Antimalarial drug resistance // Drug Repurposing

Antimalarial drug resistance

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Infections with Plasmodium parasites cause human malarias. Among the five species of Plasmodium that infect humans, P. falciparum is the deadliest, causing more than one million malaria-related deaths per year in endemic areas of sub-Saharan Africa, where 90% of all malaria-related deaths occur. Plasmodium parasites are unicellular and eukaryotic organisms. Various species of female Anopheles mosquitoes transmit them. Hence, malaria is a vector-borne disease. All malarial parasites have a complex life cycle that involves sexual and asexual reproductive stages (Figure 1). Parasites reproduce asexually (clonally) in human hosts. The sexual stage takes place inside the mosquito vector. Hence, the genetic material of parasites mixes in the mosquitoes during sexual recombination. The number of sexual reproductions and the amount of sexual recombination increases with the number of mosquitoes that participate in the transmission of the parasite.

Illustration of the malaria transmission cycle.Figure 1: Illustration of the malaria transmission cycle.

So far, no preventative vaccination against malaria exists, and its control depends heavily upon antimalarial drugs that kill parasites inside the human body. Malaria has been noted for more than 4, 000 years. In ancient China, India, the Middle East, Greece, and Rome, malaria and its possible treatments were documented. Ancient Chinese used a treatment based on artemisinin (documented 168 BC), the active ingredient in some high-end drugs nowadays. Treatments with Quinine are known to the western world since the early 17th century. In British colonies, tonic water (which contains large amounts of Quinine) was mixed with gin and became a popular drink.

Selective sweep (or hitchhiking effect) of a resistant mutation.The discovery of Chloroquine (CQ) in the 1930s revolutionized malaria treatments. CQ was the most widely-used drug from the early 1950s to until the 1990s. After about ten years of use, mutations within P. falciparum that conferred resistance to CQ arose independently in Columbia and Thailand. Since then CQ-resistant mutations have been spreading quickly through most endemic areas. CQ clears out resistant parasites less efficiently from the human body than sensitive (non-resistant) parasites. Hence, infections with resistant parasites result in increased morbidity and mortality.

Sulfadoxine-pyrimethamine (SP), a combination of two drugs, replaced CQ. However, resistance to SP evolved rapidly and now occurs at high frequency in major malarious regions (Laxminarayan 2004). Currently, alternative drugs (e.g., artemisinin-based combination therapies) are available and others continue to be developed. However, higher production costs limit their widespread application in major endemic areas. The evolution of resistance against affordable drugs incurs an enormous societal cost for fighting the spread of the disease. Facing this reality, the focus of public health policy should be shifted to increasing the sustainability of treatment regimes by delaying the emergence and spread of drug resistance as much and early as possible.

Is it possible to prevent or delay the spread of anti-malaria drug resistance? The answer requires approaches that integrate the disease ecology, epidemiology, genetics, and evolutionary biology of malaria. Such interdisciplinary research started to dissect the dynamics of drug-resistance evolution under various clinical and demographic settings. The complex problem of identifying key determinants in the spread of resistance could be tackled from many starting points. However, a critical path to the heart of the problem is to recognize that the evolution of drug resistance is an example of Darwinian evolution by natural selection.

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The ring (part 2 of 2)

by slummy

And as for the petty incidentals (start world smallest violin solo 3 2 1 now): my wife (who i love) wants a divorce (because, um, guess what, i'm depressed and emotionally unstable and because i lash-out; which i am, which i do, and i don't blame her a bit), my dog, who i love like a child, is on her last legs, i'm in constant pain, and i hate my meaningless f'ing job at the button pushing factory (christ, why did i ever stop selling drugs in high school?). oh, and btw, i can't afford to go back to school (for repurposing) because i'm ineligible (ineligible receiver downfield, 10 yard penalty, says the ref) for financial aid (you should have registered for Selective Service back when we were invading Grenada (remember that one, kids?)) -- and besides, school is a lot of work and i'm old and worn out, not as shiney as the hung…

Book (LAP LAMBERT Academic Publishing)

Fighting resistance to antimalarial drug  — Cordis News
When it comes to the emergence of antimalarial drug resistance, it's not a question of 'if' but 'when'.

LAP LAMBERT Academic Publishing Emergence and spread of antimalarial drug resistance: Dynamics of malaria parasite resistance markers in two areas of different transmission intensity
Book (LAP LAMBERT Academic Publishing)
Antimalarial Drugs I. Biological Background, Experimental Methods, and Drug Resistance
Book (Springer)
Biological Background, Experimental Methods and Drug Resistance (Handbook of Experimental Pharmacology / Antimalarial Drugs)
Book (Springer)
Springer Basel Treatment and Prevention of Malaria (Milestones in Drug Therapy)
eBooks (Springer Basel)