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Objective: To evaluate the pharmacokinetics of alpha- and beta-diastereomers of arteether in healthy male volunteers., Participants and Methods: The study was a single-centre clinical pharmacokinetic trial in healthy male subjects. A group comprising 13 subjects aged 25-50 years received a single intramuscular 150 mg individual dose of the arteether formulation containing alpha- and beta-isomers in a 30:70 ratio. Serial blood samples collected over a period of 0-192 hours were analysed by high-performance liquid chromatography-electrospray ionisation/tandem mass spectrometry and the plasma concentrations were subjected to compartmental and noncompartmental analyses. Pharmacodynamic parameters such as area under the inhibitory curve, ratio of area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC), maximum plasma concentration to MIC (Cmax/MIC) and time that plasma concentration exceeds the MIC (T>MIC) were calculated in vitro in four strains of Plasmodium falciparum to evaluate the in vivo effectiveness of the proposed dosage regimen., Results: There were no adverse effects observed during the study. The extent of metabolism of arteether to dihydroartemisinin (DHA) was low (approximately 5%) so as to be therapeutically nonsignificant. The pharmacokinetic profiles of the arteether diastereomers were different, and the maximum plasma concentrations of alpha- and beta-isomers were reached at 4.77+/-1.21 hours and 6.96+/-1.62 hours, respectively, after which they showed biphasic decline with apparent terminal elimination half-lives of 13.24+/-1.08 hours and 30.17+/-2.44 hours, respectively. The plasma and renal clearances, as well as whole blood to plasma partition ratios of the isomers, were comparable, while the apparent volume of distribution during terminal phase of the beta-isomer was approximately 3-fold higher than that of the alpha-isomer. In vitro erythrocyte culture experiments with four strains of P. falciparum showed similar MICs for both isomers of arteether. The highest observed MIC of 8 microg/L was selected for estimating the pharmacokinetic and pharmacodynamic parameters, which showed excellent correlation with published data on the clinical efficacy of arteether., Conclusion: The pharmacokinetics of arteether isomers demonstrated stereoselectivity, which was reflected mainly in the volume of distribution and the terminal elimination half-life. The alpha- and beta-isomers of arteether appeared to compliment each other pharmacokinetically, with the alpha-isomer providing comparatively rapid and higher plasma concentrations resulting in immediate reduction in percentage parasitaemia, while the beta-isomer, with its longer terminal elimination half-life, mean residence time and sustained plasma concentrations, maintained the activity for longer periods. The extent of metabolic conversion of arteether to DHA was minimal, so as to have any therapeutic or toxic significance.

Objective: To undertake post-marketing surveillance (PMS) of arteether (E-Mal) with the aim of obtaining feedback from clinicians regarding its safety, tolerability, efficacy and adverse event profile in patients of P. falciparum malaria., Method: Post-marketing surveillance proforma to collect data from clinicians using arteether (E-Mal) was provided to institutions/nursing homes and hospitals where Arteether (E-Mal) was available for use in treatment of P. falciparum malaria. These clinicians were informed about the need and relevance of providing this feedback regarding their reexperience on E-Mal therapy on predesigned proforma. Duly filled proformas were received by Central Drug Research Institute, Lucknow for data analysis, documentation and conclusions regarding E-Mal therapy., Result: A total of 300 reports were received for analysis from states of Bihar, Gujarat, Madhya Pradesh, Maharashtra, Rajasthan and Uttar Pradesh. The results show that 294 cases (98%) were cured, five cases improved and one patient did not show any change in the clinical status. The side effects (headache, nausea, vomiting and giddiness) reported in the proforma of 14 cases were mild in nature and no causal relationship with arteether could be ascertained., Conclusion: An indepth analysis of these 300 reports confirmed the safety, highlighted excellent tolerability and further proved the efficacy of three-day schedule of arteether (IMI) for treatment of malaria. Arteether should not be used in P. Vivax malaria (E-Mal) except when smear is positive for both (P. falciparum and P. vivax). In such a situation risk-benefit should be carefully evaluated before advocating the use of E-Mal therapy. The post-marketing surveillance is continuing and it is hoped that with more feedback from the clinicians from various parts of the country PMS data on this novel antimalarial drug (E-Mal) would further be documented.

Objective: To evaluate efficacy of alpha;beta arteether in patients of P. falciparum malaria presenting with complications was undertaken in a multicentric clinical trial., Method: Each patient who consented to undergo clinical trial with parenteral Arteether was treated with a fixed dose schedule of Arteether given intramuscularly in a dose of 150 mg once a day on three consecutive days. Every patient was followed upto 28 days with clinical, haematological and parasitological monitoring every day upto one week and thereafter at 14, 21 and 28 days. The response was assessed in terms of fever clearance time, parasite clearance time, cure rate and parasite reappearance rate., Results: A total of 211 patients of P. falciparum malaria were included in the study from four centres (Bhilai, Guwahati, Jamshedpur and Rourkela). Results of this study showed that fever clearance time ranged between 24-168 hours, parasite clearance time ranged between 24-120 hours and overall mortality ranged between 4-8.5%. Out of 211, only 14 patients expired during the study, of these, 10 patients expired within first two days i.e. before completing the three day schedule of arteether therapy. Tolerability to arteether injection was good in all these patients and no untoward effects were experienced or reported during the study. Overall cure rate observed in these studies was 93%., Conclusion: This study shows a rapid parasite and fever clearance in patients of complicated P. falciparum malaria.

Two hundred and sixty seven patients of uncomplicated P. falciparum malaria completed study in a multicentric phase III clinical trial of Arteether. Arteether was given intramuscularly in a dose of 150 mg daily for three consecutive days. Each patient was followed upto 28 days of alpha, beta arteether therapy. The cure rate was 97% with fever clearance time between 1-7 days (24-168 hours) and parasite clearance time between 1-3 days (24-72 hours). Parasite reappearance rate was found to be 3% and reported at only three of the centres. Following the treatment no adverse effect was observed on haematological, biochemical and vital clinical parameters.

Forty-six patients (25 Females + 21 Males) of uncomplicated Plasmodium falciparum in districts Jabalpur and Mandla of central India (Madhya Pradesh) were administered alpha-beta arteether (an ethyl derivative of qinghaosu), intramuscularly for 3 consecutive days (150 mg once a day). The results revealed that there was rapid control of fever in all the patients without administration of any antipyretic drug. The mean parasite clearance time was 30.78 +/- 10.92 hours and recrudescence/reinfection rate was 6.7% within 28 days. Study indicates that arteether, besides being a potent and fast acting schizontocidal drug, also exhibited gametocytocidal action on P. falciparum.

A phase-III clinical trial was conducted in 50 patients (42M + 8F) with acute uncomplicated falciparum malaria from Delhi during the period of September to November 1995. Their mean age was 27.2 years, and the mean parasitaemia on day 0 was 0.65%. Patients were hospitalized and treated with a new ethyl derivative of artemisinin developed at CDRI called alpha, beta-arteether, at the dosage of 150 mg l/M for three consecutive days. Peripheral smears were examined every day for 4 days and then weekly up to 28 days. The results of the study showed that the mean parasite and fever clearance times were respectively 19.94 +/- 6.87 and 37.81 +/- 21.67 hours. Within 48 h, 70% of the cases became afebrile and the peripheral smear was negative in 100% of the cases. The drug was well tolerated. Three cases (6%) had recrudescence within 28 days. It is concluded that alpha, beta-arteether is a safe, effective and rapidly acting antimalarial.

With the emergence of widespread chloroquine resistance and a world-wide scarcity of quinine, a search for newer antimalarial drugs has become imperative. Different derivatives of qinghaosu have been successfully tried. alpha,beta-Arteether, an ethyl derivative of qinghaosu, was administered to 51 patients with Plasmodium falciparum malaria, in a dose of 150 mg intramuscularly once a day on 3 consecutive days. Complete parasite clearance from the peripheral blood was observed in 80% of the patients at 48 h and in 98% at 72 h. The median parasite clearance time was 2 d (range 1-4 d). 65% of the patients became afebrile within 48 h and 81% by 72 h. The mean fever clearance time was 52.04 h (standard deviation 27.09). No side effect was seen. Patients were followed-up for 4 weeks; 7 were readmitted with P. falciparum infection but it could not be ascertained definitely whether these cases were reinfections or recrudescences. alpha-beta Arteether was a safe, effective and convenient drug for treating P. falciparum malaria. This is the first clinical study with arteether in falciparum malaria.