 +/- 1.7%), probably due to a high first-pass effect and possible decomposition in the acidic gastric environment.

Topics: Absorption; Administration, Oral; Administration, Rectal; Animals; Antimalarials; Artemisinins; Biological Availability; Injections, Intramuscular; Injections, Intravenous; Malaria; Mice; Plasmodium berghei; Sesquiterpenes

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.

Topics: Animals; Antimalarials; Artemisinins; Macaca mulatta; Malaria; Plasmodium knowlesi; Sesquiterpenes

Artelinic acid, a derivative of the naturally occurring antimalarial artemisinin, has been incorporated into a gel suitable for transdermal administration. The formulation was tested for efficacy in Plasmodium berghei-infected mice for both curative and prophylactic properties by application to their partially denuded backs, beginning on days 3 and 0, respectively, after injection of parasitized erythrocytes. In the curative experiments, rapid elimination of the parasitemia and 60-day survival of five of five mice was achieved by dermal application of gel containing 0.9 mg of artelinic acid that was administered twice a day, beginning on day 3 after infection, for three days (total dosage of 270 mg/kg). In the prophylactic trials, the establishment of parasitemia was prevented and 60-day survival was achieved in five of five mice at a dose of 0.9 mg of artelinic acid administered twice a day, beginning on the day of inoculation, for two days (total dosage of 180 mg/kg). The transdermal medium, with or without drug, caused no topical or systemic toxicity.

Topics: Administration, Cutaneous; Animals; Antimalarials; Artemisinins; Gels; Malaria; Mice; Plasmodium berghei; Sesquiterpenes

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.

Topics: Administration, Oral; Animals; Antimalarials; Artemisinins; DNA; Drugs, Chinese Herbal; Flow Cytometry; Injections, Subcutaneous; Malaria; Mice; Plasmodium berghei; Sesquiterpenes