The World Bank: false financial and statistical accounts and medical malpractice in malaria treatment.
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Africa↗
Biomedical subjects
William M Watkins
Publications and source records attributed to William M Watkins.
Tolerance is the key to understanding antimalarial drug resistance.
The evolution of antimalarial drug resistance is often considered to be a single-stage process in which parasites are either fully resistant or completely sensitive to a drug. However, this does not take into account the important intermediate stage of drug tolerance. Drug-tolerant parasites are killed by the high serum concentrations of drugs that occur during direct treatment of the human host. However, these parasites can spread in the human population because many drugs persist long after treatment, and the tolerant parasites can infect people in which there are residual levels of the drugs. This intermediate stage between fully sensitive and fully resistant parasites has far-reaching implications for the evolution of drug-resistant malaria.
Animals↗
Sulfadoxine-pyrimethamine pharmacokinetics in malaria: pediatric dosing implications.
OBJECTIVE: Our objective was to characterize the pharmacokinetic properties of sulfadoxine-pyrimethamine in African adults and children with acute falciparum malaria. Despite decades of widespread use, there are few data to inform dose recommendations. METHODS: In a prospective multicenter pharmacokinetic study in 307 patients with acute falciparum malaria, capillary blood concentrations of sulfadoxine and pyrimethamine were determined at 9 visits over a period of 42 days by mass spectrometry. RESULTS: After adjustment for dose, the area under the concentration-time curves (AUCs) of sulfadoxine and pyrimethamine in children aged 2 to 5 years were half of those in adults (median AUC, 410 microg/mL x d [interquartile range (IQR), 126-705 microg/mL x d] versus 816 microg/mL x d [IQR, 536-1150 microg/mL x d] [P = .0001] for sulfadoxine and 620 ng/mL x d [IQR, 229-1399 ng/mL x d] versus 1518 ng/mL x d [IQR, 1117-2013 ng/mL x d] for pyrimethamine). The effect of age on the AUC of sulfadoxine and pyrimethamine reflected higher clearance rates and larger apparent volumes of distribution in children aged 2 to 5 years when compared with adults (median clearance, 64.5 mL x kg(-1) x d(-1) [IQR, 46.2-132.6 mL x kg(-1) x d(-1)] versus 32.7 mL x kg(-1) x d(-1) [IQR, 22.3-52.2 mL x kg(-1) x d(-1)] for sulfadoxine [P = .0001] and 1.77 L x kg(-1) x d(-1) [IQR, 1.0-3.0 L x kg(-1) x d(-1)] versus 0.85 L x kg(-1) x d(-1) [IQR, 0.62-1.21 L x kg(-1) x d(-1)] for pyrimethamine [P = .0001]; median volume of distribution, 413 mL/kg [IQR, 299-711 mL/kg] versus 372 mL/kg [IQR, 267-488 mL/kg] for sulfadoxine [P = .0021] and 6.28 L/kg [IQR, 3.83-11.24 L/kg] versus 3.83 L/kg [IQR, 2.73-5.11 L/kg] for pyrimethamine [P = .0001]). Day 7 concentrations of both sulfadoxine and pyrimethamine provided good surrogate measures (R(2) >or= 0.72) of their respective AUCs. CONCLUSIONS: Pharmacokinetic factors may contribute to the increased risk of sulfadoxine-pyrimethamine antimalarial treatment failure in young children. The current dose recommendations need revision. We predict that children aged 2 to 5 years should be treated with 1 g sulfadoxine/50 mg pyrimethamine to achieve drug concentrations equivalent to those in adults.
Adolescent↗
Intensity of malaria transmission and the evolution of drug resistance.
The intensity of malaria transmission varies both naturally and as a consequence of human public health intervention. The relationship between transmission intensity and the rate at which antimalarial drug resistance evolves affects the design of surveillance programmes, and the likely impact of malaria control programmes. Several theoretical studies have investigated this relationship and their key results are summarised and interpreted. The most important result is that transmission intensity does not directly affect the evolution of resistance. It exerts its influence through three clinical/epidemiological "mediators" (clonal multiplicity, the threat of infection, level of human immunity) which ultimately determine the dynamics of resistance via five "effector" variables: sexual recombination, intrahost dynamics, community drug use, proportion of malaria infections treated, and the number of parasites per host. We argue that the evolution of resistance is likely to be a two-stage process: mutations encoding drug tolerance preceding those encoding resistance. The evolution of drug tolerance is determined solely by the level of drug use in the community which is likely to have an extremely weak relationship with transmission intensity. The evolution of resistance is more complex and affected by all five effectors. The most likely scenarios are that resistance evolves faster in areas of high transmission if encoded by a single gene but if encoded by two or more genes it evolves fastest in areas of high or low transmission, with a minimum at intermediate levels of transmission.
Animals↗
Antimalarial benzo[c]phenanthridines.
Analogues of the antimalarial alkaloid nitidine have been prepared with high potency against both chloroquine-sensitive and -resistant strains of Plasmodium falciparum in vitro. Simple modifications, using an established synthetic route, resulted in an analogue with IC(50) below 5ng/mL against a chloroquine-sensitive strain of P. falciparum. N-Ethylethoxidine had IC(50) below 30ng/mL against both chloroquine-sensitive and chloroquine-resistant strains of P. falciparum.
Animals↗
The search for effective and sustainable treatments for Plasmodium falciparum malaria in Africa: a model of the selection of resistance by antifolate drugs and their combinations.
The extensive data on the relationship between parasite genotype and susceptibility to antifolate drugs can now be coupled with pharmacokinetic information to allow construction of models of the selection and spread of antifolate-resistant Plasmodium falciparum. In this report, we have modeled the effect on resistance selection processes of combinations of antifolate antimalarial drugs with artesunate and with amodiaquine under a variety of conditions that can be defined by the user. The model is intended to assist policymakers in forecasting the useful therapeutic life (UTL) for a range of potential combination treatments. The model is especially designed for use by African malaria programs so that the interactions of key variables can be explored and appropriate combinations of drugs can be chosen for field testing. The model provides some important general conclusions: 1) for optimal extension of UTL, combination therapy must be deployed before either constituent drug is used as monotherapy; 2) even short periods of monotherapy can severely limit the usefulness of subsequent combination therapy; and 3) that adding a second drug to rescue an antifolate antimalarial that is overtly failing is an inappropriate and ultimately wasteful exercise.
Africa↗
Reduction of the efficacy of antifolate antimalarial therapy by folic acid supplementation.
Malaria and anemia are common conditions in patients presenting to outpatient clinics in Kenya. Anemia is usually due to malaria infection with underlying micronutrient deficiency. Iron therapy has been shown to enhance recovery from anemia in children with malaria, without affecting malaria treatment. Iron and folic acid are often prescribed together for anemic individuals. Until recently in Kenya, the drug of first choice for non-severe malaria was sulfadoxine-pyrimethamine (SP), an antifolate antimalarial drug. In this study, 303 patients of all ages with anemia and uncomplicated Plasmodium falciparum malaria attending an outpatient clinic in an area of seasonal malaria were treated with SP and iron, and were randomized to receive folic acid. Parasite clearance rates were measured using a survival analysis plot for both parasitologic and clinical failure. There was a significant reduction in the efficacy of SP in patients taking standard therapeutic doses of folic acid using the survival curve for parasitologic failure (P < 0.0001), but no difference for clinical failure (P = 0.7008). Folic acid supplementation did not enhance recovery from anemia.
Anemia↗
Rare, highly pyrimethamine-resistant alleles of the Plasmodium falciparum dihydrofolate reductase gene from 5 African sites.
In eastern and southern Africa, there has been a rapid increase in the prevalence of alleles with mutations in the Plasmodium falciparum dihydrofolate reductase gene (dhfr) associated with increased risk of clinical failure of sulfadoxine-pyrimethamine (S/P). Molecular methods for surveillance of these mutations are now widespread, but the usual analysis detects only the most prevalent allele in a polyclonal sample. We used a yeast-expression system to identify rare, highly pyrimethamine-resistant alleles of dhfr in isolates from 5 African countries--Kenya, Tanzania, Malawi, Gabon, and Nigeria. Only the isolates from Nigeria yielded significant numbers of novel resistant alleles, and only 1 of the alleles from any location showed a >3-fold increase in resistance to S/P or to chlorproguanil-dapsone. Overall, these results suggest that dhfr alleles that confer high levels of resistance to antifolates are rare, even in eastern and southern Africa, where pyrimethamine has been intensively used.
Alleles↗
WHO, the Global Fund, and medical malpractice in malaria treatment.
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Africa↗
Pharmacokinetics and clinical effects of phenytoin and fosphenytoin in children with severe malaria and status epilepticus.
AIMS: Status epilepticus is common in children with severe falciparum malaria and is associated with poor outcome. Phenytoin is often used to control status epilepticus, but its water-soluble prodrug, fosphenytoin, may be more useful as it is easier to administer. We studied the pharmacokinetics and clinical effects of phenytoin and fosphenytoin sodium in children with severe falciparum malaria and status epilepticus. METHODS: Children received intravenous (i.v.) phenytoin as a 18 mg kg-1 loading dose infused over 20 min followed by a 2.5 mg x kg(-1) 12 hourly maintenance dose infused over 5 min (n = 11), or i.v. fosphenytoin, administered at a rate of 50 mg x min(-1) phenytoin sodium equivalents (PE; n = 16), or intramuscular (i.m.) fosphenytoin as a 18 mg x kg(-1) loading dose followed by 2.5 mg x kg(-1) 12 hourly of PE (n = 11). Concentrations of phenytoin in plasma and cerebrospinal fluid (CSF), frequency of seizures, cardiovascular effects (respiratory rate, blood pressure, trancutaneous oxygen tension and level of consciousness) and middle cerebral artery (MCA) blood flow velocity were monitored. RESULTS: After all routes of administration, a plasma unbound phenytoin concentration of more than 1 microg x ml(-1) was rapidly (within 5-20 min) attained. Mean (95% confidence interval) steady state free phenytoin concentrations were 2.1 (1.7, 2.4; i.v. phenytoin, n = 6), 1.5 (0.96, 2.1; i.v. fosphenytoin, n = 11) and 1.4 (0.5, 2.4; i.m. fosphenytoin, n = 6), and were not statistically different for the three routes of administration. Median times (range) to peak plasma phenytoin concentrations following the loading dose were 0.08 (0.08-0.17), 0.37 (0.33-0.67) and 0.38 (0.17-2.0) h for i.v. fosphenytoin, i.v. phenytoin and i.m. fosphenytoin, respectively. CSF: plasma phenytoin concentration ratio ranged from 0.12 to 0.53 (median = 0.28, n = 16). Status epilepticus was controlled in only 36% (4/11) following i.v. phenytoin, 44% (7/16), following i.v. fosphenytoin and 64% (7/11) following i.m. fosphenytoin administration, respectively. Cardiovascular parameters and MCA blood flow were not affected by phenytoin administration. CONCLUSIONS: Phenytoin and fosphenytoin administration at the currently recommended doses achieve plasma unbound phenytoin concentrations within the therapeutic range with few cardiovascular effects. Administration of fosphenytoin i.v. or i.m. offers a practical and convenient alternative to i.v. phenytoin. However, the inadequate control of status epilepticus despite rapid achievement of therapeutic unbound phenytoin concentrations warrants further investigation.
Adolescent↗
The evolution of drug-resistant malaria: the role of drug elimination half-life.
This paper seeks to define and quantify the influence of drug elimination half-life on the evolution of antimalarial drug resistance. There are assumed to be three general classes of susceptibility of the malaria parasite Plasmodium falciparum to a drug: Res0, the original, susceptible wildtype; Res1, a group of intermediate levels of susceptibility that are more tolerant of the drug but still cleared by treatment; and Res2, which is completely resistant to the drug. Res1 and Res2 resistance both evolve much faster if the antimalarial drug has a long half-life. We show that previous models have significantly underestimated the rate of evolution of Res2 resistance by omitting the effects of drug half-life. The methodology has been extended to investigate (i) the effects of using drugs in combination, particularly when the components have differing half-lives, and (ii) the specific example of the development of resistance to the antimalarial pyrimethamine-sulphadoxine. An important detail of the model is the development of drug resistance in two separate phases. In phase A, Res1 is spreading and replacing the original sensitive forms while Res2 remains at a low level. Phase B starts once parasites are selected that can escape drug action (Res1 genotypes with borderline chemosensitivity, and Res2): these parasites are rapidly selected, a process that leads to widespread clinical failure. Drug treatment is clinically successful during phase A, and health workers may be unaware of the substantial changes in parasite population genetic structure that predicate the onset of phase B. Surveillance programs are essential, following the introduction of a new drug, to monitor effectively changes in treatment efficacy and thus provide advance warning of drug failure. The model is also applicable to the evolution of antibiotic resistance in bacteria: in particular, the need for these models to incorporate drug pharmacokinetics to avoid potentially large errors in their predictions.
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Plasmodium falciparum: in vitro activity of sulfadoxine and dapsone in field isolates from Kenya: point mutations in dihydropteroate synthase may not be the only determinants in sulfa resistance.
We have determined the relationship between point mutations in the gene that encodes the sulfa target, dihydropteroate synthase (DHPS) and the chemosensitivity profile to sulfadoxine and dapsone in 67 isolates from Kilifi, Kenya. We assessed the presence of mutations at codons 436, 437, 540, 581, and 613 of dhps. The results showed that the dhps genotype had a strong influence on the sensitivity to sulfadoxine and dapsone, but that the correlation was far from perfect. Eleven isolates carried a wild-type dhps allele, but were resistant to sulfadoxine (IC(50) values >10 microg/ml), and 4/28 isolates were classed as sensitive to sulfadoxine (IC(50) values <10 microg/ml), but carried a triple mutant (436/437/613) allele of dhps. These data show that in low folate medium in vitro, the dhps genotype alone did not account completely for sulfadoxine or dapsone resistance; other factors such as the utilisation of exogenous folate must also be considered.
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