Saving Lives, Buying Time Economics of Malaria Drugs in an Age of Resistance (2004) / Chapter Skim
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9 Antimalarial Drugs and Drug Resistance
9 Antimalarial Drugs and Drug Resistance
Pages 252-298
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From page 252... ...
triggered by the release of plasmodia into the bloodstream from mature blood schizonts, are the most common symptoms heralding the onset of a clinical case of uncomplicated falciparum malaria (see Chapter 6 for a description of the evolution of clinical symptoms)
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; they are recommended only in combination with other antimalarial drugs. Drugs active against Plasmodium falciparum also are active against the other three malaria species that affect humans -- P.
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Quinine 10 mg salt/kg three times daily plus tetracycline 4 mg/kg four times daily or doxycycline 3 mg/kg once daily or clindamycin 10 mg/kg twice daily for 7 days2 a For acute treatment of falciparum malaria combinations containing an artemisinin-derivative are preferred. Artesunate (4 mg/kg/day for 3 days)
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B Pregnancy: There are insufficient data on the safety of most antimalarial drugs in pregnancy.
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256 Clinic: Facilities Health Injection Rural No by 1:2 given both a diluted into dose: water Possible 8-hourly dihydrochloride thighs. salt/kg sterile injection Intravenous mg mg/kg No Infusions Quinine 20 with split anterior Maintenance 10 hours b over mg over over by salt/kg 10 2-8 by hour a mg/kg mg hours.
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257 at daily insufficient e mg/kg ar mg/kg 20 regimen 10 There pon.u daily nasogastric oral hour. or relied for then as per be rectocap: suppository daily hrs.
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Pharmacodynamics The way drugs act on their target -- in this case, plasmodia -- is called pharmacodynamics. The principal effect of antimalarial drugs in uncomplicated malaria is to inhibit parasite multiplication by killing parasites.
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In contrast, although their degree of immune protection cannot be quantitated or assumed, older children or adults in high-transmission areas may do surprisingly well with failing drugs because much of their therapeutic response stems from immunity rather than antimalarial drug action. In severe falciparum malaria, the stage at which an antimalarial drug acts is especially important since the ultimate goal of treatment is to halt parasite maturation to late-stage, cytoadherent parasites (i.e., mature schizonts that attach to endothelial cells lining small blood vessels)
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. Reduced intracellular drug concentrations accompany chloroquine resistance because resistant parasites expel chloroquine from their acid food vacuoles 40-50 times faster than do drug-sensitive parasites (Bray et al., 1998)
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. Other Antimalarial Drugs In general, antimalarial drug resistance to mefloquine, quinine, lumefantrine, and halofantrine is linked, whereas chloroquine, and mefloquine resistance are not.
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successfully isolated artemisinin derivatives from air-dried parts of plants growing in the wild near Washington, D.C., using petroleum ether extraction (Klayman, 1985)
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. There is clear consensus, however, that artemisinin derivatives kill early-stage gametocytes and are more active over a broader range of the parasite life cycle than any other antimalarial drug currently in use.
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falciparum malaria were randomly assigned 3 days treatment with amodiaquine plus artesunate, or amodiaquine plus placebo. Both regimens were well tolerated.
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falciparum malaria, artemether-lumefantrine was as effective (94-100 percent) and overall better tolerated than mefloquine-artesunate (van Vugt et al., 1999, 2000; Lefevre et al., 2001)
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Coartem has been better tolerated than either mefloquine alone or artesunate plus mefloquine (van Vugt et al., 1998; Looareesuwan et al., 1999)
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Neurotoxicity in Humans One case report to date has described acute cerebellar dysfunction including slurred speech, ataxia, impaired heel to shin movement, and dysdiadochokinesis after treatment of falciparum malaria with oral artesunate (Miller and Panosian, 1997)
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. Most recently, neuropathologic assessments of the brain stems of patients who died from severe falciparum malaria following treatment with high dose intramuscular artemether (the doses were higher than generally recommended)
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. In summary, current data are encouraging but more safety data for the artemisinin derivatives are needed to support use in pregnant women with uncomplicated malaria.
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Once formed, however, resistant mutants have a survival advantage in the presence of antimalarial drugs and, conversely, a survival disadvantage in the absence of at least certain antimalarial drugs. The resulting fitness cost may lead to a declining prevalence of resistance once drug pressure is removed (this pattern has been demonstrated for chloroquine resistance in Malawi [Kublin et al., 2003]
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. Plasmodium falciparum infections appearing between days 15 and 52 after SP treatment were more likely to exhibit pyrimethamine resistance in vitro.
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One way to look at the relationship between resistance and transmission intensity is as follows. In low-transmission areas the majority of malaria is symptomatic, and selection therefore takes place at a time when relatively large numbers of parasites in a given individual encounter antimalarial drugs.
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. The following is a brief summary of current levels of global drug resistance to chloroquine and SP based on in vivo assessment of therapeutic treatment failure (TTF)
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Dates of studies in upper right corner; PF = parasitologic failure; CF = clinical failure. Median (range)
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. Plasmodium vivax Chloroquine Resistance It was not until 1989 -- 30 years after chloroquine resistance first emerged in P
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ASSESSING ANTIMALARIAL DRUG EFFICACY AND RESISTANCE Four methods are currently available to study or measure antimalarial drug efficacy vis-à-vis drug resistance: in vivo, in vitro, animal model studies, and molecular markers (Bloland, 2001)
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when evaluating slowly eliminated antimalarial drugs. Shorter periods of follow-up in assessing antimalarial treatment often underestimate drug-resistant recrudescent infections, which, even in areas of high stable transmission, cause significant morbidity, especially anemia.
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In brief, malaria parasites obtained from venous blood samples are co-cultured in microtiter wells with known concentrations of antimalarial drugs. The drug effect is then quantified according a given agent's ability to inhibit the growth of parasites or their maturation into schizonts (Rieckmann et al., 1978)
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. At present, attention is focused on four drug resistance genes (Wernsdorfer and Noedl, 2003)
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falciparum chloroquine resistance transporter gene (pfcrt) which is located on chromosome 7 and encodes the digestive vacuole transmembrane protein PfCRT (Wellems et al., 1991; Djimde et al., 2001)
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2001. High level chloroquine resistance in Sudanese isolates of Plasmodium falciparum is associated with mutations in the chloroquine resistance transporter gene pfcrt and the multidrug resistance gene pfmdr1.
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2000. The mechanisms of parasite clearance after antimalarial treatment of Plasmodium falciparum malaria.
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2000. Predictors of chloroquine treatment failure in children and adults with falciparum malaria in Kampala, Uganda.
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2003. Assessing the Efficacy of chloroquine and sulfadoxine-pyrimethamine for treat ment of uncomplicated Plasmodium falciparum malaria in the Democratic Republic of Congo.
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with mefloquine in the treatment of acute Plasmodium falciparum malaria in Thailand. American Journal of Tropical Medicine and Hygiene 60(2)
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2000. Effects of artesunate-mefloquine combina tion on incidence of Plasmodium falciparum malaria and mefloquine resistance in West ern Thailand: A prospective study.
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1999a. Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives.
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-resistant Plasmodium falciparum malaria in Ugandan sentinel sites with high Cq resistance. Transactions of the Royal Society of Tropical Medicine and Hygiene 96(5)
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2000. A case-control auditory evaluation of patients treated with artemisinin derivatives for multidrug-resistant Plasmodium falciparum malaria.
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1996. Assessment of Therapeutic Efficacy of Antimalarial Drugs for Uncomplicated Falciparum Malaria in Areas With Intense Transmission.
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It is safe in infants and pregnant women, and was the historical drug of choice for treatment of nonsevere or uncomplicated malaria and to prevent malaria in travelers. Chloroquine acts primarily against bloodborne asexual stages, although it also works against the bloodstream stage infective to mosquitoes.
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Common side effects include nausea, vomiting, diarrhea, secondary yeast infections, and photosensitivity. PRIMAQUINE, an 8-aminoquinoline, acts against malaria parasites in the liver, thereby reducing the likelihood of P
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It is especially useful in areas where multidrug-resistant falciparum malaria is present. Cardiac conduction abnormalities (specifically, prolongation of the PR and QT intervals on a standard electrocardiogram)
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Malarone has also been combined with artesunate for treatment of uncomplicated multidrug-resistant falciparum malaria (van Vugt et al., 2002)
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2003. Assessing the Efficacy of chloroquine and sulfadoxine-pyrimethamine for treat ment of uncomplicated Plasmodium falciparum malaria in the Democratic Republic of Congo.
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2000. A case-control auditory evaluation of patients treated with artemisinin derivatives for multidrug-resistant Plasmodium falciparum malaria.
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1999. Antimalarial drug resistance and mortality in falciparum malaria.
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