1921
Volume 71, Issue 6
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645

Abstract

Pharmacokinetic data were obtained to evaluate the therapeutic potential of Artemotil (β-arteether) in 56 Thai patients with severe malaria. Intramuscular administration was given at 1) a low dose of 3.2 mg/kg on day 0 and 1.6 mg/kg/day on days 1–4 and 2) a high dose of 4.8 mg/kg on day 0 at 0 hours, 1.6 mg/kg at 6 hours, and 1.6 mg/kg/day on days 1–4. Cmax values of 63.7 ng/mL at 6.1 hours and 140.8 ng/mL at 5.7 hours were reached in low-dose and high-dose patients, respectively. Drug concentrations decreased slowly with half-lives of 12.5–22.4 hours on day 0 and 31.6–40.7 hours on day 4 for both dosage regimens. Although the maintaining dosage on the last day was much lower than the loading dose on day 0, the area under the curve (AUC) and Cmax on day 4 were significantly increased (2.85–4.55 fold), suggesting drug accumulation in the blood. Dihydroartemisinin (DHA), an active metabolite of Artemotil, was detected in most patients. The mean ratios of DHA and Artemotil were 0.16–0.19 in both dosage regimens for the entire study period. Similar to previous reports, all patients showed a slow response to treatment with mean values of 77.2 hours for the fever clearance time (FCT) and 75.8 hours for the parasite clearance time (PCT) (low dose) and 70.1 hours for the FCT and 64.4 hours for the PCT (high dose). Interestingly, a very rapid response to the treatment was exhibited in patient 151, with an FCT of 4 hours and a PCT of 36 hours, with different pharmacokinetic data from others on day 0. The patient had a very high Cmax (2,407 ng/mL) and AUC (12,259 ng·hr/mL) values without an intramuscular absorption phase on the first day. These values were approximately 21.9 (Cmax) and 2.6 (AUC) times higher than in other patients; this patient may have been to be injected through a vessel at first dosing. In conclusion, the patients treated with the high dosage regimen had higher AUC values and higher antimalarial efficiency (cure rate = 48%) than the low-dose subjects (cure rate = 23%). Despite the high accumulation and longer exposure time (9–11 days) when compared with other artemisinin agents, due to the slow prolonged absorption of Artemotil from injection sites, the two dosage regimens did not show a better therapeutic effects than other artemisinin drugs, including α/β-arteether dissolved in peanut oil used in Indian patients.

Loading

Article metrics loading...

/content/journals/10.4269/ajtmh.2004.71.723
2004-12-01
2017-09-21
Loading full text...

Full text loading...

/deliver/fulltext/14761645/71/6/0700723.html?itemId=/content/journals/10.4269/ajtmh.2004.71.723&mimeType=html&fmt=ahah

References

  1. Davidson DE, 1994. Role of arteether in the treatment of malaria and plans for further development. Trans R Soc Trop Med Hyg 88 (Suppl 1): 51–52.
  2. Kager PA, Schultz MJ, Zijlstra EE, van Berg B, van Boxtel ChJ, 1994. Arteether administration in humans: preliminary studies of pharmacokinetics, safety and tolerance. Trans R Soc Trop Med Hyg 88 (Suppl 1): 53–54.
  3. Looareesuwan S, Wilairatana P, 1998. The rational use of qinhaosu and its derivatives: what is the future of new compounds? Med Trop (Mars) 58 (Suppl 3): 89S–92S.
  4. Thuma PE, Bhat GJ, Mabeza GF, Osborne C, Biemba G, Shakankale GM, Peeters PAM, Oosterhuis B, Lugt CB, Gordeuk VR, 2000. A randomized controlled trial of artemotil (β-arteether) in Zambian children with cerebral malaria. Am J Trop Med Hyg 62 : 524–529.
  5. Moyou-Somo R, Tietche F, Ondoa M, Kouemeni LE, Ekoe T, Mbonda E, Nsangou C, Jemea B, Guemkam G, 2001. Clinical trial of beta-arteether versus quinine for the treatment of cerebral malaria in children in Yaounde, Cameroon. Am J Trop Med Hyg 64 : 229–232.
  6. de Vries PJ, Dien TK, 1996. Clinical pharmacology and therapeutic potential of artemisinin and its derivatives in the treatment of malaria. Drugs 52 : 818–836.
  7. Looareesuwan S, Oosterhuis B, Schilizzi BM, Sollie FA, Wilairatana P, Krudsood S, Lugt CB, Peeters PA, Peggins JO, 2002. Dose-finding and efficacy study for i.m. artemotil (beta-arteether) and comparison with i.m. artemether in acute uncomplicated P. falciparum malaria. Br J Clin Pharmacol 53 : 492–500.
  8. Mishra SK, Asthana OP, Mohanty S, Patnaik JK, Das BS, Srivastava JS, Satpathy SK, Dash S, Rath PK, Varghese K, 1995. Effectiveness of α/β-arteether in acute falciparum malaria. Trans R Soc Trop Med Hyg 89 : 299–301.
  9. Mohanty S, Mishra SK, Satpathy SK, Dash S, Patnaik J, 1997. Alpha, beta-arteether for the treatment of complicated falciparum malaria. Trans R Soc Trop Med Hyg 91 : 328–330.
  10. Mohapatr PK, Khan AM, Prakash A, Mahanta J, Srivastava VK, 1996. Effect of arteether alpha/beta on uncomplicated falciparum malaria cases in Upper Assam. Indian J Med Res 104 : 284–287.
  11. Singh N, Shukla MM, Asthana OP, Sharma VP, 1998. Effectiveness of alpha-beta arteether in clearing Plasmodium falciparum parasitemia in central India (Madhya Pradesh). Southeast Asian J Trop Med Public Health 29 : 225–227.
  12. Valecha N, Gupta S, Usha D, Biswas S, Sharma A, Adak T, Asthana OP, Sharma VP, 1997. Efficacy of alpha, beta-arteether in acute uncomplicated P. falciparum malaria. Int J Clin Pharmacol Res 17 : 11–15.
  13. van Hensbroek MB, van Onyiorah E, Jaffar S, Schneider G, Palmer A, Frenkel J, Enwere G, Forck S, Nusmeijer A, Bennett S, Greenwood B, Kwiatkowski D, 1996. A trial of arte-mether or quinine in children with cerebral malaria. N Engl J Med 335 : 69–75.
  14. Tran TH, Day NP, Nguyen HP, Nguyen TH, Tran TH, Pham PL, Dinh XS, Ly VC, Ha V, Waller D, Peto TE, White NJ, 1996. A controlled trial of artemether or quinine in Vietnamese adults with severe falciparum malaria. N Engl J Med 335 : 76–83.
  15. Karbwang J, Na-Bangchang K, Thanavibul A, Molunto P, 1998. Plasma concentrations of artemether and its major plasma metabolite, dihydroartemisinin, following a 5-day regimen of oral artemether, in patients with uncomplicated falciparum malaria. Ann Trop Med Parasitol 92 : 31–36.
  16. Looareesuwan S, Wilairatana P, Viravan C, Vanijanonta S, Pitisutitithum P, Kyle DE, 1997. Open randomized trial of oral artemether alone and a sequential combination with mefloquine for acute uncomplicated falciparum malaria. Am J Trop Med Hyg 56 : 613–617.
  17. Mohamed SS, Khalid SA, Ward SA, Wan TS, Tang HP, Zheng M, Haynes RK, Edwards G, 1999. Simultaneous determination of artemether and its major metabolite dihydroartemisinin in plasma by gas chromatographymass spectrometry-selected ion monitoring. J Chromatogr B Biomed Sci Appl 731 : 251–260.
  18. Murphy S, English M, Waruiru C, Mwangi I, Amukoye E, Crawley J, Newton C, Winstanley P, Peshu N, Marsh K, 1996. An open randomized trial of artemether versus quinine in the treatment of cerebral malaria in African children. Trans R Soc Trop Med Hyg 90 : 298–301.
  19. Na-Bangchang K, Karbwang J, Thomas CG, Thanavibul A, Sukontason K, Ward SA, Edwards G, 1994. Pharmacokinetics of artemether after oral administration to health Thai males and patients with acute, uncomplicated falciparum malaria. Br J Clin Pharmacol 37 : 249–253.
  20. Salako LA, Walker O, Sowunmi A, Omokhodion SJ, Adio R, Oduola AM, 1994. Artemether in moderately severe and cerebral malaria in Nigerian children. Trans R Soc Trop Med Hyg 88 (Suppl 1): 13–15.
  21. Sowunmi A, Oduola AMJ, 1996. Efficacy of artemether in severe falciparum malaria in African children. Acta Trop 61 : 57–63.
  22. Walker O, Salako LA, Omokhodion SI, Sowunmi A, 1993. An open randomized comparative study of intramuscular artemether and intravenous quinine in cerebral malaria in children. Trans R Soc Trop Med Hyg 87 : 564–566.
  23. Barradell LB, Fitton A, 1996. Artesunate, A review of its pharmacology and therapeutic efficacy in the treatment of malaria. Drugs 50 : 714–741.
  24. Li GQ, Wang XH, Guo XB, Fu LC, Jian HX, Chen PQ, 1999. Dose finding of dihydroartemisinin in treatment of falciparum malaria. Southeast Asian J Trop Med Public Health 30 : 17–19.
  25. Looareesuwan S, Wilairatana P, Vanijanonta S, Pitisuttithum P, Viravan C, 1996. Treatment of acute, uncomplicated, falciparum malaria with oral dihydroartemisinin. Ann Trop Med Parasitol 90 : 21–28.
  26. Wilairatana P, Chanthavanich P, Singhasivanon P, Treeprasertsuk S, Krudsood S, Chalermrut K, Phisalaphong C, Kraisintu K, Looareesuwan S, 1998. A comparison of three different dihydroartemisinin formulations for the treatment of acute uncomplicated falciparum malaria in Thailand. Int J Parasitol 28 : 1213–1218.
  27. Xu C, Ding Y, Qi Z, 1997. Efficacy of dihydroartemisinin in treatment of 37 malaria cases. Chin J Intern Med 36 : 187–189.
  28. Noedl H, Wernsdorfer WH, Krudsood S, Wilairatana P, Kollaritsch H, Wiedermann G, Looareesuwan S, 2001. Antimalarial activity of azithromycin, artemisinin and dihydroartemisinin in fresh isolates of Plasmodium falciparum in Thailand. Acta Trop 80 : 39–44.
  29. Shmuklarsky MJ, Klayman DL, Milhous WK, Rossan RN, Ager AL, Tang DB Jr, Heiffer MH, Canfield CJ, Schuster BG, 1993. Comparison of β-artemether and β-arteether against malaria parasites in vivo and in vitro. Am J Trop Med Hyg 48 : 377–384.
  30. Bustos MDG, Gay F, Diquet B, 1994. In vitro tests on Philippine isolates of Plasmodium falciparum against four standard anti-malarials and four qinghaohu derivatives. Bull World Health Organ 72 : 729–735.
  31. Kager PA, 2003. Three newly registered drugs in the Netherlands for the treatment and chemoprophylaxis of malaria: atovaquone-proguanil, artemether-lumefantrine and Artemotil. Ned Tijdschr Geneeskd 147: 291–295.
  32. Melendez V, Peggins JO, Brewer TG, Theoharides AD, 1991. Determination of the antimalarial arteether and its deethylated metabolite dihydroartemisinin in plasma by high-performance liquid chromatography with reductive electrochemical detection. J Pharm Sci 80 : 132–138.
  33. Li QG, Peggins JO, Fleckenstein L, Masonic K, Heiffer MH, Brewer TG, 1998. Bioavailability and pharmacokinetics of dihydroartemisinin, arteether, artemether, artesunic acid and artelinic acid in rats. J Pharm Pharmacol 50 : 173–182.
  34. Classen W, Altmann B, Gretener P, Souppart C, Skelton-Stroud P, Krinke G, 1999. Differental effects of orally versus parenterally administered qinghaosu derivatives artemether in dogs. Exp Toxicol Pathol 51 : 507–516.
  35. Li QG, Brueckner RP, Peggins JO, Brewer TG, 1999. Arteether pharmacokinetics in rats after 25 mg/kg/day single and multiple doses. Eur J Drug Metab Pharmacokinet 24 : 283–294.
  36. Titulaer HAC, Zuidema J, Lugt CB, 1991. Formulation and pharmacokinetics of artemisinin and its derivatives. Int J Pharm 69 : 83–92.
  37. Lugt CB, 2000. Dutch registration for artemotil injections. TDR News 63 : 13.
  38. van Agtmael MA, Gupta V, van der Graaf CA, van Boxtel CJ. 1999. The effect of grapefruit juice on the time-dependent decline of artemether plasma levels in healthy subjects. Clin Pharmacol Ther 66 : 408–414.
  39. van Agtmael MA, Shan CQ, Jiao XQ, Mul R, van Boxtel CJ, 1999. Multiple dose pharmacokinetics of artemether in Chinese patients treated for falciparum malaria. Int J Antimicrob Agents 12 : 151–158.
  40. Ashton M, Nguyen DS, Nguyen VH, Gordi T, Trinh NH, Dinh XH, Nguyen TN, Le DC, 1998. Artemisinin kinetics and dynamics during oral and rectal treatment of uncomplicated malaria. Clin Pharmacol Ther 63: 482–493.
  41. Ashton M, Hai TN, Sy ND, 1998. Artemisinin pharmacokinetics is time-dependent during repeated oral administration in healthy male adults. Drug Metab Dispos 26 : 2601–2605.
  42. Khanh NX, de Vries PJ, Ha LD, van Boxtel CJ, Koopmans R, Kager PA, 1999. Declining concentrations of dihydroartemisinin in plasma during 5-day oral treatment with artesunate for falciparum malaria. Antimicrob Agents Chemother 43 : 690– 692.
  43. Park BK, O’Neill PN, Maggs JL, Pirmohamed M, 1998. Safety assessment of peroxide antimalarials: clinical and chemical perspectives. Br J Clin Pharmacol 46 : 521–529.
  44. Giao PT, de Vries PJ, 2001. Pharmacokinetic interactions of antimalarial agents. Clin Pharmacokinet 40 : 343–373.
  45. Alin MH, Bjorkman A, 1994. Concentration and time dependence of artemisinin efficacy agaist Plasmodium falciparum in vitro. Am J Trop Med Hyg 50 : 771–776.
  46. Li QG, Mog SR, Si YZ, Kyle DE, Gettayacamin M, Milhous WK, 2002. Neurotoxicity and efficacy of arteether related to its exposure times and exposure levels in rodents. Am J Trop Med Hyg 66 : 516–525.
  47. White NJ, Krishna S, 1989. Treatment of malaria: some considerations and limitations of the current methods of assessment. Trans R Soc Trop Med Hyg 83 : 767–777.
  48. White NJ, 1992. Antimalarial pharmacokinetics and treatment regimens. Br J Clin Pharmacol 34 : 1–10.
  49. World Health Organization, 2000. Severe falciparum malaria (Severe and Complicated Malaria, third edition). Trans R Soc Trop Med Hyg 94 (Suppl 1): 1–90.
  50. Krudsood S, Wilairatana P, Vannaphan S, Treeprasertsuk S, Silachamroon U, Phomrattanaprapin W, Gourdeuk VR, Brittenham GM, Looareesuwan S, 2003. Clinical experience with intravenous quinine, intramuscular artemether and intravenous artesunate for the treatment of severe malaria in Thailand. Southeast Asian J Trop Med Public Health 34 : 54–61.
  51. Hassan AM, Bjorkman A, Ashton M, 1990. In vitro activity of artemisinin, its derivatives, and pyronaridine against different strains of Plasmodium falciparum. Trans R Soc Trop Med Hyg 84 : 635–637.
  52. Lee IS, Hufford CD, 1990. Metabolism of antimalarial sesquiterpene lactones. Pharmacol Ther 48 : 345–355.
http://instance.metastore.ingenta.com/content/journals/10.4269/ajtmh.2004.71.723
Loading
/content/journals/10.4269/ajtmh.2004.71.723
Loading

Data & Media loading...

  • Received : 05 Feb 2004
  • Accepted : 30 Jun 2004

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error