DRUG RESISTANCE AMONG MALARIA AND OTHER PARASITES

doi:10.1016/S0891-5520(05)70400-1

Infectious Disease Clinics of North America

Volume 11, Issue 4, 1 December 1997, Pages 969-987

https://doi.org/10.1016/S0891-5520(05)70400-1 Get rights and content

Parasitic infections are among the most common infectious diseases worldwide. Intestinal parasites, such as Ascaris, hookworms, and Trichuris, infect many hundreds of millions of people. Malaria is responsible for between 300 and 500 million clinical cases and 1.5 to 2.5 million deaths each year. More than 200 million people are infected with Schistosoma and another 200 million are infected with Giardia.

The greatest public health threat posed by drug resistance among parasites is from malaria, and most of this article is devoted to discussing issues related to the development, spread, and impact of drug resistant malaria. Concern also is growing, however, about the development of drug resistance among non-malarial parasites; we discuss metronidazole resistance in both Giardia and Trichomonas, and the possibility of ivermectin resistance in human filariasis.

Section snippets

MALARIA

The development of antimalarial drug resistance has had a tremendous impact on malaria control. Drug resistance has been implicated in the spread of malaria to new areas and re-emergence of malaria in areas in which the disease had been eradicated. Drug resistance also has played a significant role in the occurrence and severity of epidemics in some parts of the world. Population movement has introduced resistant parasites to areas previously free of drug resistance. Currently, at a time when

DRUG RESISTANCE IN NON-MALARIA PARASITES

Although other parasites demonstrate the same characteristics of drug resistance, their global public health impact has not been as great as that for malaria.

CONCLUSIONS

Several consistent themes arise in drug resistance among parasites: widespread and uncontrolled use of drugs, heavy reliance on a small number of drugs, use of single drug therapy, poor compliance with recommended treatment regimens, and slow development of new therapeutic alternatives. All facilitate development and spread of drug resistance. In response, a concerted effort must be made to limit the frequency and impact of these practices.

The way in which existing drugs are used needs to be

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Ever since it was discovered and used widely in the synthesis of different organic compounds, quinoline became an interesting framework among chemists and pharmacists due to its unique properties. There are many familiar named reactions developed for the synthesis of quinoline based structures, among which the Friedländer reaction plays an important role. This method involves the condensation between 2-aminobenzaldehydes and a ketone. By developing the Friedländer synthesis, different types of heterocycles have been prepared in addition to the quinolines. In this chapter, the focus is on the applicability of the Friedländer reaction to the synthesis of various types of heterocyclic compounds.
The role of antimalarial quality in the emergence and transmission of resistance
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It has been proposed that the long-comparative half-lives of sulfadoxine-pyrimethamine and mefloquine resulting in sub-therapeutic levels of API may promote the emergence of resistance and thus the transmission of resistance [13]. Additionally, when there are sub-therapeutic API concentrations persisting in the bloodstream weeks to months after the treatment, it acts as a selection pressure for any re-infection that occurs [13,28]. In combination therapies, the choice of partner drugs and their half-lives further highlight the effect of sub-therapeutic API concentrations on the emergence and transmission of resistance [53].
The emergence and transmission of antimalarial resistance is hampering malaria eradication efforts and is shortening the useful therapeutic life of currently available antimalarials. Drug selection pressure has been identified as a contributing factor to the emergence and transmission of resistance, especially population treatment coverage and sub-therapeutic concentrations of active pharmaceutical ingredient (API) in the bloodstream. Medicine quality can be defined as good quality or poor quality. Poor quality antimalarials can be falsified, substandard or degraded and are estimated to make up between 10 and 50% of the antimalarial market in developing countries, and can be a source of sub-therapeutic doses of antimalarial API(s). The availability and use of poor quality antimalarials and the non-recommended use of quality assured monotherapies have historically been linked to treatment failure and in some cases, have coincided with the emergence and transmission of resistance in regions. We propose and outline the hypotheses that the use of poor quality antimalarial treatments and non-recommended quality assured monotherapies promote the (i) emergence and/or (ii) transmission of antimalarial resistance.
Plasmodium vivax: Prevalence of mutations associated with sulfadoxine-pyrimethamine resistance in Plasmodium vivax clinical isolates from Pakistan
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The main aim of the present study was to investigate the frequency of SNPs-haplotypes of dhfr and dhps genes associated to sulfadoxine–pyrimethamine (SP) resistance in Plasmodium vivax clinical isolates circulating in a malaria endemic area, Pakistan. All 164 collected isolates were analyzed for SNPs-haplotypes at positions 13, 33, 57, 58, 61, 117 and 173 of pvdhfr and 383 and 553 of pvdhps genes using PCR–RFLP methods. All examined isolates were found to carry wild-type amino acids at positions 13, 33, 57, 61 and 173, while 58R and 117N mutations were detected among 15.2% and 53.6% of isolates, respectively. Based on the size polymorphism of pvdhfr genes at repeat region, type B (79.3%) was the most prevalent variant. The combination of pvdhfr and pvdhps haplotypes demonstrated nine distinct haplotypes. The three most prevalent haplotypes were I₁₃P₃₃F₅₇S₅₈T₆₁S₁₁₇I₁₇₃/A₃₈₃A₅₅₃ (43.9%), I₁₃P₃₃F₅₇S₅₈T₆₁N₁₁₇I₁₇₃/A₃₈₃A₅₅₃ (33.6%) and I₁₃P₃₃F₅₇R₅₈T₆₁N₁₁₇I₁₇₃/A₃₈₃A₅₅₃ (12.2%). The presence of mutant haplotypes is worrying and indicates the emergence of drug tolerant/resistant P. vivax isolates in Pakistan in near future.
Genetic structure of Plasmodium vivax isolates from two malaria endemic areas in Afghanistan
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In this study, the nature and extent of genetic diversity of Plasmodium vivax populations circulating in Afghanistan have been investigated by analyzing three genetic markers: csp, msp-1, and msp-3α. Blood samples (n = 202) were collected from patients presenting with vivax malaria from south-western (Herat) and south-eastern (Nangarhar) parts of Afghanistan, and analysed using nested-PCR/RFLP and sequencing methods. Genotyping pvmsp-1 revealed type 1, type 2 and recombinant type 3 allelic variants, with type 1 predominant in parasites in both study areas. The sequence analysis of 57 P. vivax isolates identified a total of 26 distinct alleles. Genotyping pvcsp gene showed that VK210 type (86.6%) is predominant in Afghanistan. Moreover, three major types of the pvmsp-3α locus: type A, type B and type C were distinguished among Afghani isolates. The predominant fragments among Nangarhar and Herat parasites were type A (70.8% and 67.9%, respectively). PCR/RFLP products with Hha I and Alu I were detected 52 and 38 distinct variants among Nangarhar and Herat isolates, respectively. These results strongly indicate that the P. vivax populations in Afghanistan are highly diverse.
IgG subclasses pattern and high-avidity antibody to the C-terminal region of merozoite surface protein 1 of Plasmodium vivax in an unstable hypoendemic region in Iran
2009, Acta Tropica
Citation Excerpt :
This parasite re-appeared in Asian countries such as Uzbekistan (Severini et al., 2004), Azerbaijan (Leclerc et al., 2004), Turkey (Zeyrek et al., 2008), north of Iran (Zakeri et al., 2004), and the Republic of Korea (Lim et al., 2000) where eradication efforts had been successful in 1960s. Growing chloroquine and primaquine resistance strains of P. vivax in malaria endemic regions (Barat and Bloland, 1997; Nomura et al., 2001) could call for new tools and strategies to combat P. vivax. Therefore, to achieve this goal, vaccine development must be considered.
The C-terminal region of Plasmodium vivax merozoite surface protein 1 (PvMSP-1₁₉) is a leading vaccine candidate for inclusion in a polyvalent malaria vaccine. In the present study, the IgG subclasses profile and the avidity of IgG to PvMSP-1₁₉ were evaluated in individuals (n = 94) naturally exposed to P. vivax parasite in malaria endemic areas in Chabahar districts, Iran. In individuals with patent P. vivax malaria, 86.1% was sero-positive to PvMSP-1₁₉ and IgG1 (81.9%) was the predominant subclass. In addition, to determine the persistence of specific IgG, IgG1 and IgG3 antibodies to PvMSP-1₁₉, the frequency of antibodies was determined in the infected subjects (n = 74) after treatment with standard chloroquine and it was detected that the frequency of responders was significantly reduced to 51.3%, 51% and 16.2%, respectively. The antigen-binding avidity of IgG antibodies to PvMSP-1₁₉ was measured in sero-positive sera and the high-avidity of IgG, IgG1 and IgG3 was found in 66.6%, 61% and 47% of the infected subjects with P. vivax, respectively. The present result shows that individuals who exposed to vivax malaria in the endemic region in Iran develop antibodies with high-avidity to PvMSP-1₁₉. These results could help to understand the interactions between the host and P. vivax parasite in development of MSP-1₁₉-based vaccine.
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Hypoestoxide (HE) is a diterpene isolated from Hypoestes rosea (Acanthaceae), a plant indigenous to Nigeria. Previous studies demonstrated that HE exhibited potent anti-inflammatory and anti-cancer activities in well established animal models but weak in vitro activities in both the anti-inflammation and anti-cancer in vitro screening systems. We now report a similar observation in the in vitro and in vivo screening systems for antimalarial activity. The results indicate that while HE exhibits a relatively weak in vitro activity (IC₅₀= 10 μM versus 0.11 μM for chloroquine) against different strains of cultured P. falciparum parasites, the dose of HE required to reduce parasitemia by 90% in Plasmodium berghei-infected mice, is much lower than standard antimalaria drugs (SD₉₀= 250 μg/kg versus 5 mg/kg for chloroquine). Furthermore, lower doses of HE were much more effective than higher doses in inhibiting parasite development. The implications of these findings are discussed.

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: Address reprint requests to Lawrence M. Barat, MD, MPH, Centers for Disease Control and Prevention, 4770 Buford Highway, Mail Stop F-22, Atlanta, GA 30341

^*: From the Malaria Epidemiology Section, Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia

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DRUG RESISTANCE AMONG MALARIA AND OTHER PARASITES

Section snippets

MALARIA

DRUG RESISTANCE IN NON-MALARIA PARASITES

CONCLUSIONS

Chemotherapy of Malaria

Availability of parenteral quinidine gluconate for treatment of severe or complicated malaria

MMWR

Short-term in vitro culture of Plasmodium vivax and P. ovale for drug-susceptibility testing

Parasitol Res

The epidemiology of drug-resistant malaria

Trans R Soc Trop Med Hyg

Beyond chloroquine: implications of drug resistance for evaluating malaria therapy efficacy and treatment policy in Africa

J Infect Dis

Patterns of in vitro resistance to chloroquine, quinine, and mefloquine of Plasmodium falciparum in Cameroon, 1985–1986

Am J Trop Med Hyg

The current status of drug resistance in malaria

Chloroquine-resistant Plasmodium falciparum from East Africa: cultivation and drug sensitivity of the Tanzanian 1/CDC strain from an American tourist

Lancet

Primaquine resistance in Plasmodium vivax

Am J Trop Med Hyg

Sulfadoxine-pyrimethamine for the treatment of acute malaria in children of Papua New Guinea. II. Plasmodium vivax

Am J Trop Med Hyg

Treatment of vivax malaria with sulfadoxine-pyrimethamine and with pyrimethamine alone

Trans R Soc Trop Med Hyg

High prevalence of mefloquine-resistant falciparum malaria in eastern Thailand

Bull WHO

Vivax malaria resistant to chloroquine: case reports from Bombay

Trans R Soc Trop Med Hyg

Iron chelation as a chemotherapeutic strategy for falciparum malaria

Am J Trop Med Hyg

Amodiaquine resistant falciparum malaria in Thailand

Am J Trop Med Hyg

Quinine resistant falciparum malaria acquired in east Africa

Trop Med Parasitol

Metronidazole and drug resistance

Parasitol Today

Long-term malaria prophylaxis with weekly mefloquine

Lancet

Clinical studies of atovaquone, alone or in combination with other antimalarial drugs for the treatment of acute uncomplicated malaria in Thailand

Am J Trop Med Hyg

Randomised trial of artesunate and mefloquine alone and in sequence for acute uncomplicated falciparum malaria

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Single day mefloquine-artesunate combination in the treatment of multi-drug resistant falciparum malaria

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Treatment of primaquine-resistant Plasmodium vivax malaria

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Development of resistance to chloroquine by Plasmodium vivax in Myanmar

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Mefloquine resistance in Plasmodium falciparum

Parasitol Today

Vivax malaria resistant to treatment and prophylaxis with chloroquine

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Mefloquine-resistant falciparum malaria on the Thai-Burmese border

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