Publications

ERYTHROCYTIC DIGOXIN RECEPTOR NUMBERS AND ACTIVITY - RELATION TO CLINICAL CHANGES FOLLOWING DIGOXIN WITHDRAWAL AFTER LONG-TERM TREATMENT FOR HEART-FAILURE IN SINUS RHYTHM

No abstract is provided for this article.

Pharmacokinetics of intravenous amodiaquine.

Amodiaquine hydrochloride (3 mg base kg‐1) was given by constant rate intravenous injection over 10 min to seven healthy adult male volunteers, and by constant rate infusion (10 mg base kg‐1) over 4 h to 10 adult patients admitted to hospital with falciparum malaria. After intravenous injection in volunteers there was considerable variation in plasma concentration profiles between subjects; peak plasma concentrations ranged between 65 and 1921 ng ml‐1. A biexponential equation was fitted to the plasma concentration time data and the following estimated pharmacokinetic parameters (geometric mean; range) were derived; lambda 1 = 24.4 (7.6‐95.0) h‐1, lambda 2 = 0.33 (0.12‐ 0.79) h‐1, V1:1.1 (0.3‐3.6) 1 kg‐1, Vss: 17.4 (2.3‐95.9) 1 kg‐1 and systemic clearance 13.0 (4.7‐56.6) 1 kg‐1 h‐1. After intravenous infusion there was also considerable variability between patients with post‐infusion plasma concentrations ranging between 82 and 836 ng ml‐1. The plasma concentration‐time profiles were biphasic with the following estimated pharmacokinetic parameters (geometric mean; range) alpha = 1.87 (0.60‐8.52) h‐1, beta = 0.069 (0.021‐0.265) h‐1, V1: 4.6 (0.5‐ 29.3) 1 kg‐1, Vss: 38.3 (3.7‐127.9) 1 kg‐1 and systemic clearance CL (1.6‐17.3) 1 kg‐1 h‐1. There was no measurable long terminal elimination phase, and the principal metabolite desethyl amodiaquine was not detected in the plasma samples. There was no serious toxicity in either group. During intravenous injection there was a significant fall in systolic blood pressure in four subjects (mean fall 16 mm Hg) but there was no significant change in heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Dynamic Alteration in Splenic Function during Acute falciparum Malaria

Plasmodium-infected erythrocytes lose their normal deformability and become susceptible to splenic filtration. In animal models, this is one mechanism of antimalarial defense. To assess the effect of acute falciparum malaria on splenic filtration, we measured the clearance of heated 51Cr-labeled autologous erythrocytes in 25 patients with acute falciparum malaria and in 10 uninfected controls. Two groups of patients could be distinguished. Sixteen patients had splenomegaly, markedly accelerated clearance of the labeled erythrocytes (clearance half-time, 8.4 +/- 4.4 minutes [mean +/- SD] vs. 62.5 +/- 36.5 minutes in controls; P less than 0.001), and a lower mean hematocrit than did the patients without splenomegaly (P less than 0.001). In the nine patients without splenomegaly, clearance was normal. After institution of antimalarial chemotherapy, however, the clearance in this group accelerated to supernormal rates similar to those in the patients with splenomegaly, but without the development of detectable splenomegaly. Clearance was not significantly altered by treatment in the group with splenomegaly. Six weeks later, normal clearance rates were reestablished in most patients in both groups. We conclude that splenic clearance of labeled erythrocytes is enhanced in patients with malaria if splenomegaly is present and is enhanced only after treatment if splenomegaly is absent. Whether this enhanced splenic function applies to parasite-infected erythrocytes in patients with malaria and has any clinical benefit will require further studies.

Antimalarial mass drug administration in large populations and the evolution of drug resistance

Mass drug administration (MDA) with antimalarials has been shown to reduce prevalence and interrupt transmission in small populations, in populations with reliable access to antimalarial drugs, and in populations where sustained improvements in diagnosis and treatment are possible. Effective MDA eliminates drug-resistant parasites which has the long-term benefit of extending the useful therapeutic life of first-line therapies for all populations, not just the focal population where MDA was carried out. However, in order to plan elimination measures effectively, it is necessary to characterize the conditions under which failed MDA could exacerbate resistance. We use an individual-based stochastic model of Plasmodium falciparum transmission to evaluate this risk in large populations (>40K) where access to antimalarial treatments may not be uniformly high and where re-importation of drug-resistant parasites may be common. We find that drug-resistance evolution can be accelerated by MDA when all three of the following conditions are met: (1) strong genetic bottlenecking that falls short of elimination, (2) re-importation of resistant genotypes, and (3) continued selection pressure during routine case management post-MDA. Accelerated resistance levels are not immediate but follow the rebound of malaria cases post-MDA, if this is allowed to occur. Crucially, resistance is driven by the selection pressure during routine case management post-MDA and not the selection pressure exerted during the MDA itself. Second, we find that increasing treatment coverage post-MDA increases the probability of local elimination in low-transmission regions (PfPR < 2%) in scenarios with both low and high levels of drug-resistance importation. This emphasizes the importance of preparation and planning to ensure that MDA has a high probability of leading to elimination, and the necessity of supporting public health infrastructure to provide high coverage of diagnosis and treatment post-MDA.

Host vascular endothelial growth factor is trophic for Plasmodium falciparum-infected red blood cells.

Plasmodium falciparum, the protozoan parasite responsible for severe malaria infection, undergoes a complex life cycle. Infected red blood cells (iRBC) sequester in host cerebral microvessels, which underlies the pathology of cerebral malaria. Using immunohistochemistry on post mortem brain samples, we demonstrated positive staining for vascular endothelial growth factor (VEGF) on iRBC. Confocal microscopy of cultured iRBC revealed accumulation of VEGF within the parasitophorous vacuole, expression of host VEGF-receptor 1 and activated VEGF-receptor 2 on the surface of iRBC, but no accumulation of VEGF receptors within the iRBC. Addition of VEGF to parasite cultures had a trophic effect on parasite growth and also partially rescued growth of drug treated parasites. Both these effects were abrogated when parasites were grown in serum-free medium, suggesting a requirement for soluble VEGF receptor. We conclude that P. falciparum iRBC can bind host VEGF-R on the erythrocyte membrane and accumulate host VEGF within the parasitophorous vacuole, which may have a trophic effect on parasite growth.

The role of mathematical modelling in malaria elimination and eradication (Comment on: Can malaria be eliminated?)

For many countries, as Professor Greenwood points out, the answer to his question is a resounding ‘yes’.1 Perhaps the more pertinent question is, with so many more interventions now available, ‘how?’. The two most important new tools that have been added to our malaria control arsenal since the 1950s are artemisinin combination therapies and insecticide-treated bed nets. These are most likely to be effective when used together, in combination with indoor residual spraying where there are suitable vectors. The problem we are faced with is a lack of experience of using such an elimination strategy on a large scale, leading to a lack of data, particularly on the best way to roll out ACTs. In the past, mass screening and treatment, mass drug administration and large-scale replacement of first-line therapies have all been attempted, with varying degrees of success. In the context of newly arisen artemisinin resistance and the diminishing effectiveness of the pyrethroid insecticides, particular care must be taken to preserve the effectiveness of these compounds for as long as possible, whilst achieving maximum impact in a wide variety of epidemiological settings.

Erratum: Abnormal blood flow and red blood cell deformability in severe malaria (Parasitology Today 16 (228-232))

Mefloquine pharmacokinetics in pregnant women with acute falciparum malaria

Mefloquine has an established place in the treatment of chloroquine-resistant falciparum malaria. To investigate mefloquine pharmacokinetics in pregnancy, 9 untreated pregnant women aged 16-33 years and 8 non-pregnant females aged 16-38 years received an average of 15 (range 13-19) mg mefloquine/kg body-weight as single-dose treatment for uncomplicated falciparum malaria. Regular blood samples were taken during the subsequent 48 h and then intermittently for 3-26 d after treatment. Whole blood mefloquine concentrations were analysed by high-performance liquid chromatography and a one-compartment open pharmacokinetic model was fitted to the data. Peak mefloquine concentrations were significantly lower in the pregnant patients (median [range]; 1257 [650-1584] vs. 1617 [1051-3111] ng/mL) and the total apparent volume of distribution (Vd/f) was larger (10.8 [8.3-26.1] vs. 10.0 [4.8-13.9] L/kg; P < 0.05 in each case), consistent with an expanded circulating blood volume and increased tissue binding in pregnancy. There was no significant difference between the 2 groups in half-times of absorption or elimination (P > 0.1), and systemic clearance rates were also similar. These results suggest that pregnant patients need larger doses of mefloquine than non-pregnant women to achieve comparable blood levels, an important consideration in areas where multi-drug resistant falciparum malaria is emerging.

Early development, survival and reproduction in humans

Environmental factors commonly influence the growth and early development of individuals in wild populations of mammals. Such influences can exert downstream effects on the phenotypic quality and breeding success of the same individuals in adulthood, as well as on the growth and subsequent reproductive success of their offspring. Recent studies of humans indicate that similar effects occur both in Western human populations and in human populations subject to nutritional stress. Here, we compare evidence for the effects of early development on growth, survival and breeding performance in humans to similar trends in food-restricted populations of other mammals. We highlight the relevance of findings from animal studies to humans and vice versa, and suggest that the integration of wild animal and human studies could increase our knowledge about how early development shapes reproductive performance across generations.

THE DEMOGRAPHIC CONSEQUENCES OF RELEASING A POPULATION OF RED DEER FROM CULLING

A change in population density can generate spatial and demographic effects that can have an impact on fluctuations in population size for many years. Although the demographic effects of time lags have been incorporated into analyses of time series data, there are few detailed descriptions of the long-term demographic consequences of a change in density. We use detailed, individual-based data from a population of red deer (Cervus elaphus) from the North Block of the Isle of Rum, Scotland, to describe long-term demographic and spatial effects of a change in density. The population was released from hunting pressure in 1972. Over the following 10 years population density doubled and, since the early 1980s, has fluctuated around ecological carrying capacity. The cessation of culling led to long-term transient spatial and demographic effects that have persisted for 30 years. Different vital rates responded to the increase in density at different rates, causing long-term changes to the demographic and spatial structure of the population. These changes altered the impact of different age- and sex-specific vital rates on annual changes in population size. These changes are still ongoing, 30 years after cessation of the cull, suggesting that a change in density may generate transient dynamics that persist for several generations.

Two Randomized Controlled Trials of Ceftazidime Alone versus Ceftazidime in Combination with Trimethoprim-Sulfamethoxazole for the Treatment of Severe Melioidosis

Two antibiotic regimens are used commonly in Thailand for the initial treatment of severe melioidosis: ceftazidime in combination with trimethoprim-sulfamethoxazole (TMP-SMX) and ceftazidime monotherapy. It is not known whether TMP-SMX provides an additional benefit.Two prospective, randomized trials that compared these regimens for patients presenting with acute severe melioidosis were started independently at tertiary care hospitals in Ubon Ratchathani and Khon Kaen (in northeastern Thailand), and the results were analyzed together as a prospective, individual-patient data meta-analysis. The primary end point was in-hospital mortality rate.The in-hospital mortality rate among all enrolled patients (n=449) was not significantly different between those randomized to ceftazidime alone (25.1%; 56 of 223 subjects) and those randomized to ceftazidime with TMP-SMX (26.6%; 60 of 226 subjects; odds ratio [OR], 1.08; 95% confidence interval [CI], 0.7-1.7; stratified P=.73). Of the 241 patients with culture-confirmed melioidosis, 51 (21.2%) died. Of these 241 patients, 31 (12.9%) died > or =48 h after the time of study entry. Among patients with melioidosis, there was no difference in death rate between the 2 treatment groups for either all deaths (OR, 0.88; 95% CI, 0.48-1.6; stratified P=.70) or for deaths that occurred > or =48 h after hospital admission (OR, 0.88; 95% CI, 0.41-1.9; stratified P=.73). Conditional logistic regression analysis revealed that bacteremia, respiratory failure, and renal failure were independently associated with death and treatment failure. Drug regimens were not associated with death or treatment failure in this model.We conclude that the addition of TMP-SMX to ceftazidime therapy during initial treatment of severe melioidosis does not reduce the acute mortality rate.

Genetic diversity of Plasmodium vivax in Kolkata, India

Background Plasmodium vivax malaria accounts for approximately 60% of malaria cases in Kolkata, India. There has been limited information on the genotypic polymorphism of P. vivax in this malaria endemic area. Three highly polymorphic and single copy genes were selected for a study of genetic diversity in Kolkata strains. Methods Blood from 151 patients with P. vivax infection diagnosed in Kolkata between April 2003 and September 2004 was genotyped at three polymorphic loci: the P. vivax circumsporozoite protein ( pvcs ), the merozoite surface protein 1 ( pvmsp 1) and the merozoite surface protein 3-alpha ( pvmsp 3-alpha). Results Analysis of these three genetic markers revealed that P. vivax populations in Kolkata are highly diverse. A large number of distinguishable alleles were found from three genetic markers: 11 for pvcs , 35 for pvmsp 1 and 37 for pvmsp 3-alpha. These were, in general, randomly distributed amongst the isolates. Among the 151 isolates, 142 unique genotypes were detected the commonest genotype at a frequency of less than 2% (3/151). The overall rate of mixed genotype infections was 10.6%. Conclusion These results indicate that the P. vivax parasite population is highly diverse in Kolkata, despite the low level of transmission. The genotyping protocols used in this study may be useful for differentiating re-infection from relapse and recrudescence in studies assessing of malarial drug efficacy in vivax malaria.

Schizontocidal antimalarials: a reply

Journal Article Schizontocidal antimalarials: a reply Get access N.J. White, N.J. White Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Headington Oxford, OX3 9DU, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Sanjeev Krishna Sanjeev Krishna Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Headington Oxford, OX3 9DU, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Transactions of The Royal Society of Tropical Medicine and Hygiene, Volume 84, Issue 4, July-August 1990, Page 610, https://doi.org/10.1016/0035-9203(90)90063-K Published: 01 August 1990

Constraints on plastic responses to climate variation in red deer

Influences of climate on life history traits in natural populations are well documented. However, the implications of between-individual variation in phenotypic plasticity underlying observed trait–environment relationships are rarely considered due to the large, long-term datasets required for such analysis. Studies typically present correlations of annual trait means with climate or assume that individual phenotypic responses are constant. Here, we examine this additional level of variation and show that, in a red deer population on the Isle of Rum, Scotland, changes in climate generate changes in phenotype only amongst individuals who have experienced favourable ecological conditions. Examination of relationships between offspring birth weight and spring temperature within the lifetimes of individual females revealed that the tendency to respond to climate declined as the population density experienced early in life increased. The presence of such systematic variation in individual plasticity is rarely documented in the wild, and has important implications for our understanding of the environmental dependencies of traits under varying ecological conditions.

Therapeutic Responses to Different Antimalarial Drugs in Vivax Malaria

The therapeutic responses to the eight most widely used antimalarial drugs were assessed in 207 adult patients with Plasmodium vivax malaria. This parasite does not cause marked sequestration, so parasite clearance can be used as a direct measure of antimalarial activity. The activities of these drugs in descending order were artesunate, artemether, chloroquine, mefloquine, quinine, halofantrine, primaquine, and pyrimethamine-sulfadoxine (PS). Therapeutic responses to PS were poor; parasitemias did not clear in 5 of the 12 PS-treated patients, whereas all the other patients made an initial recovery. Of 166 patients monitored for ≥28 days, 35% had reappearance of vivax malaria 11 to 65 days later and 7% developed falciparum malaria 5 to 21 days after the start of treatment. There were no significant differences in the times taken for vivax malaria reappearance among the different groups except for those given mefloquine and chloroquine, in which all vivax malaria reappearances developed &gt;28 days after treatment, suggesting suppression of the first relapse by these slowly eliminated drugs. There was no evidence of chloroquine resistance. The antimalarial drugs vary considerably in their intrinsic activities and stage specificities of action.

Ethical criteria in clinical research in developing countries: Is there a global standard?

No abstract is provided for this article.

Contributions to cooperative rearing in meerkats

In vertebrate societies where young are reared communally, nonbreeding helpers are usually closely related to young but often vary widely in their contributions to feeding them. Evolutionary explanations of helping behaviour have focused on whether differences in the level of contributions between helpers are related to variation in kinship. We investigated the contribution of helpers in meerkats, Suricata suricatta. The helpers varied widely in the number of food items they gave to pups and individual differences were related to variation in foraging success as well as to sex and age. When we controlled the influence of these variables, the level of contributions that helpers made to rearing pups was not significantly correlated with variation in kinship to the litters they were rearing.

Breeding Together: Kin Selection and Mutualism in Cooperative Vertebrates

In cooperatively breeding vertebrates, nonbreeding helpers raise young produced by dominant breeders. Although the evolution of cooperative breeding has often been attributed primarily to kin selection (whereby individuals gain “indirect” benefits to their fitness by assisting collateral relatives), there is increasing evidence that helpers can be unrelated to the young they are raising. Recent studies also suggest that the indirect benefits of cooperative behavior may often have been overestimated while the direct benefits of helping to the helper's own fitness have probably been underestimated. It now seems likely that the evolutionary mechanisms maintaining cooperative breeding are diverse and that, in some species, the direct benefits of helping may be sufficient to maintain cooperative societies. The benefits of cooperation in vertebrate societies may consequently show parallels with those in human societies, where cooperation between unrelated individuals is frequent and social institutions are often maintained by generalized reciprocity.