Is Artemisinin-Based Combination Therapy a More Efficacy Way to Cure Malaria - Book Report/Review Example

?Is Artemisinin-based combination therapy (ACTs) a more efficacy way to cure malaria when comparing it with Chloroquine therapy? Introduction Malariais considered to be one of the major health problems in the Third World countries, impeding people’s health and their growth. Malarial endemic conditions vary from country to country based on the malaria epidemiology and the level of the control program implementation in those countries. 300 – 350 million cases are found to be caused by malaria with a mortality rate of 2-3 million deaths per year (Gbotosho et al., 2011). Malaria is caused by four species of protozoan parasites and they are Plasmodium falciparum (P.falciparum), P. vivax, P.ovale and P.Malariae. Although, P.vivax is the most wide spread form of malaria infection in the world, Plasmodium falciparum causes the most severe disease and responsible for most deaths and serious morbidity (Gbotosho et al., 2011). Malaria is also regarded as a social and behavioral problem, and that contributes to the perception and treatment of the disease. Malaria has become one of the deadly diseases in the world. The first line drug initially used for the treatment of malaria was Chloroquine. Plasmodium falciparum became resistant to the chloroquine drug. Hence, the search for the new potential drug for the treatment for malaria was started and drugs such as Sulfaxonine – pyrimethamide, Mefloquine, Halofantrine, 4- aminoquinoline, amidiaquine, hydroxyl chloroquine and artemisinin based combination therapies were tried for the treatment of malaria. The Artemisinin – based combination therapies (ACTS) are found to be more effective than all the other drugs. The extensive studies for the treatment of malaria have proved that ACTs could be the optimal solution for this disease. Background The history of drugs used for the treatment of malaria goes back to hundreds of years. In 1820, quinine, an alkaloid, was identified as an important therapeutic agent for malaria. However, quinine has very short shelf life and hence, chloroquine was identified and used for the treatment of malaria. Chloroquine has a prolonged half-life of 33 days and is active against asexual stages of all human species, except for strains of P.falciparum (Rukaria-Kaumbutho, Ojwang, & Oyieke, 1996). The low toxicity, low cost and importantly effectiveness to treat malaria are the essential factors, which are focused when choosing the treatment for malaria. Many malarial programs were planned and implemented but there are certain barriers for the complete success of the program. The major barrier for the treatment of malaria is the lack of proper attention to the right drugs. Multiple drug resistance to P.falciparum is the major health problem in the tropics, and for example, on the Thailand – Myanmar border, P.falciparum is resistant to all the available malarial drugs. Chloroquine resistance of P.falciparum was first suspected in Thailand 1957 (Rukaria-Kaumbutho, Ojwang, & Oyieke, 1996). The details about the agents, vectors and hosts within a particular ecosystem must be understood for improving the malaria control programs. Hence the need for the development of the new drug has emerged and the usage of the artesunate drugs for the treatment of malaria is under progress in many African countries. In Ghana, malaria is the hyper- endemic disease causing maximum mortality and morbidity in the country. The major drugs initially used for the treatment of malaria such as Fansidar and Maladrin failed to treat the disease and the need for the development of new drugs became necessary (Asase, Akwetey, & Achel, 2010). Need for the new drug The mechanism of resistance, factors that contribute to the spread of resistance and the parasite genetics are not well understood. The main basis of the chloroquine resistance is related to the capacity of resistant P.falciparum strains to excrete chloroquine rapidly, so that the intracellular concentration did not reach the toxic level. A better understanding of the mechanism, underlying the resistance and factors that contribute to the spread, will require the combination of genetics, entomology, and epidemiology disciplines. In a study conducted in Southwest Nigeria, the drug chloroquine was used by 41.1% of the people, followed by pyrimethamine-sulphadoxine (33. 5%), and amodiaquine (25. 4%) for the treatment of malaria (Babalola & Lamikanra, 2007). This study indicated that the people are much aware about the drug chloroquine and to a lesser level about the combined drugs such as pyrimethamine-sulphadoxine. The main side effects of this therapy are fatigue, gastrointestinal disturbances and anorexia, along with headache, vomiting and nausea. The study conducted in Nigeria has also proved that the resistance to the chloroquine drug to P.falciparum was encountered all over the country.(Babalola & Lamikanra, 2007). The resistance of P.falciparum to the commonly used anti-malarial drugs creates heavy challenge to malaria control in the Sub-Saharan Africa. To test the efficacy of the common anti-malarial drugs, a study was conducted in Ghana with the support from National Malaria Control Programme. The children between 59 months to 6 years were chosen for the study (Koram et al., 2005). The treatment groups were given the anti-malarial drugs such as chloroquine (CHQ), sulphadoxine/pyrimethamine (SP), amodiaquine + artesunate (ADQ +ART) combination, and artemether + lumefantrine (Coartem) combination (Koram et al., 2005).168 children were studied based on these combinations. The parasite clearance was effective in the sulphadoxine/pyrimethamine (SP) combination and similarly the prevalence of gametocytaemia was highest than other groups, and not to the chloroquine (Koram et al., 2005). The resistance to chloroquine by P.falciparum was first identified in Thailand in the year 1957, with the resistance being confirmed in Kenya in 1979. Since then about 10 – 60% of the patients who come for treatment were found to have resistance to chloroquine (Rukaria-Kaumbutho, Ojwang, & Oyieke, 1996).The drug resistance was found in the pregnant women too. The study conducted in Kenya to determine the efficacy of chloroquine therapy in pregnant women with the therapeutic doses of 25mg/ kg body weight in 300 pregnant women was carried out in Kilifi District Hospital. Malaria was endemic in the Kilifi District (Rukaria-Kaumbutho, Ojwang, & Oyieke, 1996).The malarial parasite resistance was identified in those women and they were treated with Amodiaquine at a dose range of 25mg/ kg body weight and followed for 7 days. The treatment effects were monitored for 42 days. This study concluded that the resistance was present in the 65% of the pregnant women and the administration of the Amodiaquine was found to be less effective in many cases. These results concluded that some effective anti-vectors must be introduced and the development of new drugs is very essential (Rukaria-Kaumbutho, Ojwang, & Oyieke, 1996). Studies have found that more children are affected by the chloroquine drug resistance than the old people. Lower concentrations of chloroquine in the plasma of the children indicate that children are using over dose of chloroquine as tablets or syrup. The response of the parasite to the drug is very less and hence the need for the formulation of the first line drug that can reduce the parasite concentration in the blood after the complete course became important (Maitland et al., 1997). Anti-bacterial drugs were also tried for the treatment of malaria parasite infection. Monotherapy with tetracycline, doxycycline and clindamycin were studied in 92 adult patients in Thailand (Pukrittayakamee et al., 2001).The patients recovered from malaria at an average mean clearance time of 57 hours. All the 92 patients recovered from malaria but the reappearance of malaria happened in 41% of the patients. All the groups had comparatively the same recovery rate when compared to the azithromycin treatment. From these studies, it was concluded that antibacterial drugs can also be used for the treatment of malaria for short period. But the reappearance is the big problem in the use of antibacterial drugs; hence the need for the development of right anti-malarial drug has become very essential (Pukrittayakamee et al., 2001). When better treatment options were focused, the Artemisinin– based combination therapies (ACTs) appeared to be a key solution. Artemisinin therapy increases the efficacy of treatment and lowers the resistance emergence in the human. ACTs reduces the overall transmission rate than the other drugs. If Artemisinin based combination therapy is used at the early stages of malaria, it prevents the occurrence of the disease and also reduces the malaria mortality rate. They have gametocytocidal effect on the early development stages of the parasite. In Gambia, the rate of transmission of malaria was found to be less in the children treated with artesunate than those treated with sulfadoxine and pyrimethamine (McGready et al., 2001). Importantly, World Health Organization has recommended the usage of ACT since 2001. However, the disadvantages with the use of ACTs are the high cost, limited knowledge and less public awareness of the combination therapy concept. Artemisinin reduces the viability of the gametocytes, thus reducing the infectivity of the mosquitoes. Till now, there are no reports of the resistance of the parasite to ACTs (Valecha et al., 2009). By the 2005, 45 countries accepted the use of ACTs for the treatment of malaria (Mutabingwa, 2005). Mutabingwa (2005) points out that more funding is required for the wide adaptation of the drug and requests the governments to take necessary actions. Time for the switch over to new therapy for malaria Drug resistance is the biggest challenge in the target to control malaria in all the developing countries. Many 28 day efficacy studies have confirmed the occurrence of chloroquine resistance for malaria (Singh et al., 2011). The efficacy of the treatment of uncomplicated malaria was tested in four states in India. The studies have concluded that at the end of the 28th day, the complete recovery rate was 57% and out of this 57%, the early treatment failure rate was 12.5% (Valecha et al., 2009). All the investigations were performed using the standard World Health Organization procedures. Highly effective chemoprophylaxis is very essential for the soldiers servicing in the malaria transmission areas. Mefloquine has high toxicity and not preferred in the army. Atovaquone- proguanil combination is limited to 3 months usage. The in vitro studies have shown that doxycyline is well tolerated and effective against malaria. A double-blind, placebo- controlled randomized field trial was designed to test the efficacy of the drugs with eligible participants in the French Army. It was found that doxycycline – chloroquine combination showed better results for the treatment of malaria (Michel et al., 2010). Sulfaxonine – pyrimethamide (Fansidar) was more effective against malaria than chloroquine. However, defervesence was more rapid and the clinical failure was 9% (Van Dillen et al., 1999). Mefloquine, a synthetic 4- quinoline methanol has an unusual long half life. It is also metabolized with great variability in the individuals. As this drug is more expensive this drug is not preferred much for the treatment of malaria (Koram et al., 2005). Halofantrine is another drug that is effective against the chloroquine resistant P.falciparum. The toxicity level of this drug is very high and the long term usage is not recommended (Van Dillen et al., 1999). A number of other drugs such as 4- aminoquinoline, amidiaquine, hydroxyl chloroquine are effective only when they are used in combinations and not alone (Kolaczinski et al., 2007). Artemisinin related compounds, derived from the Chinese herb medicine Qing-Hao-Su are found to be more effective against the chloroquine resistant P.falciparum (Kolaczinski et al., 2007). The reoccurrence of malaria was very less and the complete clearance of the parasite was also achieved by the drug. Artesunate, Artemisinin , Artemether, dihydroartemisinin, Arteether, artelinic acid are some of the derivatives used for the treatment of malaria (Mutabingwa, 2005). Efficacy of Artemisinin than other drugs Artemisinin based combination therapies came out as the solution to the resistant problems of the chloroquine. In Afghanistan, a study was conducted to test the efficacy of sulfadoxine—pyrimethamine plus artesunate (SP+AS) versus chloroquine (Kolaczinski et al., 2007).190 P.falciparum were included in this randomized, non inferiority trial. 180 patients completed the 42 days trail. Most of the patients had 96% success in the treatment at the 28th day for both the drug combinations. But at the end of the 42nd day, increased parasitological failure was observed in the chloroquine treated arm. (Kolaczinski et al., 2007). Around 46% of the patients in the chloroquine arm failed in the treatment. This study thus confirms that artemisinin shows excellent clinical cure for P.falciparum malaria and also clears the parasetemia at a faster rate than chloroquine (Kolaczinski et al., 2007). A study conducted in Thailand between 1997 and 1998, provides more evidence for the use of ACTs. A 6 –dose regimen study was conducted to check the safety and efficacy of artemether – lumefantrine and artesunate – lumefantrine and mefloquine in 150 patients (Vugt et al., 2000). For these drugs, the initial parasite clearance was very good. The cure rate was better at the end of 28th day. But at the end of 42 day course, artesunate- mefloquine combination therapy had 100% cure rate than other two regimens (Vugt et al., 2000). This study also tested the efficacy of 6- dose regimen therapy with that of 3 day AM combination therapy (Vugt et al., 2000). Plasmodium falciparum hyperparasitaemia ( PfHP) depends on the epidemiologic setting. If the malaria is severe, then the parasite clearance time will be high and the chance for the reoccurrence of the infection is also high. In the Nigerian Children, the PfHP is less associated with the major symptoms and anemia is an inevitable complication. The artemisinin based combination drugs (ACTs) were used in a study to check whether they can reduce or modify the risk of anemia. The study was conducted in the years 2008 – 2010 in 6807 children, aged between 0.5 – 17 years (Gbotosho et al., 2011). The children were given artemether – lumefantrine tablets, each containing 20 mg of artemisinin and 120 mg of lumefantrine. The co – formulation drug of artesunate and amodiaquine was also given to the children. Each tablet contains 270 mg amodiaquine and 100 mg artesunate. Both the drugs were given randomly to the children at a 6- dose regimen. The evaluation of the parasite and clinical investigation was carried at 1, 7, 14, 21, 28, 35 and 42nd days (Gbotosho et al., 2011). The parasite clearance was same in both the artemether – lumefantrine and artesunate- amodiaquine and so the half – lives of parasitaemia. The clearance of the parasites from the peripheral blood was 10 times higher in patients without hyperparasitaemia and there was no change in the haematocrit following the treatment. The study concluded that oral administration of ACTs responded well for PfHP in the young malarious Nigerian children (Gbotosho et al., 2011). Conclusion The drug resistance to Plasmodium falciparum poses a major threat to malaria control globally. Chloroquine (CQ) was considered as the effective drug for the treatment of malaria in many countries. However, the efficacy of chloroquine for the treatment of malaria was investigated using the standard procedure of the World Health Organization in many parts of the world and it was found that the parasite Plasmodium falciparum was resistant to the drug and the need for the development of new first line drug became important. Artemisinin – based combination therapies (ACTs) have high parasite clearance after 42 days and the less reoccurrence of the disease. This was widely accepted in many countries as the first line drug for the treatment of malaria. Although ACT is providing effective results, further reduction in the high level of mortality and morbidity from malaria in various countries requires better management of the existing programs. Moreover, better understanding of the parasites, vector and human hosts and the accelerated research in the malaria are required to eradicate malaria. References Asase, A., Akwetey, G. A., & Achel, D.G. (2010). Ethnopharmacological use of herbal remedies for the treatment of malaria in the Dangme West District of Ghana. Journal of Ethnopharmacology, 129: 367–376. Babalola, O. O., & Lamikanra, A. (2007). The response of students to malaria and malaria therapy in a university in Southwest Nigeria. Research in Social and Administrative Pharmacy. 3: 351- 362. Gbotosho, G. O., Okuboyejo, T. M., Happi, C. T., & Sowunmi, A. (2011). Plasmodium falciparum hyperparasitaemia in Nigerian children: epidemiology, clinical characteristics, and therapeutic responses to oral artemisinin-based combination treatments. Asian Pacific Journal of Tropical Disease, pp: 85- 93. Kolaczinskia, K., Durrani, N., Rahim, S., & Rowland, M. (2007). Sulfadoxine— pyrimethamine plus artesunate compared with chloroquine for the treatment of vivax malaria in areas co-endemic for Plasmodium falciparum and P. vivax: a randomised non-inferiority trial in eastern Afghanistan. Transactions of the Royal Society of Tropical Medicine and Hygiene, 101: 1081—1087 Koram, K. A., Abuaku, B., Duah, N., & Quashie, N. (2005). Comparative efficacy of antimalarial drugs including ACTs in the treatment of uncomplicated malaria among children under 5 years in Ghana. Acta Tropica, 95: 194 – 203. Maitland. K., Williams, T. N., Kotecka, B. M., Edstin, M.D., & Rieckmann, K.H. (1997). Plasma chloroquine concentrations in young and older malaria patients treated with chloroquine. Acta Tropica, 66:155 – 161. McGready, R., Cho, T., Samuel, V. L., Brockman, A., Vugt, M. V., Looareesuwan, S., White, N. J., & Nosten, F. (2001). Randomized comparison of quinine- clindamycin versus attesunate in the treatment of falciparum malaria in pregnancy. Transactions of the Royal Society of Tropical medicine and Hygiene, 95: 651- 656. Michel, R., Bardot, S., Queyriaux, B., Boutin, J. P., & Touze, J. E. (2010). Doxycycline- chloroquine vs. doxycycline-placebo for malaria prophylaxis in nonimmune soldiers: a double-blind randomized field trial in sub-Saharan Africa. Transactions of the Royal Society of Tropical Medicine and Hygiene, 104: 290–297 Mutabingwa, T.K. (2005). Artemisinin- based combination therapies (ACTs): Best hope for malaria treatment but inaccessible to the needy. Acta Tropica 95: 305 – 315. Nelson, K. E., Williams, C.M., & Graham, N. M. H. (2004). Infectious disease Epidemiology, Theory and Practice. Jones and Bartlett Publishers. Pukrittayakamee, S., Clemens, R., Chantra, A., Nontprasert, A., Luknam,T., Looareesuwan, S., & White, N.J. (2001). Therapeutic responses to antibacterial drugs in vivax malaria, Transactions of The Royal Society of Tropical Medicine And Hygiene, 95:524 – 528. Rukaria-Kaumbutho, R. M., Ojwang, S. B. O., & Oyieke, J. B. (1996). Resistance to chloroquine therapy in pregnant women with malaria parasitemia. International Journal of Gynecology & Obstetrics, 53:235-241. Singh, N., Shukla, M. M., Chand, G., Bharti, P.K., Singh, M.P., Shukla, M.K., Mehra, R.K., Sharma, R.K., & Dash, A.P. (2011). Epidemic of Plasmodium falciparum malaria in Central India, an area where chloroquine has been replaced by artemisinin- based combination therapy. Transactions of the Royal Society of Tropical Medicine and Hygiene, 105:133–139. Valecha, N., Joshi, H., Mallick, P. K., Sharma, S. K., Kumar, A., Tyagi, P. K., Shahi, B., Das, M. K., Nagpal, B.N., & Dash, A. P. (2009). Low efficacy of chloroquine: Time to switch over to artemisinin-based combination therapy for falciparum malaria in India. Acta Tropica, 111: 21 – 28. van Dillen, J., Custers, M., Wensink, A., Wounters, B., Voorthuizen, T. V., Voorn, W., Khan, B., Muller, L., & Nevill, C. (1999). A comparison of amodiaquine and sulfadoxine-pyrimethamine as first-line treatment of falciparum malaria in Kenya. Transactions of the Royal Society of Tropical Medicine and Hygiene, 93:185–188. van Vugt, M., Looareesuwan, S., Wilairatana, P., McGready, R., ViUegas, L.,Gathmann’, I., Mull, R., Brockman, A., White, N. J., & Nosten, F. (2000). Artemether-lumefantrine for the treatment of multidrug-resistant falciparum Malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene. 94:545-548 Read More