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Inhibitors Of Plasmodium Falciparum Phosphoethanolamine

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4-aminoquinoline drug, used to treat malaria infection (Plasmodium ovale, P. vivax and P. malariae) (Na-Bangchang and Karbwang, 2009; Petersen, Eastman and Lanzer, 2011). Malaria parasite is present in its asexual stage in the red blood corpuscles (RBC) where it breaks hemoglobin, thereby releasing ‘heme’, which is converted to ‘hemozoin’. Chloroquine enters RBC and gets protonated and prevents hemozoin formation, thus causing buildup of heme protein. Then, chloroquine attaches to heme to form a toxic complex which disrupts the membrane function, thus leading to cell-lysis and eventually autodigestion of the parasite (Hempelmann, 2007; Lin et al., 2015). Its adverse effects include appetite distress, diarrhea, low RBC, muscular damage, vision problems, seizures, skin rash etc. (Michaelides et al., 2011; Murambiwa et al., 2011; Reich, Ständer and Szepietowski, 2009; Tönnesmann, Kandolf and Lewalter, 2013). The first incident of chloroquine-resistance falciparum was reported in 1950s; since then, various resistant forms have surfaced. Falciparum efficiently counteract the effects of chloroquine due to mutations in transporter (PfCRT) gene (Martin et al., 2009). Other genes involved in development of drug-resistance are ABC transporter multidrug-resistance (PfMDR1) and chloroquine-transporter CG2 protein (Tripathi, 2013). Chloroquine has been the drug of choice for unconfirmed cases of malaria or vivax infection. But chances of developing drug-resistance are higher due to improper drug use. So, one must consider the chances of increase of chloroquine-resistant vivax infection in Pakistan (Price et al., 2014). The appearance of the F1076L mutation in pvmdr1 gene in Pakistan, responsible for drug-resistance in vivax in 2013 draws attention to the looming threat of resistance development (Khattak et al., 2013; Waheed et al., 2015).

Amodiaquine - It is another drug of 4-aminoquinoline category, used against uncomplicated reports of falciparum malaria. It is highly recommended in combination with artesunate to decrease the risk of drug-resistance (Bobenchik et al., 2010; WHO, 2015), but is usually not prescribed due to its rare but severe adverse effects. Some adverse effects include decrease in blood cell or hepatic distress and at high doses, it may cause cardiac arrest, headaches, seizures, and troubled vision (Nair et al., 2012; Olliaro and Mussano, 2016; Tagbor, Chandramohan, and Greenwood, 2007). It has become a chief drug used along with artensunate in uncomplicated case of falciparum infection and is a frequently chosen alternative to chloroquine, due to its affordability and efficacy against chloroquine-resistant species in Pakistan. It is extensively preferred for the management of vivax and falciparum infection. Yet, there were reports of cross-resistance between chloroquine and amodiaquine in the South Asian region (Hay et al., 2009).


Sulfadoxine + Pyrimethamine - The combination of sulfadoxine (sulfonamide) and pyrimethamine (antiprotozoal) is used against malaria infection (WHO, 2008) in combination with other antimalarial drugs. Sulfonamide acts by competing with the p-amino benzoic acid during folate synthesis while the pyrimethamine selectively inhibits the dihydrofolate reductase enzyme present in protozoa, thus stopping the production of tetrahydrofolate. Combined treatment of the two drugs was approved in 1981 for use in USA and is now present on the List of Essential Medicines released by the WHO (WHO, 2015). It is more successful in the management of falciparum infection and undiagnosed malaria cases (Leslie et al., 2007). Yet, it is not recommended as a routine drug owing to its adverse effects, but simply to manage severe malaria or in areas where other medicaments are ineffective. Adverse effects include headache, rash, diarrhea, hair loss, abdominal cramps, aplastic anemia, atrophic glossitis, fever, hepatic inflammation, liver necrosis, renal toxicity, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, weight loss etc.

Indoor residual spraying (IRS) - It is the procedure of spraying the indoors of a closed facility with insecticides to eradicate mosquitoes that carry malaria infection. Insecticides are sprayed on the inner walls so that the mosquitoes can be killed or kept at bay which prevents the transmission of malaria infection (Aregawi et al., 2009). Earlier, it was only recommended for vicinities with sporadic infection of malaria, but in 2006 it started advocating the use of IRS in regions of endemic, and stable malaria infection (van den Berg , 2009). According to the Cochrane review, IRS is a successful strategy for decreasing malaria infection (Pluess et al., 2010). But only a handful of studies have evaluated the economical aspects of IRS with any other means of controlling malaria infection (Yukich et al., 2008). Yet with respect to the usage of a variety of pesticides, DDT has been thought to be the cost effective, since it last for longer time thus reducing the frequency of spraying. Yet, studies on cost effectiveness and adverse effects of pesticides use on human and environment health are still less. Another aspect to be considered is that almost 80% of dwellings must be sprayed with pesticides for IRS to be effective (WHO, 2006) otherwise the program won’t be a success. People are often more resistant towards DDT spray due to its smell or stains on the inner walls (Mabaso, Sharp & Lengeler, 2004; Thurow, 2001). In that case, pyrethroid insecticides are more satisfactory as they don’t leave any visible residues. Malathion spraying in the North West Frontier Province in Pakistan provided protective efficacy of 52.5% against falciparum infection while 40.5% against vivax infection. The vector (Anopheles stephensi) is identified as resistant to malathion in the region, and changing from malathion to another insecticide, lambda-cyhalothrin for spraying increased the protection efficacy. Conversely, a constant malathion spraying drive decreased the frequency of malaria infection, when used along with ITNs by almost 90% in Pakistan. It was estimated that the spraying plans would be economical than the use of ITNs (Rowland et al., 1997a; Rowland et al., 1997b; Rowland, 1999).

Insecticide-treated nets (ITNs)

Mosquito bed-nets which are previously treated with insecticides (ITNs) were first made for malaria prevention in the 1980s. They are presumed to be twice as efficient as common bed-nets, and almost 70% more effective than having no net (Bachou et al., 2006). These nets are dipped in a pyrethroid insecticide (permethrin or) which aids in killing or repelling the mosquitoes. For maximum efficiency, ITNs must be dipped in pesticides after every six months. But, it poses a considerable logistical setback in rural parts. So, now latest ITNs with long lasting insecticides (Long lasting insecticidal nets [LLINs]) have replaced the older versions in many nations (Masum et al., 2010). ITNs have been demonstrated to be cost-efficient & effective in malaria prevention (WHO, 2013). ITNs defend people who sleep under them and concurrently kill mosquitoes that get in touch with the nets. It offers some security to others sleeping in the same vicinity but without a net. But, studies have also suggested that transmission of disease may be aggravated with the loss of insecticidal property of bed-nets. Also, those who are not using ITN near the net users might experience elevated bites as mosquitoes get deflected from the non fatal ITN users. This could augment the malaria transmission in densely populated areas (Yakob & Guiyun, 2009). In the North West Frontier Province, Pakistan, the permethrin-treated bed-nets offered a protective efficacy of 61% against falciparum infection while 47% against vivax infection (Rowland et al., 1997a; Rowland et al., 1997b; Rowland, 1999).



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Bachou, H., Tylleskär, T., Kaddu-Mulindwa, D.H. and Tumwine, J.K., 2006. Bacteraemia among severely malnourished children infected and uninfected with the human immunodeficiency virus-1 in Kampala, Uganda. BMC infectious diseases, 6(1), p.160.

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Leslie, T., Mayan, M.I., Hasan, M.A., Safi, M.H., Klinkenberg, E., Whitty, C.J. and Rowland, M., 2007. Sulfadoxine-pyrimethamine, chlorproguanil-dapsone, or chloroquine for the treatment of Plasmodium vivax malaria in Afghanistan and Pakistan: a randomized controlled trial. Jama, 297(20), pp.2201-2209.

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Martin, R.E., Marchetti, R.V., Cowan, A.I., Howitt, S.M., Bröer, S. and Kirk, K., 2009. Chloroquine transport via the malaria parasite’s chloroquine resistance transporter. science, 325(5948), pp.1680-1682.

Masum, H., Shah, R., Schroeder, K., Daar, A.S. and Singer, P.A., 2010. Africa's largest long-lasting insecticide-treated net producer: lessons from A to Z Textiles. BMC international health and human rights, 10(1), p.S6.

Michaelides, M., Stover, N.B., Francis, P.J. and Weleber, R.G., 2011. Retinal toxicity associated with hydroxychloroquine and chloroquine: risk factors, screening, and progression despite cessation of therapy. Archives of ophthalmology, 129(1), pp.30-39.

Murambiwa, P., Masola, B., Govender, T., Mukaratirwa, S. and Musabayane, C.T., 2011. Anti-malarial drug formulations and novel delivery systems: a review. Acta tropica, 118(2), pp.71-79.

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Olliaro, P. and Mussano, P., 2016. Amodiaquine for treating malaria. Cochrane Database of Systematic Reviews, (2), pp.1-37.

Petersen, I., Eastman, R. and Lanzer, M., 2011. Drug?resistant malaria: Molecular mechanisms and implications for public health. FEBS letters, 585(11), pp.1551-1562.

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Price, R.N., von Seidlein, L., Valecha, N., Nosten, F., Baird, J.K. and White, N.J., 2014. Global extent of chloroquine-resistant Plasmodium vivax: a systematic review and meta-analysis. The Lancet infectious diseases, 14(10), pp.982-991.

Reich, A., Ständer, S. and Szepietowski, J.C., 2009. Drug-induced pruritus: a review. Acta dermato-venereologica, 89(3), pp.236-244.

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Rowland, M., Hewitt, S., Durrani, N., Bano, N. and Wirtz, R., 1997. Transmission and control of vivax malaria in Afghan refugee settlements in Pakistan. Transactions of the Royal Society of Tropical Medicine and Hygiene, 91(3), pp.252-255.b

Rowland, M., Hewitt, S., Durrani, N., Saleh, P., Bouma, M. and Sondorp, E., 1997. Sustainability of pyrethroid-impregnated bednets for malaria control in Afghan communities. Bulletin of the World Health Organization, 75(1), p.23.a

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