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Intraneuronal accumulation of misfolded α-synuclein is the pathological hallmark of Parkinson's disease and dementia with Lewy bodies, often co-occurring with variable degrees of Alzheimer's disease related neuropathology. Genetic association studies have successfully identified common variants associated with disease risk and phenotypic traits in Lewy body disease, yet little is known about the genetic contribution to neuropathological heterogeneity. Using summary statistics from Parkinson's disease and Alzheimer's disease genome-wide association studies, we calculated polygenic risk scores and investigated the relationship with Lewy, amyloid-β and tau pathology. Associations were nominated in neuropathologically defined samples with Lewy body disease from the Netherlands Brain Bank (n = 217) and followed up in an independent sample series from the Mayo Clinic Brain Bank (n = 394). We also generated stratified polygenic risk scores based on single-nucleotide polymorphisms annotated to eight functional pathways or cell types previously implicated in Parkinson's disease and assessed for association with Lewy pathology in subgroups with and without significant Alzheimer's disease co-pathology. In an ordinal logistic regression model, the Alzheimer's disease polygenic risk score was associated with concomitant amyloid-β and tau pathology in both cohorts. Moreover, both cohorts showed a significant association between lysosomal pathway polygenic risk and Lewy pathology, which was more consistent than the association with a general Parkinson's disease risk score and specific to the subset of samples without significant concomitant Alzheimer's disease related neuropathology. Our findings provide proof of principle that the specific risk alleles a patient carries for Parkinson's and Alzheimer's disease also influence key aspects of the underlying neuropathology in Lewy body disease. The interrelations between genetic architecture and neuropathology are complex, as our results implicate lysosomal risk loci specifically in the subset of samples without Alzheimer's disease co-pathology. Our findings hold promise that genetic profiling may help predict the vulnerability to specific neuropathologies in Lewy body disease, with potential relevance for the further development of precision medicine in these disorders., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Krabbe disease is an infantile neurodegenerative disorder resulting from pathogenic variants in the GALC gene that causes accumulation of the toxic sphingolipid psychosine. GALC variants are also associated with Lewy body diseases, an umbrella term for age-associated neurodegenerative diseases in which the protein α-synuclein aggregates into Lewy bodies. To explore whether α-synuclein in Krabbe disease has pathological similarities to that in Lewy body disease, we performed an observational post-mortem study of Krabbe disease brain tissue (n = 4) compared to infant controls (n = 4) and identified widespread accumulations of α-synuclein. To determine whether α-synuclein in Krabbe disease brain displayed disease-associated pathogenic properties we evaluated its seeding capacity using the real-time quaking-induced conversion assay in two cases for which frozen tissue was available and strikingly identified aggregation into fibrils similar to those observed in Lewy body disease, confirming the prion-like capacity of Krabbe disease-derived α-synuclein. These observations constitute the first report of prion-like α-synuclein in the brain tissue of infants and challenge the putative view that α-synuclein pathology is merely an age-associated phenomenon, instead suggesting it results from alterations to biological pathways, such as sphingolipid metabolism. Our findings have important implications for understanding the mechanisms underlying Lewy body formation in Lewy body disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The majority of genome-wide association studies have been conducted using samples with a broadly European genetic background. As a field, we acknowledge this limitation and the need to increase the diversity of populations studied. A major challenge when designing and conducting such studies is to assimilate large samples sizes so that we attain enough statistical power to detect variants associated with disease, particularly when trying to identify variants with low and rare minor allele frequencies. In this review, we aimed to illustrate the benefits to genetic characterization of Alzheimer's disease, in researching currently understudied populations. This is important for both fair representation of world populations and the translatability of findings. To that end, we conducted a literature search to understand the contributions of studies, on different populations, to Alzheimer's disease genetics. Using both PubMed and Alzforum Mutation Database, we systematically quantified the number of studies reporting variants in known disease-causing genes, in a worldwide manner, and discuss the contributions of research in understudied populations to the identification of novel genetic factors in this disease. Additionally, we compared the effects of genome-wide significant single nucleotide polymorphisms across populations by focusing on loci that show different association profiles between populations (a key example being APOE). Reports of variants in APP, PSEN1 and PSEN2 can initially determine whether patients from a country have been studied for Alzheimer's disease genetics. Most genome-wide significant associations in non-Hispanic white genome-wide association studies do not reach genome-wide significance in such studies of other populations, with some suggesting an opposite effect direction; this is likely due to much smaller sample sizes attained. There are, however, genome-wide significant associations first identified in understudied populations which have yet to be replicated. Familial studies in understudied populations have identified rare, high effect variants, which have been replicated in other populations. This work functions to both highlight how understudied populations have furthered our understanding of Alzheimer's disease genetics, and to help us gauge our progress in understanding the genetic architecture of this disease in all populations., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([(123)I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane single photon computed tomography) findings of four unrelated pedigrees with DOPA-responsive dystonia in which pathogenic GCH1 variants were identified in family members with adult-onset parkinsonism. Dopamine transporter imaging was abnormal in all parkinsonian patients, indicating Parkinson's disease-like nigrostriatal dopaminergic denervation. We subsequently explored the possibility that pathogenic GCH1 variants could contribute to the risk of developing Parkinson's disease, even in the absence of a family history for DOPA-responsive dystonia. The frequency of GCH1 variants was evaluated in whole-exome sequencing data of 1318 cases with Parkinson's disease and 5935 control subjects. Combining cases and controls, we identified a total of 11 different heterozygous GCH1 variants, all at low frequency. This list includes four pathogenic variants previously associated with DOPA-responsive dystonia (Q110X, V204I, K224R and M230I) and seven of undetermined clinical relevance (Q110E, T112A, A120S, D134G, I154V, R198Q and G217V). The frequency of GCH1 variants was significantly higher (Fisher's exact test P-value 0.0001) in cases (10/1318 = 0.75%) than in controls (6/5935 = 0.1%; odds ratio 7.5; 95% confidence interval 2.4-25.3). Our results show that rare GCH1 variants are associated with an increased risk for Parkinson's disease. These findings expand the clinical and biological relevance of GTP cycloydrolase 1 deficiency, suggesting that it not only leads to biochemical striatal dopamine depletion and DOPA-responsive dystonia, but also predisposes to nigrostriatal cell loss. Further insight into GCH1-associated pathogenetic mechanisms will shed light on the role of dopamine metabolism in nigral degeneration and Parkinson's disease., (© The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Theoretical and experimental data support the geographic differentiation strategy as a valuable tool for detecting loci under selection. In the context of Plasmodium falciparum malaria, few populations have been studied, with limited genomic coverage., Methods: We examined geographic differentiation in P. falciparum populations on the basis of 12 single-nucleotide polymorphisms (SNPs) in 4 genes encoding drug resistance determinants, 5 SNPs in 2 genes encoding antigens, and a set of 17 putatively neutral SNPs dispersed on 13 chromosomes. We sampled 326 parasite isolates representing 7 P. falciparum populations from regions with varied levels of malaria transmission (Gabon, Kenya, Madagascar, Mali, Mayotte, Haiti, and the Philippines)., Results: Frequencies of drug resistance alleles varied considerably among populations (mean F(ST), 0.52). In contrast, allele frequencies varied significantly less for antigenic and neutral SNPs (mean F(ST), 0.16 and 0.24, respectively). This contrasting pattern was more pronounced when only the African populations were considered. Signature of selection was detected for most of the resistant SNPs but not for the antigenic SNPs., Conclusion: These data further validate the utility of geographic differentiation for identifying loci under strong positive selection, such as drug resistance loci. This study also provides frequencies of molecular makers of resistance in some overlooked populations.

Mutations in the glucocerebrosidase gene (GBA) are associated with Gaucher's disease, the most common lysosomal storage disorder. Parkinsonism is an established feature of Gaucher's disease and an increased frequency of mutations in GBA has been reported in several different ethnic series with sporadic Parkinson's disease. In this study, we evaluated the frequency of GBA mutations in British patients affected by Parkinson's disease. We utilized the DNA of 790 patients and 257 controls, matched for age and ethnicity, to screen for mutations within the GBA gene. Clinical data on all identified GBA mutation carriers was reviewed and analysed. Additionally, in all cases where brain material was available, a neuropathological evaluation was performed and compared to sporadic Parkinson's disease without GBA mutations. The frequency of GBA mutations among the British patients (33/790 = 4.18%) was significantly higher (P = 0.01; odds ratio = 3.7; 95% confidence interval = 1.12-12.14) when compared to the control group (3/257 = 1.17%). Fourteen different GBA mutations were identified, including three previously undescribed mutations, K7E, D443N and G193E. Pathological examination revealed widespread and abundant alpha-synuclein pathology in all 17 GBA mutation carriers, which were graded as Braak stage of 5-6, and had McKeith's limbic or diffuse neocortical Lewy body-type pathology. Diffuse neocortical Lewy body-type pathology tended to occur more frequently in the group with GBA mutations compared to matched Parkinson's disease controls. Clinical features comprised an early onset of the disease, the presence of hallucinations in 45% (14/31) and symptoms of cognitive decline or dementia in 48% (15/31) of patients. This study demonstrates that GBA mutations are found in British subjects at a higher frequency than any other known Parkinson's disease gene. This is the largest study to date on a non-Jewish patient sample with a detailed genotype/phenotype/pathological analyses which strengthens the hypothesis that GBA mutations represent a significant risk factor for the development of Parkinson's disease and suggest that to date, this is the most common genetic factor identified for the disease.

Background: Controversy exists about the management of patients with imported Plasmodium falciparum malaria. We postulated that rapid parasite clearance supports ambulatory care, or, conversely, that factors associated with longer parasite clearance time (PCT) could be used as hospitalization criteria., Methods: Hospitalized patients with imported falciparum malaria recruited through one single travel clinic between 1993 and 2000. We used a linear regression to identify factors independently associated with PCT defined as the time in hours from antimalarial drug administration until the first negative malaria smear., Results: Among 400 patients hospitalized with falciparum malaria, mean (range) PCT was 58 (1-189) hours. In multivariate analysis, severe malaria, gastrointestinal signs, initial temperature greater than or equal to 40 degrees C, parasitemia greater than or equal to 1%, and platelet counts less than 50,000/microL were associated with longer PCT. Offering ambulatory care to patients aged 15 to 64 years with none of the factors associated with longer PCT in the study would have resulted in 147 (37%) patients receiving outpatient care., Conclusion: Factors identified in this model may help physicians determine which P falciparum malaria patients can be treated on an ambulatory basis, and contribute to revisions of national guidelines for imported malaria management.

Here we provide direct evidence that two adaptive nucleotide changes in the same codon (268) of the cytochrome b gene (pfcytb) each occurred repeatedly in independent Plasmodium falciparum lineages exposed to the antimalarial drug atovaquone-proguanil (AP). We analyzed the history of 7 AP resistance alleles from clinical isolates by sequencing the mitochondrial (mt) genome that encodes the pfcytb gene and found that a distinct mt haplotype was associated with each AP resistance allele. By comparing mt sequences and microsatellite genotypes of the isolates both before treatment initiation and at the day of failure for each uncured patient, we observed that the AP resistance alleles occurred and spread within the patients. These data demonstrate that identical AP resistance alleles have multiple independent origins and provide an example of parallel evolution driven by drug treatment selection in P. falciparum.

Background: Usefulness of sulfadoxine-pyrimethamine as first-line therapy for uncomplicated Plasmodium falciparum malaria and intermittent preventive treatment in pregnancy throughout sub-Saharan Africa is compromised by the spread of dhfr alleles associated with pyrimethamine resistance. A predominant haplotype associated with the N51I+C59R+S108N triple-mutant dhfr allele has been reported recently in 4 African countries. A more comprehensive picture of the evolution of this mutant allele in Africa is lacking., Methods: Seventy-five P. falciparum isolates carrying the wild-type dhfr allele and 204 carrying the triple-mutant dhfr allele from 11 African countries were selected. The genetic diversity of the chromosomes bearing these alleles was analyzed with 4 microsatellite markers closely linked to the dhfr gene., Results: Seventy-three different 4-locus haplotypes carrying the wild-type dhfr allele were found. By contrast, 175 (85%) of 204 isolates carrying the triple-mutant dhfr allele shared a unique haplotype, identical to the one identified in Thailand. For the remaining triple-mutant isolates and one isolate with the quadruple-mutant dhfr allele (N51I+C59R+S108N+I164L), haplotypes were closely related to the predominant haplotype by mutation or recombination., Conclusions: Migration of parasites carrying an ancestral triple-mutant dhfr allele drives the spread of dhfr alleles associated with pyrimethamine resistance throughout West and Central Africa.

Congenital malaria (CM) has been considered to be rare, even in malaria-endemic areas but the disease can result in significant neonatal morbidity. Because of its rarity, the disease may go undiagnosed for a prolonged period in a seriously ill infant. We report the first case of Plasmodium malariae CM from a HIV mother. HIV could have facilitated the transfer of erythrocytic persistent P. malariae through the placenta to the fetus.

Objectives: We examined the atovaquone in vitro susceptibility and the cytochrome b (cytb) gene polymorphism of African Plasmodium falciparum isolates during the first years of atovaquone/proguanil use., Patients and Methods: Between 1999 and 2004, we collected blood samples from French P. falciparum-infected patients returning from African countries. Atovaquone susceptibility was determined using an in vitro isotopic test and cytb genotyping was performed by restriction fragment length polymorphism analysis and sequencing. These results were analysed according to the clinical response to atovaquone/proguanil treatment., Results: No in vitro atovaquone resistance (IC50 > 1900 nM) and no cytb mutation leading to the Y268S substitution were detected among 477 unexposed African P. falciparum isolates. Eight cytb polymorphisms were found outside the ubiquinone reduction site by sequencing the entire gene of 270 isolates. One atovaquone/proguanil treatment failure was documented; the post-treatment isolate had an atovaquone susceptibility of 8230 nM and the Ser268 Cytb change; the pre-treatment isolate, obtained 4 weeks previously, was Cytb Tyr268 (wild-type)., Conclusions: No atovaquone/proguanil resistance was detected by phenotyping or genotyping among 477 unexposed African P. falciparum isolates. Atovaquone/proguanil-resistant parasite was detectable only in the post-treatment isolate from a treatment failure.

Controversy exists about which antimalarial chemoprophylaxis regimen should be used among travellers to Africa: the WHO and other experts recommend the use of mefloquine throughout sub-Saharan Africa, whereas French experts still support the combination of chloroquine and proguanil in most of West Africa (the so-called zone 2 countries). In this case-control study based at a travel clinic, we examined the compliance with antimalarial chemoprophylaxis and its efficacy among travellers to tropical areas. Cases were patients with Plasmodium falciparum malaria (n = 131). Controls were patients who had a negative malaria film (n = 158). Of all controls, only 36 (22.8%) were adequately protected (i.e. compliant with an adapted regimen of chemoprophylaxis). In zone 2 countries, the efficacy of the combined chloroquine and proguanil was 58% (95% CI 22-78%) for all users, but increased to 100% (95% CI 89-100%) for compliant users. In zone 3 countries, the efficacy of mefloquine was 90% (95% CI 51-98%) and 100% (95% CI 58-100%) for all users and compliant users, respectively.

We have developed a new fragment-analysis method to enumerate the clones and to quantify their proportions within Plasmodium falciparum isolates. We prospectively enrolled 20 adult patients with uncomplicated malaria who were returning to France from various sub-Saharan countries, from January 2000 through July 2001. The analysis of clonal populations was performed on blood samples obtained at 10 times: 1 before treatment with oral quinine and 9 during the first 96 h of the treatment. The resistance genotypes pfcrt and dhfr were determined for chloroquine and antifolinics. Multiple P. falciparum genotypes were detected in 19 (95%) of 20 patients: 2, 3, 4, and 5 genotypes were found in 4, 9, 4 and 2 patients, respectively. Disappearance and reappearance of some clones within a few hours was observed. Individual clones represented 0.4%-99.4% of total parasitemia. Surprisingly, in 10 of 15 subjects tested, resistance genotypes varied according to the time of blood collection. These findings may have important implications with regard to the interpretations of resistance studies.

Objectives: To assess the relationship between the presence of DHFR and DHPS mutations in Plasmodium falciparum, parasite in vitro resistance, and in vivo efficacy of sulfadoxine-pyrimethamine (SP) treatment., Patients and Methods: Measurement of SP treatment efficacy in malaria-infected children in Gabon was combined with in vitro tests of susceptibility to pyrimethamine and cycloguanil, and molecular genotyping at several DHFR and DHPS loci of parasites isolated before treatment. DHFR was studied at codons 108, 51, and 59, whereas DHPS gene was typed at positions 436, 437, 540 and 581., Results: SP treatment was effective in 86% of children by day 28. Seventy-five percent of isolates were in vitro resistant to pyrimethamine and 65.5% to cycloguanil. No mutation was detected at codons 540 and 581 of the DHPS gene. Most isolates (71.8%) presented with the triple mutant DHFR genotype, whereas 64.3% combined at least three DHFR and one DHPS mutations. The increase in the number of DHFR mutations was associated with an increase in in vitro resistance to pyrimethamine and cycloguanil; three DHFR mutations conferred pyrimethamine and to a lesser extent cycloguanil resistance. Treatment failures only occurred with isolates presenting at least two DHFR mutations (S108N and C59R) and one DHPS mutation (S436A or A437G), but SP treatment of infections with such parasites gave treatment success in 82.0% of children., Conclusions: DHFR mutations that lead to high-level in vitro resistance to pyrimethamine plus 1-2 DHPS mutations are not sufficient to induce in vivo failure of SP treatment in young children from Gabon.

In Liberia, little information is available on the efficacy of antimalarials against Plasmodium falciparum malaria. We measured parasitological resistance to chloroquine and sulfadoxine-pyrimethamine (SP) in Harper, south-west Liberia in a 28-d study in vivo. A total of 50 patients completed follow-up in the chloroquine group, and 66 in the SP group. The chloroquine failure rate was 74.0% (95% confidence interval [95% CI] 59.7-85.4%) after 14 d of follow-up and 84.0% (95% CI 70.9-92.8%) after 28 d (no polymerase chain reaction [PCR] analysis was performed to detect reinfections in this group). In the SP group, the failure rate was 48.5% (95% CI 36.2-61.0%) after 14 d and 69.7% (95% CI 57.1-80.4%) after 28 d, readjusted to 51.5% (95% CI 38.9-64.0%) after taking into account reinfections detected by PCR. Genomic analysis of parasite isolates was also performed to look for point mutations associated with resistance. Genotyping of parasite isolates revealed that all carried chloroquine-resistant K-76T mutations at gene pfcrt, whereas the triple mutation (S108N, N511, C59R) at dhfr and the A437G mutation at dhps, both associated with resistance to SP, were present in 84% and 79% of pretreatment isolates respectively. These results seriously question the continued use of chloroquine and SP in Harper and highlight the urgency of making alternative antimalarial therapies available. Our study confirms that resistance to chloroquine may be high in Liberia and yields hitherto missing information on SP.

The present study was undertaken to explore the antimalarial effect of a series of dicatecholate iron chelators. They may be made more or less lipophilic by increasing or reducing the length of the R substituent on the nitrogen. In vitro activity against the W2 and 3D7 clones of Plasmodium falciparum, toxicity on Vero cells and toxicity on uninfected erythrocytes by measure of the released haemoglobin were assessed for each compound. These findings were compared with the ability of iron(III), iron(II) and ferritin to reverse the inhibitory effect of catecholates. This study shows that increased lipid solubility of catecholate iron chelators does not lead to improved antimalarial activity. However, their activity is well correlated with their interaction with iron and with their toxicity against Vero cells. This study demonstrates a potent antimalarial effect of FR160 (R = C9H19) on five different strains of P. falciparum in vitro. FR160 inhibited parasite growth with an IC50 between 0.8 and 1.5 micro M. The effects of FR160 on mammalian cells were minimal compared with those obtained with malaria parasites. FR160 acted on parasites at considerably higher rates than desferrioxamine, and at all stages of parasite growth. The drug was more effective at the late trophozoite and young schizont stages, although FR160 affected rings and schizonts as well. Ascorbic acid, a free radical scavenger, reduced the activities of FR160 and artesunate. FR160 might induce formation of free radicals, which could explain why FR160 antagonized the effects of artesunate and dihydroartemisinin.

An increase in parasitaemia is not uncommon after initiation of treatment for Plasmodium falciparum malaria, but its exact significance is unknown. The time-course of parasitaemia was assessed retrospectively in 33 patients with severe imported malaria. In 19 patients (group 1) mean parasitaemia (+/- SEM) fell promptly after starting quinine treatment, from 24.9 +/- 4.1% on day 0 to 9.7 +/- 2.3% on day 1 and 1.8 +/- 0.7% on day 2. In 14 other patients (group 2), parasitaemia did not change significantly or increased, with mean parasitaemia (+/- SEM) of 9.5 +/- 2.1% on day 0, 17.2 +/- 2.6% on day 1, and 3.7 +/- 1.8% on day 2. Simplified acute physiology scores on admission (mean +/- SEM) were 17.4 +/- 1.4 in group 1 and 11.7 +/- 1.0 in group 2 (P = 0.006). The mean number of complications of malaria per patient (+/- SEM) was 2.9 +/- 0.5 in group 1 and 1.6 +/- 0.3 in group 2 (P = 0.046). Two group 1 patients died. Initially, more than 95% of peripheral blood parasites were tiny and small rings in both groups, and this distribution was unchanged on day 1, suggesting that the parasitaemia increase in group 2 was not due to release of sequestered mature parasites. In severe falciparum malaria, a rise in parasitaemia after treatment initiation may be of favourable prognostic significance and should not lead to aggressive therapeutic approaches such as exchange transfusion.

A multifactorial study of 58 variables of alcohol, dietary and tobacco habits of 106 chronic alcoholic and normal subjects was conducted over 2 years. The alcoholic population included subjects with either calcifying chronic pancreatitis (CCP) or cirrhosis (Ci). A standardized, previously validated questionnaire was used to investigate dietary intakes, drinking and smoking habits. The patients with CCP consumed a richer diet than those with Ci, consisting mainly of saturated fats and animals proteins. Although the alcoholics with CCP drank the same total quantity of alcohol as the alcoholics with Ci, they drank it over a shorter time period (less than 20 years) before diagnosis. Differences in the nutritional profiles of the two groups indicate that the population with alcohol-related digestive diseases is made up of subjects with different drinking and eating habits. These behavioural differences with respect to dietary and alcohol intake indicate that the alcoholic patients with CCP or Ci belong to different subgroups.

Twenty freshly isolated strains of Plasmodium falciparum from non-immune and semi-immune patients infected in Central and West Africa were tested for in vitro drug sensitivity to chloroquine alone and to a combination of chloroquine and desipramine without prior adaptation to continuous culture. Combination of desipramine at 625 nmol/litre and chloroquine reversed resistance totally (IC50 less than 100 nmol/litre) in all 14 chloroquine-resistant isolates. No effect on chloroquine sensitivity was noted in the 6 chloroquine-sensitive isolates. These observations provide additional evidence that reversal of chloroquine resistance in the presence of desipramine is not a phenomenon unique to culture-adapted strains and that desipramine may exert the same potentiating effect in vivo, provided that effective plasma concentration can be attained without serious side-effects.

High levels of antimalarial drugs have been shown to be inhibitory to the oxidative metabolism of human neutrophils in vitro. In this study, chemiluminescence of, and chloroquine concentrations in, neutrophils from volunteers treated with prophylactic or therapeutic malaria regimens were assessed. Although detectable chloroquine levels were found in neutrophils, their chemiluminescence was not reduced at prophylactic or at therapeutic drug levels, in comparison with controls without chloroquine treatment. At these clinically achievable concentrations, chloroquine was not found to interfere with the oxidative metabolism of neutrophils.

The activity of four antimalarial drugs against 66 Plasmodium falciparum isolates from 15 countries was assessed by an in vitro semi-microtest. Median inhibitory concentrations (IC50) for chloroquine were less than 120 nM in 22 isolates from patients successfully treated with chloroquine, and more than 250 nM in six isolates from patients with chloroquine-resistant malaria. 10 of 15 isolates from Brazil (Amazonia), 7 of 12 isolates from Madagascar, two from Kenya and two from Thailand had IC50 for chloroquine of more than 250 nM. None of the 35 isolates from West and Central Africa had IC50 of more than 120 nM. Very different levels of sensitivity were observed in Brazil and Madagascar. 27 of 28 isolates (including two that were chloroquine-resistant in vivo) had IC50 of less than 50 nM for dichlorquinazine, a 4-aminoquinoline. The IC50 for mefloquine was less than 160 nM in 55 isolates including ten from patients who were successfully treated with mefloquine. IC50 for quinine were between 140 and 660 nM for 30 isolates. This test has proved useful in epidemiological studies, therapeutic monitoring of clinical cases and in the evaluation of new drugs.

Halofantrine is a 9-phenanthrenemethanol which is effective against multi-drug resistant strains of Plasmodium falciparum. It has been shown to be highly effective and extremely well tolerated in the treatment of imported cases of falciparum malaria in France. A total of 1,500 mg administered in three 500 mg doses at six-hour intervals results in a 100% cure rate in semi-immune subjects. This dosage should be repeated after 14 days to obtain the same cure rate in non-immune patients. Minor clinical side effects included epigastric pains, nausea and, in one case, a skin rash.