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http://www.inosr.net/inosr-scientific-research/ INOSR Scientific Research 4(1): 1-12, 2018. Eugene ©INOSR PUBLICATIONS International Network Organization for Scientific Research ISSN: 2705-1706

Drug Resistance in Eugene Mark Department of Biochemistry University of Ghana

ABSTRACT Drug resistant malaria is primarily caused Established and strong drug pressure by falciparum, a species combined with low immunity highly prevalent in tropical. It causes probably explains the multidrug-resistance severe fever or anaemia that leads to more encountered in the forests of South-east than a million deaths each year. The Asia and South America. In Africa, emergence of resistance has frequent genetic recombination in been associated with a dramatic increase Plasmodium originate from a high level of in malaria mortality among inhabitants of malaria transmission, and falciparum some endemic regions. The mechanisms of chloroquine-resistant prevalence seems to resistance for amino-alcohols (, stabilize at the same level as chloroquine- and ) are still sensitive malaria. Nevertheless, resistance unclear. Epidemiological studies have levels may differ according to place and established that the frequency of time. In vivo and in vitro tests do not chloroquine resistant mutants varies provide an adequate accurate map of among isolated parasite populations, while resistance. Biochemical tools at a low cost resistance to is highly prevalent are urgently needed for prospective in most malarial endemic countries. monitoring of resistance. Keywords: Drug, Resistance, Malaria. INTRODUCTION Malaria is a mosquito-borne infectious reproduce [3]. Five species of Plasmodium that affects humans and other can infect and be spread by humans. Most animals. Malaria causes symptoms that deaths are caused by P. falciparum typically include fever, tiredness, because P. vivax, P. ovale, and P. malariae vomiting, and headaches [1]. In severe generally cause a milder form of malaria. cases it can cause yellow skin, seizures, The species P. knowlesi rarely causes coma, or death. Symptoms usually begin disease in humans. Malaria is typically ten to fifteen days after being bitten by an diagnosed by the microscopic infected mosquito. If not properly treated, examination of blood using blood films, people may have recurrences of the or with antigen-based rapid diagnostic disease months later. In those who have tests [4]. Methods that use the polymerase recently survived an infection, reinfection chain reaction to detect the parasite's usually causes milder symptoms. This DNA have been developed, but are not partial resistance disappears over months widely used in areas where malaria is to years if the person has no continuing common due to their cost and complexity exposure to malaria [2]. [5]. It is caused by single-celled The risk of disease can be reduced by microorganisms of the Plasmodium group. preventing mosquito bites through the The disease is most commonly spread by use of mosquito nets and insect an infected female mosquito. repellents, or with The mosquito bite introduces the measures such as spraying parasites from the mosquito's saliva into and draining standing water. Several a person's blood. The parasites travel to are available to prevent the where they mature and malaria in travellers to areas where the

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http://www.inosr.net/inosr-scientific-research/ INOSR Scientific Research 4(1): 1-12, 2018. disease is common. Occasional doses of making it economically unfeasible in the combination some areas [10]. / are Prevention of malaria may be more cost- recommended in infants and after the effective than treatment of the disease in first trimester of in areas with the long run, but the initial costs required high rates of malaria [6]. Despite a need, are out of reach of many of the world's no effective vaccine exists, although poorest people. There is a wide difference efforts to develop one are ongoing. The in the costs of control (i.e. maintenance of recommended treatment for malaria is a low endemicity) and elimination programs combination of antimalarial medications between countries. In areas where malaria that includes an . The second is common, children under five years old medication may be either mefloquine, often have , which is sometimes , or due to malaria. Giving children with sulfadoxine/pyrimethamine. Quinine anemia in these areas preventive along with may be used if an improves red artemisinin is not available [7]. It is blood cell levels slightly but does not recommended that in areas where the affect the risk of death or need for disease is common, malaria is confirmed hospitalization [11]. if possible before treatment is started due Prevention of malaria includes: to concerns of increasing .  Preventing infection, by avoiding Resistance among the parasites has bites by parasite-carrying developed to several antimalarial mosquitoes, or medications; for example, chloroquine-  Preventing disease, by using resistant P. falciparum has spread to most antimalarial drugs malarial areas, and resistance to prophylactically. The drugs do not artemisinin has become a problem in prevent initial infection through a some parts of Southeast Asia. The disease mosquito bite, but they prevent is widespread in the tropical and the development of malaria subtropical regions that exist in a broad parasites in the blood, which are band around the equator. Malaria is the forms that cause disease. This commonly associated with poverty and type of prevention is also called has a major negative effect on economic “suppression. development [8].  Prevention of disease by Prevention of Malaria administration of antimalarial Methods used to prevent malaria include drugs to particularly vulnerable medications, mosquito elimination and population groups such as the prevention of bites. There is no pregnant women and infants. vaccine for malaria. The presence of  Personal protection measures such malaria in an area requires a combination as -treated bed nets of high human population density, high  Preventive treatment with anopheles mosquito population density antimalarial drugs of vulnerable and high rates of transmission from groups such as pregnant women, humans to mosquitoes and from who receive intermittent mosquitoes to humans. If any of these is preventive treatment lowered sufficiently, the parasite  Provision of equipment and eventually disappears from that area, as supplies (e.g., microscopes, drugs, happened in North America, Europe, and bed nets) to allow the health parts of the Middle East [9]. However, workers and the communities to unless the parasite is eliminated from the carry out the interventions. whole world, it could re-establish if  Drug-resistant malaria parasites conditions revert to a combination that hinder case management by favors the parasite's reproduction. decreasing the efficacy of Furthermore, the cost per person of antimalarial drugs and by eliminating anopheles mosquitoes rises requiring the use of alternate with decreasing population density,

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http://www.inosr.net/inosr-scientific-research/ INOSR Scientific Research 4(1): 1-12, 2018. drugs that are often more costly, of liver forms with [13]. less safe and less easy to Treatment with prevents administer. relapses after confirmed P. vivax malaria  Insecticide resistance decreases severe and complicated malaria are the efficacy of interventions that almost always caused by infection with P. rely on insecticides such as falciparum. The other species usually insecticide-treated bed nets and cause only febrile disease. insecticide spraying. Severe and complicated malaria are  Inadequate health infrastructures medical emergencies since mortality rates in poor countries are unable to are high (10% to 50%). Cerebral malaria is conduct the recommended the form of severe and complicated interventions. malaria with the worst neurological  The people most exposed to symptoms. Recommended treatment for malaria are often poor and lack severe malaria is the intravenous use of education. They often do not know antimalarial drugs. For severe malaria, how to prevent or treat malaria. parenteral was superior to Even when they do know, they quinine in both children and adults. In often do not have the financial another systematic review, artemisinin means to purchase the necessary derivatives ( and arteether) products, such as drugs or bed were as efficacious as quinine in the nets. treatment of cerebral malaria in children Treatment Of Malaria [14]. Treatment of severe malaria involves Malaria is treated with antimalarial supportive measures that are best done in medications; the ones used depends on a critical care unit. This includes the the type and severity of the disease. While management of high fevers and the medications against fever are commonly seizures that may result from it. It also used, their effects on outcomes are not includes monitoring for poor breathing clear. Simple or uncomplicated malaria effort, low blood sugar, and low blood may be treated with oral medications. The potassium [15]. most effective treatment for P. falciparum How is malaria treated? infection is the use of in  Drugs that kill the parasite that causes combination with other antimalarials malaria can be used to treat and (known as artemisinin-combination prevent the disease. These drugs are therapy, or ACT), which decreases called antimalarials. resistance to any single drug component  However, if you contract malaria while [12]. These additional antimalarials taking one type of antimalarial drug, include: , lumefantrine, the same drug cannot be used to treat mefloquine or the infection as the parasite may be sulfadoxine/pyrimethamine. Another resistant to it. recommended combination is  Different drugs target different and . ACT features of the parasite’s biology and is about 90% effective when used to treat life cycle. For example, chloroquine uncomplicated malaria. To treat malaria targets the blood stages of the life during pregnancy, the WHO recommends cycle whilst primaquine removes the the use of quinine plus early dormant? liver stages. in the pregnancy (1st trimester), and ACT  Because of this, drugs are often used in later stages (2nd and 3rd trimesters). in combination with each other to Malaria with partial resistance to make sure the malaria parasite is artemisins emerged in Southeast Asia. removed from all areas of the body. Infection with P. vivax, P. ovale or For example, primaquine can be used P. malariae usually do not require along with chloroquine to treat hospitalization. Treatment of P. vivax . requires both treatment of blood stages  Combinations of drugs are also used (with chloroquine or ACT) and clearance to try to prevent the parasite from

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http://www.inosr.net/inosr-scientific-research/ INOSR Scientific Research 4(1): 1-12, 2018. developing resistance to the and mefloquine (a quinolinemethanol individual drugs on their own. This is derivative of quinine). the strategy used in artemisinin combination drugs (ACT), which These drugs are various combinations of uses an artemisinin-based drug plus dihydrofolate- reductase inhibitors one partner drug. ACT is currently the (, , front-line treatment for Plasmodium pyrimethamine, and trimethoprim) and falciparum malaria. sulfa drugs (, ,  If any parasites are left in the body sulfamethoxazole, sulfadoxine, and after treatment, the disease may others). Although these drugs have return. For example, Plasmodium vivax antimalarial activity when used alone, and are able to lie parasitological resistance can develop dormant and hidden in the liver even rapidly. When used in combination, they if the parasite has been cleared from produce a synergistic effect on the the rest of the body. If the parasite parasite and can be effective even in the isn’t cleared properly from the liver presence of resistance to the individual the disease can return months or even components. Typical combinations years later. include sulfadoxine/ pyrimethamine,  Partial immunity? can be developed sulfalenepyrimethamine (metakelfin), and over years of exposure to the disease sulfamethoxazole- trimethoprim (co- and although it never develops into trimoxazole). A new antifolate full immunity it can reduce the combination drug is currently being severity of disease and risk of death tested in Africa [17]. This drug, a from malaria. combination of chlorproguanil and  Most malaria deaths occur in young dapsone, also known as Lap- Dap, has a children under five years whose much more potent synergistic effect on bodies have not had a chance to malaria than existing drugs such as SP. develop any immunity to the parasite. Benefits of this combination include a Drugs Use in Treating Malaria greater rate, even in areas currently There are only a limited number of drugs experiencing some level of SP resistance, which can be used to treat or prevent a lower likelihood of resistance malaria . The most widely used are developing because of a more quinine and its derivatives and antifolate advantageous pharmacokinetic and combination drugs. pharmacodynamic profile, and probable Quinine and related compounds low cost [18]. Quinine, along with its dextroisomer , has been the and derivatives such as for the treatment of malaria, especially doxycycline are very potent antimalarials severe disease. Chloroquine is a 4- and are used for both treatment and aminoquinoline derivative of quinine first prophylaxis. In areas where response to synthesized in 1934 and has since been quinine has deteriorated, are the most widely used antimalarial drug often used in combination with quinine to [16]. Historically, it has been the drug of improve cure rates. Clindamycin has been choice for the treatment of non-severe or used but offers only limited advantage uncomplicated malaria and for when compared to other available chemoprophylaxis, although drug antimalarial drugs. Parasitological resistance has dramatically reduced its response is slow to clindamycin and usefulness. Amodiaquine is a relatively recrudescence rates are high. Its efficacy widely available compound closely among non-immune individuals has not related to chloroquine. Other quinine- been fully established [19]. related compounds in common use Artemisinin compounds include primaquine (specifically used for A number of sesquiterpine lactone eliminating the exoerythrocytic forms of compounds have been synthesized from P. vivax and P. ovale that cause relapses), the plant annua (artesunate, artemether, arteether). These compounds

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http://www.inosr.net/inosr-scientific-research/ INOSR Scientific Research 4(1): 1-12, 2018. are used for treatment of severe malaria sulfadoxine/pyrimethamine. The studies and have shown very rapid parasite reviewed were mostly done in areas and clearance times and faster fever at times when both SP and resolution than occurs with quinine [20]. chloroquine/amodiaquine retained a fair In some areas of South-East Asia, amount of efficacy, and it is not clear combinations of artemisinins and from these studies how well such a mefloquine offer the only reliable combination would act in areas where one treatment for even uncomplicated of the components was significantly malaria, due to the development and compromised [24]. Additionally, to date, prevalence of multidrug resistant there are no data to suggest whether this falciparum malaria. Combination therapy slightly improved clearance would (an artemisinin compound given in translate into prolonged useful life span combination with another antimalarial, for either drug. Another combination typically a long half-life drug like therapy approach, combining an mefloquine) has reportedly been artemisinin derivative with other, longer responsible for inhibiting intensification half-life antimalarials [25]. of drug resistance and for decreased Drug Resistance malaria transmission levels [21]. Drug resistance is the reduction in Miscellaneous compounds effectiveness of a medication such as an Halofantrine is a phenanthrene-methanol antimicrobial or an antineoplastic in compound with activity against the treating a disease or condition. The term erythrocytic stages of the malaria is used in the context of resistance that parasite. Its use has been especially pathogens or cancers have "acquired", recommended in areas with multiple that is, resistance has evolved. drug-resistant falciparum. Recent studies Antimicrobial resistance and have indicated, however, that the drug antineoplastic resistance challenge can produce potentially fatal cardiac clinical care and drive research. When an conduction abnormalities, limiting its organism is resistant to more than one usefulness. is a drug, it is said to be multidrug-resistant hydroxynapthoquinonethat is currently [4]. The development of being used most widely for the treatment resistance in particular stems from the of opportunistic infections in drugs targeting only specific bacterial immunosuppressed patients [22]. It is molecules (almost always proteins). effective against chloroquine-resistant P. Because the drug is so specific, any falciparum, but because, when used in these molecules will interfere alone, resistance develops rapidly, with or negate its destructive effect, atovaquone is usually given in resulting in antibiotic resistance. combination with proguanil. A new fixed Furthermore there is mounting concern dose antimalarial combination of 250 mg over the abuse of antibiotics in the atovaquone and 100 mg proguanil farming of livestock, which in the (MalaroneTM) is being brought to market European Union alone accounts for three worldwide and is additionally being times the volume dispensed to humans – distributed through a donation leading to development of super-resistant programme, the drugs originally bacteria [7]. synthesized in China are currently Drug resistance has also played a undergoing field trials [23]. significant role in the occurrence and Combination therapy with antimalarials severity of epidemics in some parts of the The use of two antimalarials world. Population movement has simultaneously, especially when the introduced resistant parasites to areas antimalarials have different mechanisms previously free of drug resistance [12]. of action, has the potential for inhibiting The economics of developing new the development of resistance to either of pharmaceuticals for tropical , the components. The efficacy of a including malaria, are such that there is a combination of a 4-aminoquinoline drug great disparity between the (either chloroquine or amodiaquine) with importance of the disease and the amount

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http://www.inosr.net/inosr-scientific-research/ INOSR Scientific Research 4(1): 1-12, 2018. of resources invested in developing new and drug-resistant strains of Plasmodium . This disparity comes at a time falciparum are posing massive problems when malaria parasites have for health authorities. Leprosy has shown demonstrated some level of resistance to an increasing resistance to dapsone [17]. almost every antimalarial drug currently A rapid process of sharing resistance available, significantly increasing the cost exists among single-celled organisms, and and complexity of achieving is termed horizontal gene transfer in parasitological cure [8]. which there is a direct exchange of genes, Bacteria are capable of not only altering particularly in the biofilm state. A similar the enzyme targeted by antibiotics, but asexual method is used by fungi and is also by the use of enzymes to modify the called "parasexuality". Examples of drug- antibiotic itself and thus neutralize it. resistant strains are to be found in Examples of target-altering pathogens are microorganisms such as bacteria and Staphylococcus aureus, vancomycin- viruses, parasites both endo- and ecto-, resistant enterococci and macrolide- plants, fungi, arthropods, mammals, resistant Streptococcus, while examples of birds, reptiles, fish, and amphibians [2]. antibiotic-modifying microbes are In the domestic environment, drug- Pseudomonas aeruginosa and resistant strains of organism may arise aminoglycoside-resistant Acinetobacter from seemingly safe activities such as the baumannii. Resistance to chemicals is use of bleach, tooth-brushing and mouth only one aspect of the problem, another washing, the use of antibiotics, being resistance to physical factors such disinfectants and detergents, shampoos, as temperature, pressure, sound, and soaps, particularly antibacterial radiation and magnetism, and not soaps, hand-washing, surface sprays, discussed in this article, but found at application of deodorants, sunblocks and Physical factors affecting microbial life any cosmetic or health-care product, [2]. insecticides, and dips, The chemicals Drug, toxin, or chemical resistance is a contained in these preparations, besides consequence of and is a harming beneficial organisms, may response to pressures imposed on any intentionally or inadvertently target living organism. Individual organisms organisms that have the potential to vary in their sensitivity to the drug used develop resistance [17]. and some with greater fitness may be Cause of Drug Resistance capable of surviving drug treatment [7]. Antimalarial drug resistance has been Drug-resistant traits are accordingly defined as the “ability of a parasite strain inherited by subsequent offspring, to survive and/or multiply despite the resulting in a population that is more administration and absorption of a drug drug-resistant. Unless the drug used given in doses equal to or higher than makes sexual reproduction or cell- those usually recommended but within division or horizontal gene transfer tolerance of the subject”. This definition impossible in the entire target population, was later modified to specify that the resistance to the drug will inevitably drug in question must “gain access to the follow. This can be seen in cancerous parasite or the infected red blood cell for tumors where some cells may develop the duration of the time necessary for its resistance to the drugs used in normal action” Most researchers interpret chemotherapy. Chemotherapy causes this as referring only to persistence of fibroblasts near tumors to produce large parasites after treatment doses of an amounts of the protein. This protein antimalarial rather than prophylaxis stimulates the growth of cancer cells failure, although the latter is a useful tool which are drug-resistant. MicroRNAs have for early warning of the presence of drug also been shown to affect acquired drug resistance [5]. resistance in cancer cells and this can be This definition of resistance requires used for therapeutic purposes. Malaria in demonstration of malaria parasitaemia in 2012 has become a resurgent threat in a patient who has received an observed South East Asia and sub-Saharan Africa, treatment dose of an antimalarial drug

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http://www.inosr.net/inosr-scientific-research/ INOSR Scientific Research 4(1): 1-12, 2018. and simultaneous demonstration of resistance to these drugs tends to be adequate blood drug and metabolite much less widespread geographically, in concentrations using established some areas of the world, the impact of laboratory methods (such as high multi-drug resistant malaria can be performance liquid chromatography) or in extensive. Most recently, resistance to the vitro test. In practice, this is rarely done artemisinin and non-artemisinin with in vivo studies. In vivo studies of components of artemisinin-based drugs for which true resistance is well combination therapy has emerged in parts known (such as chloroquine) infrequently of Southeast Asia, impacting the efficacy include confirmation of drug absorption of this vital antimalarial class [12]. and metabolism; demonstration of Drug-Resistant P. Vivax persistence of parasites in a patient Chloroquine-resistant P. vivax malaria was receiving directly observed therapy is first identified in 1989 among Australians usually considered sufficient. Some living in or traveling to Papua New drugs, such as mefloquine, are known to Guinea. P. vivax resistance to chloroquine produce widely varying blood levels after has also now been identified in Southeast appropriate dosing and apparent Asia, Ethiopia, and Madagascar. Isolated resistance can often be explained by reports have suggested chloroquine- inadequate blood levels [11]. resistance P. vivax in other countries and Malaria Treatment Failure regions, but further evaluation is needed. A distinction must be made between a Vivax malaria parasites, particularly from failure to clear malarial parasitaemia or Oceania, show greater resistance to resolve clinical disease following a chloroquine than P. vivax isolates from treatment with an antimalarial druand other regions of the world. true antimalarial drug resistance. While Biochemical Mechanisms of Malaria drug resistance can cause treatment Drug Resistance failure, not all treatment failure is due to In general, resistance appears to occur drug resistance. Many factors can through spontaneous that contribute to treatment failure including confer reduced sensitivity to a given drug incorrect dosing, non-compliance with or class of drugs. For some drugs, only a duration of dosing regimen, poor drug single is required to quality, drug interactions, poor or erratic confer resistance, while for other drugs, absorption, and misdiagnosis. Probably multiple mutations appear to be required. all of these factors, while causing Provided the mutations are not treatment failure (or apparent treatment deleterious to the survival or failure) in the individual, may also reproduction of the parasite, drug contribute to the development and pressure will remove susceptible intensification of true drug resistance parasites while resistant parasites through increasing the likelihood of survive. Single malaria isolates have been exposure of parasites to suboptimal drug found to be made up of heterogeneous levels [14]. populations of parasites that can have Drug-Resistant P. Falciparum widely varying drug response Chloroquine-resistant P. falciparum first characteristics, from highly resistant to developed independently in three to four completely sensitive. Similarly, within a areas in Southeast Asia, Oceania, and geographical area, malaria infections South America in the late 1950s and early demonstrate a range of drug 1960s. Since then, chloroquine resistance susceptibility World Health Organization has spread to nearly all areas of the world (2010). Over time, resistance becomes where falciparum malaria is transmitted established in the population and can be levels [16]. P. falciparum has also very stable, persisting long after specific developed resistance to nearly all of the drug pressure is removed. The other currently available antimalarial biochemical mechanism of resistance has drugs, such as been well described for chloroquine, the sulfadoxine/pyrimethamine, mefloquine, antifolate combination drugs, and halofantrine, and quinine. Although atovaquone.

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http://www.inosr.net/inosr-scientific-research/ INOSR Scientific Research 4(1): 1-12, 2018. Chloroquine Resistance Numerous factors contributing to the As the malaria parasite digests advent, spread, and intensification of haemoglobin, large amounts of a toxic by- drug resistance exist, although their product are formed. The parasite relative contribution to resistance is polymerizes this by-product in its food unknown. Factors that have been , producing non-toxic haemozoin associated with antimalarial drug (malaria pigment). It is believed that resistance include such disparate issues resistance of P. falciparum to chloroquine as human behaviour (dealt with in detail is related to an increased capacity for the elsewhere), vector and parasite biology, parasite to expel chloroquine at a rate , and economics. As that does not allow chloroquine to reach mentioned previously, conditions leading levels required for inhibition of to malaria treatment failure may also haempolymerization. This chloroquine contribute to the development of efflux occurs at a rate of 40 to 50 times resistance. faster among resistant parasites than Biological influences on resistance sensitive ones [4]. Further evidence Based on data on the response of supporting this mechanism is provided by sensitive parasites to antimalarial drugs the fact that chloroquine resistance can in vitro and the pharmacokinetic profiles be reversed by drugs which interfere with of common antimalarial drugs, there is this efflux system. It is unclear whether thought to always be a residuum of parasite resistance to other quinoline parasites that are able to survive antimalarials (amodiaquine, mefloquine, treatment. Under normal circumstances, halofantrine, and quinine) occurs via these parasites are removed by the similar mechanisms [17]. immune system (non-specifically in the Antifolate combination drugs case of non-immune individuals). Factors Antifolate combination drugs, such as that decrease the effectiveness of the sulfadoxine + pyrimethamine, act through immune system in clearing parasite sequential andsynergistic blockade of 2 residuum after treatment also appear to key enzymes involved withfolate increase survivorship of parasites and synthesis. Pyrimethamine and related facilitate development and intensification compounds inhibit the step mediated by of resistance [21]. This mechanism has dihydrofolatereductase (DHFR) while been suggested as a significant sulfones and sulfonamides inhibit the contributor to resistance in South-East step mediated by dihydropteroate Asia, where parasites are repeatedly synthase (DHPS). Specific gene mutations cycled through populations of non- encoding for resistance to both DHPS and immune individuals, the nonspecific DHFR have been identified. Specific immune response of non-immune combinations of these mutations have individuals is less effective at clearing been associated with varying degrees of parasite residuum than the specific resistance to antifolate combination drugs immune response of semi-immune [10]. individuals. The same mechanism may 4Atovaquone also explain poorer treatment response Atovaquone acts through inhibition of among young children and pregnant electron transport at the cytochrome bc1 women [8]. The contribution to complex. Although resistance to development and intensification of atovaquone develops very rapidly when resistance of other prevalent used alone, when combined with a second immunosuppressive states has not been drug, such as proguanil (the combination evaluated. Among refugee children in the used in MalaroneTM) or tetracycline, former Zaire, those who were resistance develops more slowly. malnourished (low weight for height) had Resistance is conferred by single-point significantly poorer parasitological mutations in the cytochrome-b gene. response to both chloroquine and SP Factors Contributing to the Spread of treatment. Similarly, evidence from Resistance prevention of malaria during pregnancy suggests that parasitological response to

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http://www.inosr.net/inosr-scientific-research/ INOSR Scientific Research 4(1): 1-12, 2018. treatment among individuals infected other antifolate combination drugs. with the human virus Development of high levels of resistance (HIV) may also be poor. HIV-seropositive through continued accumulation of DHFR women require more frequent treatment mutations may compromise the useful life with SP during pregnancy in order to have span of newer antifolate combination the same risk of placental malaria as is drugs such as chlorproguanil/dapsone seen among HIV-seronegative women. (LapDap) even before they are brought Parasitological response to treatment of into use [5]. This increased risk of acute malaria among HIV-seropositive resistance due to SP use may even affect individuals has not been evaluated [13]. nonmalarial pathogens; use of SP for The current prevalence of malnutrition treatment of malaria increased resistance among African children under 5 years has to trimethoprim/sufamethoxazole among been estimated to be 30% and an respiratory pathogens. There is an estimated 4 to 5 million children are interesting theory that development of expected to be infected with HIV at the resistance to a number of antimalarial beginning of this new century. If it is drugs among some falciparum parasites proven that malnutrition or HIV infection produces a level of genetic plasticity that plays a significant role in facilitating the allows the parasite to rapidly adapt to a development or intensification of new drug, even when the new drug is not antimalarial drug resistance, the chemically related to drugs previously prevalence of these illnesses could pose a experienced. The underlying mechanism tremendous threat to existing and future of this plasticity is currently unknown, antimalarial drugs [23]. but this capacity may help explain the Some characteristics of recrudescent or rapidity with which South-East Asian drug resistant infections appear to strains of falciparum develop resistance provide a survival advantage or to to new antimalarial drugs [20]. facilitate the spread of resistance Programmatic influences on resistance conferring genes in a population. In one Programmatic influences on development study, patients experiencing chloroquine of antimalarial drug resistance include treatment failure had recrudescent overall drug pressure, inadequate drug infections that tended to be less severe or intake (poor compliance or inappropriate even asymptomatic. Schizont maturation dosing regimens), pharmacokinetic and may also be more efficient among pharmacodynamic properties of the drug resistant parasites [9]. There is some or drug combination, and drug evidence that certain combinations of interactions. Additionally, reliance on drug-resistant parasites and vector presumptive treatment can facilitate the species enhance transmission of drug development of antimalarial drug resistance, while other combinations resistance. Overall drug pressure inhibit transmission of resistant especially that exerted by programmes parasites. Many antimalarial drugs in utilizing , current usage are closely related probably has the greatest impact on chemically and development of resistance development of resistance. Studies have to one can facilitate development of suggested that resistance rates are higher resistance to others. Chloroquine and in urban and periurban areas than rural amodiaquine are both 4-aminoquinolines communities, where access to and use of and cross-resistance between these two drug is greater [2]. drugs is well known. Development of The use of presumptive treatment for resistance to mefloquine may also lead to malaria has the potential for facilitating resistance to halofantrine and quinine resistance by greatly increasing the [14]. number of people who are treated Antifolate combination drugs have similar unnecessarily but will still be exerting action and widespread use of selective pressure on the circulating sulfadoxine/ pyrimethamine for the parasite population. In some areas and at treatment of malaria may lead to some times of the year, the number of increased parasitological resistance to patients being treated unnecessarily for

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http://www.inosr.net/inosr-scientific-research/ INOSR Scientific Research 4(1): 1-12, 2018. malaria can be very large [10]. manufacturing practices, intentional Concurrent treatment with other drugs counterfeiting, or deterioration due to can increase the likelihood of treatment inadequate handling and storage, drugs failure and may contribute to may not contain sufficient quantities of development of drug resistance. the active ingredients. In an analysis of administration for treatment of anaemia chloroquine and antibiotics available in and possibly when used as a routine Nigeria and Thailand, between 37% and supplement during pregnancy can 40% of samples assayed had substandard increase treatment failure rates. Similarly, content of active ingredients, mostly from concurrent illness may have an influence, poor manufacturing practices. Another as was mentioned previously with regard study in Africa found chloroquine stored to malnourishment [9]. under realistic tropical conditions lost at Drug quality has also been implicated in least 10% of its activity in a little over a ineffective treatment and possibly drug year [16]. resistance. Either through poor CONCLUSION Resistance to the antimalarial drugs has identify drug-resistant marker, to prevent increased the mortality and morbidity the development of drug resistance rate that is achieved so far through the further and in the development of new malaria control program. Monitoring the antimalarial drugs/vaccines. The drug resistance to the available molecular markers of drug resistance play antimalarial drugs helps to implement a vital role in the detection of resistance effective drug policy, through the in vivo in clinical and field isolates when efficacy studies, in vitro drug compared to the in vivo efficacy studies susceptibility tests and detection of and in vitro tests. Thus, earlier detection molecular markers. It is important to of drug-resistant parasites in clinical understand the mechanism of the isolates will aid in employing immediate antimalarial drugs, as it is one of the key and appropriate treatment that in turn factors in the emergence and spread of reduces treatment failure and thereby drug resistance. mortality, and also prevents the spread of Emergence and spread of antimalarial resistance. drug resistance constitute a major threat Hence, continuous monitoring and toward the treatment of malaria and if not surveillance of drug-resistant molecular handled properly, could reverse the markers in malaria endemic regions is malaria control program and containment important in determining and assisting an achieved so far worldwide. The drug effective national drug policy for malaria resistance has been reported mainly for P. treatment. Therefore, more research is falciparum and P. vivax. Antimalarial necessary to find new antimalarial combination therapy targeting different drugs/vaccines for multidrug resistance mechanism of action could prolong the parasites and in identification and emergence and spread of drug-resistant validation of genetic markers for parasites. Understanding the site of multidrug resistance, thereby action and mechanism of the containment and treatment of malaria can antimalarials is an important tool to be achieved hand in hand. REFERENCES 1. Barat, L. (2013). Does the understand malaria? Tropical availability of blood slide Medicine and International Health, microscopy for malaria at health 4:1–3. centers improve the management 3. Craig, M.H. and Sharp, B.L. (2014). of persons with fever in Zambia? Comparative evaluation of four American Journal of Tropical techniques for the diagnosis of Medicine and Hygiene, 60: 1024– infections. 1030. Transactions of the Royal Society of 2. Beck, H.P. (2009). How does and Hygiene, molecular help to 91:279–282.

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http://www.inosr.net/inosr-scientific-research/ INOSR Scientific Research 4(1): 1-12, 2018. 4. Fortier, B. (2012). Enzyme Quantitative Buffy Coat analysis immunoassay for detection of tubes. Parasitology Today, 5:132– antigen in acute Plasmodium 133. falciparum malaria. 13. Mackey, L.J. (2016). Diagnosis of European Journal of Clinical Plasmodium falciparum infection Microbiology 1987;6:596–598. in man: detection of parasite 5. Foster, S. (2008). Phillips M. antigens by ELISA. Bulletin of the Economics and its contribution to World Health Organization, 60:69– the fight against malaria. Annals 7 of Tropical Medicine & Parasitology, 14. Makler, M.T, Palmer, C.J, Ager, 92:391–398. A.L.(2014). A review of practical 6. Foster, S.D.(2013). Pricing, techniques for the diagnosis of distribution, and use of malaria. Annals of Tropical antimalarial drugs. Bulletin of the Medicine & Parasitology, 92:419– World Health Organization, 433. 69:349–363. 15. Nabarro, D.N. and Talyer, E.M. 7. Freeman, j. (2016). Effect of (2010). The Roll Back Malaria chemotherapy on malaria campaign. Science, 280: 2067– transmission among Yanomami 2068. Amerindians: simulated 16. Nchinda, T.C. (2014). Malaria: A consequences of placebo reemerging disease in Africa. treatment. American Journal of Emerging Infectious Diseases, Tropical Medicine and Hygiene, 4:398–403. 60:774–780 in diagnostic 17. Palmer, C. J. (2016). Field techniques and vaccines for evaluation of the OptiMAL7 rapid malaria. Bulletin of the World malaria diagnostic test during anti- Health Organization, 74:47– malarial therapy in Guyana. 54. Transactions of the Royal Society of 8. Jonkman, H.O. (2012). Cost-saving Tropical Medicine & Hygiene, through microscopy based versus 93:517–518. presumptive 18. Piper R. (2012). Immunocapture in adult outpatients in Malawi. diagnostic assays for malaria using Bulletin of the World Health Plasmodium lactate dehydrogenase Organization, 73:223–227. (pLDH). American Journal of 9. Khusmith, S. (2012). Two-site Tropical Medicine and Hygiene, immunoradiometric assay for 60:109–118. detection of Plasmodium 19. Redd, S.C. (2011). Usefulness of falciparum antigen in blood using clinical case-definitions in guiding monoclonal and polyclonal therapy for African children with antibodies. Journal of Clinical malaria or pneumonia. Lance, Microbiology, 25:167–71. 340:1140–1143. 10. Knudsen, A.B and Slooff, R.. (2017). 20. Ridley, R.G. (2015). Plasmodium: Vector-borne disease problems in Drug discovery and development rapid urbanization: new an industrial perspective. approaches to vector control. Experimental Parasitology, 87:293– Bulletin of the World Health 304. Organization, 7:33-67. 21. Smith, T. (2013). Attributable 11. Kremsner, P.G. (2012). fraction estimates and case Clindamycin treatment of definitions for malaria in endemic falciparum malaria in Brazil. areas. Statistics in Medicine, 13:45– Journal of Antimicrobial 58. Chemotherapy, 23:275–281. 22. Snow, R.W. (2012). Estimating 12. Levine, R.A., Wardlaw, S.C. and mortality, morbidity and disability Patton, C.L. (2015). Detection of due to malaria among Africa’s non- haematoparasites using pregnant population. Bulletin of

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http://www.inosr.net/inosr-scientific-research/ INOSR Scientific Research 4(1): 1-12, 2018. the World Health Organization, 77:624–640. 23. Tharavanij, S. (2001). New developments in malaria diagnostic techniques. Southeast Asian Journal of Tropical Medicine & Public Health, 21:33–55. 24. Watkins, W.M. (2013).The efficacy of antifolate antimalarial combinations in Africa: a predictive model based on pharmacodynamic and pharmacokinetic analyses. Parasitology Today, 13:459–464. 25. World Health Organization (2010). A rapid dipstick antigen capture assay for the diagnosis of falciparum malaria. WHO informal consultation on recent advances

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