Therapeutic efficacy of a regimen of artesunate-mefloquine-primaquine treatment for Plasmodium falciparum malaria and treatment effects on gametocytic development
Keywords:
falciparum, malaria, artesunate, mefloquine, primaquine, treatment outcome
Abstract
Introduction. The treatment of Plasmodium falciparum malaria requires a safe and effective therapeutic treatment regimen, which in turn has high impact on the transmission. In 2006, an artesunate (AS)-mefloquine (MQ) treatment program was implemented in Antioquia. In addition, primaquine (PQ) was added to eliminate malaria gametocytes in the bloodstream.Objective. The efficacy and gametocytocidal activity was evaluated for two treatment regimens, AS-MQ-PQ and AS-MQ, in patients with uncomplicated P. falciparum malaria.
Materials and methods. Between April 2007 and February 2008, 50 patients were recruited for the trial in Turbo, Antioquia. A randomized clinical trial was conducted. Treatment compliance was supervised, with a clinical and parasitological assessment on days 1, 2, 3, 7, 14, 21, 28, 35, and 42 to evaluate response rate according to the WHO 2003 protocol.
Results. Clinical response and parasite elimination efficacy of AS-MQ (with or without PQ) was 100% (95% CI 86.3%-100%), and parasitemia and fever were absent on day 3 of treatment in all patients. Gametocyte elimination was superior when PQ was used--92% (95% CI: 74%-99%) of patients who received PQ had no gametocytes on day 3, compared to 78.3% (95% CI: 59%-93%) of patients who only received AS-MQ. Furthermore, circulating gametocytes were eliminated on average one week faster when the AS-MQ-PQ treatment scheme was used compared to the scheme without PQ.
Conclusion. These studies recommend the use of AS-MQ to treat P. falciparum malaria given its good therapeutic efficacy. However, further assessment is suggested concerning the benefit of adding PQ to this treatment scheme.
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References
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18. Davis T. Addition of artesunate to standard antimalarial drugs reduces treatment failure. Evidence Based Healthcare. 2004;8:156-8.
19. Nosten F, Luxemburger C, ter Kuile FO, Woodrow C, Eh JP, Chongsuphajaisiddhi T, et al. Treatment of multidrug-resistant Plasmodium falciparum malaria with 3-day artesunate-mefloquine combination. J Infect Dis. 1994;170:971-7.
20. Price RN, Nosten F, Luxemburger C, Kham A, Brockman A, Chongsuphajaisiddhi T, et al. Artesunate versus artemether in combination with mefloquine for the treatment of multidrug-resistant falciparum malaria. Trans R Soc Trop Med Hyg. 1995;89:523-7.
21. Bunnag D, Kanda T, Karbwang J, Thimasarn K, Pungpak S, Harinasuta T. Artemether or artesunate followed by mefloquine as a possible treatment for multidrug resistant falciparum malaria. Trans R Soc Trop Med Hyg. 1996;90:415-7.
22. Bunnag D, Kanda T, Karbwang J, Thimasarn K, Pungpak S, Harinasuta T. Two doses of artemether/mefloquine or artesunate/mefloquine combination for multidrug resistant falciparum malaria. Southeast Asian J Trop Med Public Health. 1997;28:727-30.
23. Thimasarn K, Sirichaisinthop J, Chanyakhun P, Palananth C, Rooney W. A comparative study of artesunate and artemether in combination with mefloquine on multidrug resistant falciparum malaria in eastern Thailand. Southeast Asian J Trop Med Public Health. 1997;28:465-71.
24. Price RN, Nosten F, Luxemburger C, van Vugt M, Phaipun L, Chongsuphajaisiddhi T, et al. Artesunate/mefloquine treatment of multi-drug resistant falciparum malaria. Trans R Soc Trop Med Hyg. 1997;91:574-7.
25. Price R, Luxemburger C, van Vugt M, Nosten F, Kham A, Simpson J, et al. Artesunate and mefloquine in the treatment of uncomplicated multidrug-resistant hyperparasitaemic falciparum malaria. Trans R Soc Trop Med Hyg. 1998;92:207-11.
26. van Vugt M, Brockman A, Gemperli B, Luxemburger C, Gathmann I, Royce C, et al. Randomized comparison of artemether-benflumetol and artesunate-mefloquine in treatment of multidrug-resistant falciparum malaria. Antimicrob Agents Chemother. 1998;42:135-9.
27. Massougbodji A, Kone M, Kinde-Gazard D, Same-Ekobo A, Cambon N, Mueller EA. A randomized, double-blind study on the efficacy and safety of a practical three-day regimen with artesunate and mefloquine for the treatment of uncomplicated Plasmodium falciparum malaria in Africa. Trans R Soc Trop Med Hyg. 2002;96:655-9.
28. Marquiño W, Huilca M, Calampa C, Falconí E, Cabezas C, Naupay R, et al. Efficacy of mefloquine and a mefloquine-artesunate combination therapy for the treatment of uncomplicated Plasmodium falciparum malaria in the Amazon Basin of Peru. Am J Trop Med Hyg. 2003;68:608-12.
29. Smithuis F, Shahmanesh M, Kyaw MK, Savran O, Lwin S, White NJ. Comparison of chloroquine, sulfadoxine/pyrimethamine, mefloquine and mefloquine-artesunate for the treatment of falciparum malaria in Kachin State, North Myanmar. Trop Med Int Health. 2004;9:1184-90.
30. Stohrer JM, Dittrich S, Thongpaseuth V, Vanisaveth V, Phetsouvanh R, Phompida S, et al. Therapeutic efficacy of artemether-lumefantrine and artesunate-mefloquine for treatment of uncomplicated Plasmodium falciparum malaria in Luang Namtha Province, Lao People’s Democratic Republic. Trop Med Int Health. 2004;9:1175-83.
31. Smithuis F, van der Broek I, Katterman N, Kyaw MK, Brockman A, Lwin S, et al. Optimising operational use of artesunate-mefloquine: a randomized comparison of four treatment regimens. Trans R Soc Trop Med Hyg. 2004;98:182-92.
32. Avila JC, Villaroel R, Marquiño W, Zegarra J, Mollinedo R, Ruebush TK. Efficacy of mefloquine and mefloquine-artesunate for the treatment of uncomplicated Plasmodium falciparum malaria in the Amazon region of Bolivia. Trop Med Int Health. 2004;9:217-21.
33. van den Broek IV, Maung UA, Peters A, Liem L, Kamal M, Rahman M, et al. Efficacy of chloroquine+sulfadoxine-pyrimethamine, mefloquine+artesunate and artemether +lumefantrine combination therapies to treat Plasmodium falciparum malaria in the Chittagong Hill Tracts, Bangladesh. Trans R Soc Trop Med Hyg. 2005;99:727-35
34. Hutagalung R, Paiphun L, Ashley EA, McGready R, Brockman A, Thwai KL, et al. A randomized trial of artemether-lumefantrine versus mefloquine-artesunate for the treatment of uncomplicated multi-drug resistant Plasmodium falciparum on the western border of Thailand. Malar J. 2005;4:46.
35. Tangpukdee N, Krudsood S, Thanachartwet W, Chalermrut K, Pengruksa C, Srivilairit S, et al. An open randomized clinical trial of Artekin vs. artesunate-mefloquine in the treatment of acute uncomplicated falciparum malaria. Southeast Asian J Trop Med Public Health. 2005;36:1085-91.
36. Campbell P, Baruah S, Narain K, Rogers C. A randomized trial comparing the efficacy of four treatment regimens for uncomplicated falciparum malaria in Assam state, India. Trans R Soc Trop Med Hyg. 2006; 100: 108-18.
37. Vijaykadga S, Rojanawatsirivej C, Cholpol S, Phoungmanee D, Nakavej A, Wongsrichanalai C. In vivo sensitivity monitoring of mefloquine monotherapy and artesunate-mefloquine combinations for the treatment of uncomplicated falciparum malaria in Thailand in 2003. Trop Med Int Health. 2006;11:211-9.
38. Smithuis F, Kyaw MK, Phe O, Aye KZ, Htet L, Barends M, et al. Efficacy and effectiveness of dihydroartemisinin-piperaquine versus artesunate-mefloquine in falciparum malaria: an open-label randomized comparison. Lancet. 2006;367:2075-85.
39. Denis MB, Tsuyuoka R, Poravuth Y, Narann TS, Seila S, Lim C, et al. Surveillance of the efficacy of artesunate and mefloquine combination for the treatment of uncomplicated falciparum malaria in Cambodia. Trop Med Int Health. 2006;11:1360-6.
40. Faye B, Ndiaye JL, Ndiaye D, Dieng Y, Faye O, Gaye O. Efficacy and tolerability of four antimalarial combinations in the treatment of uncomplicated Plasmodium falciparum malaria in Senegal. Malar J. 2007;6:80.
41. Bhatt KM, Samia BM, Bhatt SM, Wasunna KM. Efficacy and safety of an artesunate/mefloquine combination (artequin) in the treatment of uncomplicated P. falciparum malaria in Kenya. East Afr Med J. 2006;83:236-42.
42. RAVREDA-AMI. Antimalarial drug efficacy studies 2002-2005. Fecha de consulta: septiembre de 2008. Disponible en: http://www.paho.org/spanish/AD/DPC/CD/ravreda-ami-areas.htm
43. Giraldo C, Blair S. Mefloquina: revisión de tema. IATREIA. 2003;16:19-31.
44. Berninger E, Karlsson K, Alvan G. Quinine reduces the dynamic range of the human auditory system. Acta Otolaryngol. 1998;118:46-51.
45. Tange RA, Dreschler WA, Claessen FA, Perenboom RM. Ototoxic reactions of quinine in healthy persons and patients with Plasmodium falciparum infection. Auris Nasus Larynx. 1997;24:131-6.
46. Simoes Da Silva MV. Estudio de los efectos ototóxicos en 725 pacientes tratados con antimaláricos en el Hospital Central de Maputo (Mozambique) (tesis). Barcelona: Universidad Autónoma de Barcelona; 2004.
47. Chotivanich K, Sattabongkot J, Udomsangpetch R, Looareesuwan S, Day NP, Coleman RE, et al. Transmission-blocking activities of quinine, primaquine, and artesunate. Antimicrob Agents Chemother. 2006;50:1927-30.
48. Davis ME, Karunajeewa HA, llet KF. Artemisinin-based combination therapies for uncomplicated malaria. Med J Aust. 2005;182:181-5.
49. Shekalaghe S, Drakeley C, Gosling R, Ndaro A, van Meegeren M, Enevold A, et al. Primaquine clears submicroscopic Plasmodium falciparum gametocytes that persist after treatment with sulphadoxine-pyrimethamine and artesunate. PloS ONE. 2007;2:e1023. Doi:10.1371/journal.-pone.0001023
50.Pukrittayakamee S, Chotivanich K, Chantra A, Clemens R, Looareesuwan S, White NJ. Activities of artesunate and primaquine against asexual- and sexual-stage parasites in falciparum malaria. Antimicrob Agents Chemother. 2004;48:1329-34.
2. Phillips RS. Current status of malaria and potential for control. Clin Microbiol Rev. 2000;14:208-26.
3. Bloland PB. Drug resistance in malaria. WHO/CDS/CSR/ DRS/2001.4. Geneva: World Health Organization; 2001.
4. Wongsrichanalai C, Pickard AL, Wernsdorfer WH, Meshnick SR. Epidemiology of drug-resistant malaria. Lancet Infect Dis. 2002;2:209-18.
5. WHO. Assessment and monitoring of antimalarial drug efficacy for the treatment of uncomplicated falciparum malaria. WHO/HTM/RBM/2003.50. Geneva: World Health Organization; 2003.
6. WHO. Monitoring antimalarial drug resistance. WHO/CDS/CSR/EPH/2002.17. Geneva: World Health Organization; 2001.
7. Blair S, López M, Piñeros J, Álvarez T, Tobón A, Carmona J. Eficacia terapéutica de tres esquemas de tratamiento de malaria no complicada por Plasmodium falciparum, Antioquia, Colombia, 2002. Biomédica. 2003;23:318-27.
8. Osorio LE, Giraldo LE, Grajales LF, Arriaga AL, Andrade AL, RuebushII T, et al. Assessment of therapeutic response of Plasmodium falciparum to chloroquine and sulfadoxine/pyrimethamine in a low malaria transmission area in Colombia. Am J Trop Med Hyg. 1999;61:968-72.
9. Blair S, Lacharme L, Carmona-Fonseca J, Piñeros J, Ríos A, Álvarez T, et al. Therapeutic efficacy test in malaria falciparum in Antioquia, Colombia. Malar J. 2006;5:14.
10. Orjuela P, González I, Osorio L. Terapia combinada como estrategia en la prevención de la resistencia a los antimaláricos. Biomédica. 2004;24:423-37.
11. WHO. Guidelines for the treatment of malaria. WHO/HTM/MAL/2006.1108. Geneva: World Health Organization; 2006.
12. WHO. Susceptibility of Plasmodium falciparum to anti-malarial drugs monitoring antimalarial drug resistance. Report on global monitoring 1996-2004. WHO/HTM/MAL/ 2005.1103. Geneva: World Health Organization; 2005.
13. Nosten F, van Vugt M, Price R, Luxemburger C, Thway KL, Brockman A, et al. Effects of artesunate-mefloquine combination on incidence of Plasmodium falciparum malaria and mefloquine resistance in western Thailand: a prospective study. Lancet. 2000;356:297-302.
14. Davis TM, Karunajeewa HA, Ilett KF. Artemisinin-based combination therapies for uncomplicated malaria. Med J Aust. 2005;182:181-5.
15. Suputtamongkol Y, Chindarat S, Silpasakorn S, Chaikachonpatd S, Lim K, Chanthapakajee K, et al. The efficacy of combined mefloquine-artesunate versus mefloquine-primaquine on subsequent development of Plasmodium falciparum gametocitemia. Am J Trop Med Hyg. 2003;68:620-3.
16. Dirección Seccional de Salud de Antioquia. Protocolo de vigilancia epidemiológica para malaria, Antioquia 2007. Fecha de consulta: diciembre de 2007. Disponible en: http://www.dssa.gov.co/dowload/P0841.pdf
17. Talisuna A, Staedke S, D´Alessandro U. Pharmaco-vigilance of antimalarial treatment in Africa: is it possible? Malar J. 2006;5:50.
18. Davis T. Addition of artesunate to standard antimalarial drugs reduces treatment failure. Evidence Based Healthcare. 2004;8:156-8.
19. Nosten F, Luxemburger C, ter Kuile FO, Woodrow C, Eh JP, Chongsuphajaisiddhi T, et al. Treatment of multidrug-resistant Plasmodium falciparum malaria with 3-day artesunate-mefloquine combination. J Infect Dis. 1994;170:971-7.
20. Price RN, Nosten F, Luxemburger C, Kham A, Brockman A, Chongsuphajaisiddhi T, et al. Artesunate versus artemether in combination with mefloquine for the treatment of multidrug-resistant falciparum malaria. Trans R Soc Trop Med Hyg. 1995;89:523-7.
21. Bunnag D, Kanda T, Karbwang J, Thimasarn K, Pungpak S, Harinasuta T. Artemether or artesunate followed by mefloquine as a possible treatment for multidrug resistant falciparum malaria. Trans R Soc Trop Med Hyg. 1996;90:415-7.
22. Bunnag D, Kanda T, Karbwang J, Thimasarn K, Pungpak S, Harinasuta T. Two doses of artemether/mefloquine or artesunate/mefloquine combination for multidrug resistant falciparum malaria. Southeast Asian J Trop Med Public Health. 1997;28:727-30.
23. Thimasarn K, Sirichaisinthop J, Chanyakhun P, Palananth C, Rooney W. A comparative study of artesunate and artemether in combination with mefloquine on multidrug resistant falciparum malaria in eastern Thailand. Southeast Asian J Trop Med Public Health. 1997;28:465-71.
24. Price RN, Nosten F, Luxemburger C, van Vugt M, Phaipun L, Chongsuphajaisiddhi T, et al. Artesunate/mefloquine treatment of multi-drug resistant falciparum malaria. Trans R Soc Trop Med Hyg. 1997;91:574-7.
25. Price R, Luxemburger C, van Vugt M, Nosten F, Kham A, Simpson J, et al. Artesunate and mefloquine in the treatment of uncomplicated multidrug-resistant hyperparasitaemic falciparum malaria. Trans R Soc Trop Med Hyg. 1998;92:207-11.
26. van Vugt M, Brockman A, Gemperli B, Luxemburger C, Gathmann I, Royce C, et al. Randomized comparison of artemether-benflumetol and artesunate-mefloquine in treatment of multidrug-resistant falciparum malaria. Antimicrob Agents Chemother. 1998;42:135-9.
27. Massougbodji A, Kone M, Kinde-Gazard D, Same-Ekobo A, Cambon N, Mueller EA. A randomized, double-blind study on the efficacy and safety of a practical three-day regimen with artesunate and mefloquine for the treatment of uncomplicated Plasmodium falciparum malaria in Africa. Trans R Soc Trop Med Hyg. 2002;96:655-9.
28. Marquiño W, Huilca M, Calampa C, Falconí E, Cabezas C, Naupay R, et al. Efficacy of mefloquine and a mefloquine-artesunate combination therapy for the treatment of uncomplicated Plasmodium falciparum malaria in the Amazon Basin of Peru. Am J Trop Med Hyg. 2003;68:608-12.
29. Smithuis F, Shahmanesh M, Kyaw MK, Savran O, Lwin S, White NJ. Comparison of chloroquine, sulfadoxine/pyrimethamine, mefloquine and mefloquine-artesunate for the treatment of falciparum malaria in Kachin State, North Myanmar. Trop Med Int Health. 2004;9:1184-90.
30. Stohrer JM, Dittrich S, Thongpaseuth V, Vanisaveth V, Phetsouvanh R, Phompida S, et al. Therapeutic efficacy of artemether-lumefantrine and artesunate-mefloquine for treatment of uncomplicated Plasmodium falciparum malaria in Luang Namtha Province, Lao People’s Democratic Republic. Trop Med Int Health. 2004;9:1175-83.
31. Smithuis F, van der Broek I, Katterman N, Kyaw MK, Brockman A, Lwin S, et al. Optimising operational use of artesunate-mefloquine: a randomized comparison of four treatment regimens. Trans R Soc Trop Med Hyg. 2004;98:182-92.
32. Avila JC, Villaroel R, Marquiño W, Zegarra J, Mollinedo R, Ruebush TK. Efficacy of mefloquine and mefloquine-artesunate for the treatment of uncomplicated Plasmodium falciparum malaria in the Amazon region of Bolivia. Trop Med Int Health. 2004;9:217-21.
33. van den Broek IV, Maung UA, Peters A, Liem L, Kamal M, Rahman M, et al. Efficacy of chloroquine+sulfadoxine-pyrimethamine, mefloquine+artesunate and artemether +lumefantrine combination therapies to treat Plasmodium falciparum malaria in the Chittagong Hill Tracts, Bangladesh. Trans R Soc Trop Med Hyg. 2005;99:727-35
34. Hutagalung R, Paiphun L, Ashley EA, McGready R, Brockman A, Thwai KL, et al. A randomized trial of artemether-lumefantrine versus mefloquine-artesunate for the treatment of uncomplicated multi-drug resistant Plasmodium falciparum on the western border of Thailand. Malar J. 2005;4:46.
35. Tangpukdee N, Krudsood S, Thanachartwet W, Chalermrut K, Pengruksa C, Srivilairit S, et al. An open randomized clinical trial of Artekin vs. artesunate-mefloquine in the treatment of acute uncomplicated falciparum malaria. Southeast Asian J Trop Med Public Health. 2005;36:1085-91.
36. Campbell P, Baruah S, Narain K, Rogers C. A randomized trial comparing the efficacy of four treatment regimens for uncomplicated falciparum malaria in Assam state, India. Trans R Soc Trop Med Hyg. 2006; 100: 108-18.
37. Vijaykadga S, Rojanawatsirivej C, Cholpol S, Phoungmanee D, Nakavej A, Wongsrichanalai C. In vivo sensitivity monitoring of mefloquine monotherapy and artesunate-mefloquine combinations for the treatment of uncomplicated falciparum malaria in Thailand in 2003. Trop Med Int Health. 2006;11:211-9.
38. Smithuis F, Kyaw MK, Phe O, Aye KZ, Htet L, Barends M, et al. Efficacy and effectiveness of dihydroartemisinin-piperaquine versus artesunate-mefloquine in falciparum malaria: an open-label randomized comparison. Lancet. 2006;367:2075-85.
39. Denis MB, Tsuyuoka R, Poravuth Y, Narann TS, Seila S, Lim C, et al. Surveillance of the efficacy of artesunate and mefloquine combination for the treatment of uncomplicated falciparum malaria in Cambodia. Trop Med Int Health. 2006;11:1360-6.
40. Faye B, Ndiaye JL, Ndiaye D, Dieng Y, Faye O, Gaye O. Efficacy and tolerability of four antimalarial combinations in the treatment of uncomplicated Plasmodium falciparum malaria in Senegal. Malar J. 2007;6:80.
41. Bhatt KM, Samia BM, Bhatt SM, Wasunna KM. Efficacy and safety of an artesunate/mefloquine combination (artequin) in the treatment of uncomplicated P. falciparum malaria in Kenya. East Afr Med J. 2006;83:236-42.
42. RAVREDA-AMI. Antimalarial drug efficacy studies 2002-2005. Fecha de consulta: septiembre de 2008. Disponible en: http://www.paho.org/spanish/AD/DPC/CD/ravreda-ami-areas.htm
43. Giraldo C, Blair S. Mefloquina: revisión de tema. IATREIA. 2003;16:19-31.
44. Berninger E, Karlsson K, Alvan G. Quinine reduces the dynamic range of the human auditory system. Acta Otolaryngol. 1998;118:46-51.
45. Tange RA, Dreschler WA, Claessen FA, Perenboom RM. Ototoxic reactions of quinine in healthy persons and patients with Plasmodium falciparum infection. Auris Nasus Larynx. 1997;24:131-6.
46. Simoes Da Silva MV. Estudio de los efectos ototóxicos en 725 pacientes tratados con antimaláricos en el Hospital Central de Maputo (Mozambique) (tesis). Barcelona: Universidad Autónoma de Barcelona; 2004.
47. Chotivanich K, Sattabongkot J, Udomsangpetch R, Looareesuwan S, Day NP, Coleman RE, et al. Transmission-blocking activities of quinine, primaquine, and artesunate. Antimicrob Agents Chemother. 2006;50:1927-30.
48. Davis ME, Karunajeewa HA, llet KF. Artemisinin-based combination therapies for uncomplicated malaria. Med J Aust. 2005;182:181-5.
49. Shekalaghe S, Drakeley C, Gosling R, Ndaro A, van Meegeren M, Enevold A, et al. Primaquine clears submicroscopic Plasmodium falciparum gametocytes that persist after treatment with sulphadoxine-pyrimethamine and artesunate. PloS ONE. 2007;2:e1023. Doi:10.1371/journal.-pone.0001023
50.Pukrittayakamee S, Chotivanich K, Chantra A, Clemens R, Looareesuwan S, White NJ. Activities of artesunate and primaquine against asexual- and sexual-stage parasites in falciparum malaria. Antimicrob Agents Chemother. 2004;48:1329-34.
How to Cite
1.
Vásquez AM, Sanín F, Álvarez LG, Tobón A, Ríos A, Blair S. Therapeutic efficacy of a regimen of artesunate-mefloquine-primaquine treatment for Plasmodium falciparum malaria and treatment effects on gametocytic development. biomedica [Internet]. 2009 Jun. 1 [cited 2024 May 17];29(2):307-19. Available from: https://revistabiomedica.org/index.php/biomedica/article/view/32
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