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Piero Olliaro

Publications and source records attributed to Piero Olliaro.

At least 19 recordsLinked to original sources
PubMed2006

Methodological issues in the assessment of antimalarial drug treatment: analysis of 13 studies in eight African countries from 2001 to 2004.

The objectives of these analyses were to assess the feasibility of the latest WHO recommendations (28-day follow-up with PCR genotyping) for the assessment of antimalarial drug efficacy in vivo and to examine how different statistical approaches affect results. We used individual-patient data from 13 studies of uncomplicated pediatric falciparum malaria conducted in sub-Saharan Africa, using chloroquine (CQ), sulfadoxine/pyrimethamine (SP), or amodiaquine (AQ). We assessed the use effectiveness and test performance of PCR genotyping in distinguishing recurrent infections. In analyzing data, we compared (i) the risk of failure on target days (days 14 and 28) by using Kaplan-Meier and per-protocol evaluable patient analyses, (ii) PCR-corrected results allowing (method 1) or excluding (method 2) new infections, (iii) and day 14 versus day 28 results. Of the 2,576 patients treated, 2,287 (89%) were evaluable on day 28. Of the 695 recurrences occurring post-day 14, 650 could be processed and 584 were resolved (PCR use effectiveness, 84%; test performance, 90%). The risks of failure on day 28 with Kaplan-Meier and evaluable-patient analyses tended to be generally close (except in smaller studies) because the numbers of dropouts were minimal, but attrition rates on day 28 were higher with the latter method. Method 2 yielded higher risks of failure than method 1. Extending observation to 28 days produced higher estimated risks of failure for SP and AQ but not for CQ (high failure rates by day 14). Results support the implementation of the current WHO protocol and favor analyzing PCR-corrected outcomes by Kaplan-Meier analysis (which allows for dropouts) and retaining new infections (which minimizes losses).

Africa↗
PubMed2006

In vivo and in vitro investigations of the effects of the antimalarial drug dihydroartemisinin (DHA) on rat embryos.

Artemisinin derivatives are clinically effective and safe antimalarials, but are not recommended during the first trimester of pregnancy because of the resorptions and abnormalities seen in animal reproduction studies. Understanding how, when and what toxicity occurs is crucial to any assessment of clinical relevance. Previously, DHA has been shown in the rat whole embryo culture (WEC) to primarily affect primitive red blood cells (RBCs) causing subsequent tissue damage and dysmorphogenesis. To verify the primary target of DHA in vivo and to detect consequences induced by early damage on embryo development, pregnant female rats were orally treated on gestation days (GD) 9.5 and 10.5 with 7.5 or 15 mg/kg/day DHA and caesarean sectioned on GD11.5, 12.5, 13.5, 15 and 20. A parallel in vitro WEC study evaluated the role of oxidative damage and examined blood islands and primitive RBCs. In accordance with the WEC results, primitive RBCs from yolk sac hematopoiesis were the target of DHA in vivo. The resulting anemia led to cell damage, which depending on its degree, was either diffuse or focal. Embryonic response to acute anemia varied from complete recovery to malformation and death, depending on the extent of cell death. Malformations occurred only in litters with embryonic deaths. DHA induced low glutathione levels in RBCs, indicating that oxidative stress may be involved in artemisinin toxicity; effects were extremely rapid, with altered RBCs seen as early as GD10. In establishing the relevance of these findings to humans, one should consider differences in the development of rodents and humans. While yolk sac hematopoiesis occurs similarly in the two species, early placentation and extent of exposure differ. In particular, early hematopoiesis takes only 7 days in rats (during which RBCs expand in a clonal fashion) compared with 6 weeks in humans; thus the susceptible period in relation to the duration of exposure to an artemisinin-based treatment may be substantially different.

Abnormalities, Multiple↗
PubMed2006

Chemotherapy in the treatment and control of leishmaniasis.

Drugs remain the most important tool for the treatment and control of both visceral and cutaneous leishmaniasis. Although there have been several advances in the past decade, with the introduction of new therapies by liposomal amphotericin, oral miltefosine and paromomycin (PM), these are not ideal drugs, and improved shorter duration, less toxic and cheaper therapies are required. Treatments for complex forms of leishmaniasis and HIV co-infections are inadequate. In addition, full deployment of drugs in treatment and control requires defined strategies, which can also prevent or delay the development of drug resistance.

Animals↗
PubMed2006

Malaria in adolescence: burden of disease, consequences, and opportunities for intervention.

The problem of malaria in adolescence has largely been overshadowed by the huge burden of disease in young children. A substantial number of adolescents are at risk from malaria infection, but the burden of disease and consequences of infection in this age-group have rarely been studied. Our understanding of specific risk factors and beneficial interventions for adolescents is also limited. Data show that, from an adolescent viewpoint, malaria is a common cause of clinical illness and a preventable cause of death, even in areas of stable malaria transmission. Younger adolescents might be at a higher risk than older adolescents, because of immunological and hormonal factors. There are limited data about the adverse consequences of malaria in non-pregnant adolescents. However, in pregnant adolescents, the consequences of malaria are of great concern and simple interventions might lead to a substantial benefit. Malaria infection in adolescents is an under-recognised problem, and the prevention, diagnosis, and treatment of malaria should have a high priority within adolescent health programmes.

Adolescent↗
PubMed2006

Molecular genotyping to distinguish between recrudescents and new infections in treatment trials of Plasmodium falciparum malaria conducted in Sub-Saharan Africa: adjustment of parasitological outcomes and assessment of genotyping effectiveness.

Molecular genotyping of baseline and post-treatment recurrent Plasmodium falciparum is recommended to distinguish recrudescent from new infections. However, genotyping performance and adjustment of treatment outcomes have not been evaluated in large field trials. Parasitological outcomes were assessed in nine double-blinded trials of uncomplicated P. falciparum malaria in African children treated with artesunate/placebo plus standard monotherapies. Day 28 failure rates were adjusted by stepwise genotyping the P. falciparum glutamate rich protein (glurp), merozoite surface protein 1 (msp1) and 2 (msp2). We calculated overall and laboratory genotyping performance and compared unadjusted (crude) and PCR-adjusted outcomes. 3455 (93.6%) of 3691 enrolled patients were evaluable by Day 28. 767 (22%) had post-Day 14 recurrent parasitemias of which 686 could be genotyped: 246 were recrudescences, 286 new infections and 154 unresolved. The overall and laboratory genotyping performance were 69 (12-100)% and 78 (50-100)%, respectively. The mean Day 28 crude parasitological failure rate was 44 (range 3-87)%. PCR-adjusted rates were 36 (range 2-86)% if unresolved infections were counted as failures or 33 (range 2-86)% if excluded from analysis. The overall difference between crude Day 28 and Day 14 failure rates was 22% (95% CI 20.3, 24.6) but decreased to 14% (95% CI 12.1, 16.3) if unresolved infections are counted as failures, or to 11% (95% CI 9.8, 16.3) if unresolved infections are excluded from the analysis. Genotyping refined treatment outcomes but diligence is needed in sample collection and analysis to improve its performance. Our findings support the WHO recommendation of PCR genotyping in malaria clinical trials and suggest that stepwise genotyping of only two loci (msp2 and msp1 or glurp) can reliably discriminate recrudescences from new infections.

Africa South of the Sahara↗
PubMed2006

An open label randomized comparison of mefloquine-artesunate as separate tablets vs. a new co-formulated combination for the treatment of uncomplicated multidrug-resistant falciparum malaria in Thailand.

BACKGROUND: Delivering drugs in a fixed combination is essential to the success of the strategy of artemisinin-based combination therapy. This prevents one drug being taken without the protection of the other, reducing the chance of emergence and spread of drug resistant strains of Plasmodium falciparum. A lower tablet burden should also facilitate adherence to treatment. A new fixed combination of mefloquine plus artesunate has been developed. This was compared with the conventional regimen of separate tablets for the treatment of uncomplicated multidrug-resistant falciparum malaria. METHODS: On the north-western border of Thailand 500 adults and children with uncomplicated falciparum malaria were randomized to receive either the new fixed combination or separate tablets. They were followed up weekly for 63 days. RESULTS: The day 63 polymerase chain reaction-adjusted cure rates were 91.9% (95% CI 88.2-95.6) in the fixed combination group and 89.2% (85.0-93.4) in the loose tablets group (P=0.3). There was a lower incidence of early vomiting in the group receiving the fixed combination. CONCLUSION: This new fixed combination of mefloquine and artesunate was efficacious, well tolerated and convenient to administer.

Adolescent↗
PubMed2006

Population pharmacokinetics of artesunate and dihydroartemisinin following intra-rectal dosing of artesunate in malaria patients.

BACKGROUND: Intra-rectal artesunate has been developed as a potentially life-saving treatment of severe malaria in rural village settings where administration of parenteral antimalarial drugs is not possible. We studied the population pharmacokinetics of intra-rectal artesunate and the relationship with parasitological responses in patients with moderately severe falciparum malaria. METHODS AND FINDINGS: Adults and children in Africa and Southeast Asia with moderately severe malaria were recruited in two Phase II studies (12 adults from Southeast Asia and 11 children from Africa) with intensive sampling protocols, and three Phase III studies (44 children from Southeast Asia, and 86 children and 26 adults from Africa) with sparse sampling. All patients received 10 mg/kg artesunate as a single intra-rectal dose of suppositories. Venous blood samples were taken during a period of 24 h following dosing. Plasma artesunate and dihydroartemisinin (DHA, the main biologically active metabolite) concentrations were measured by high-performance liquid chromatography with electrochemical detection. The pharmacokinetic properties of DHA were determined using nonlinear mixed-effects modelling. Artesunate is rapidly hydrolysed in vivo to DHA, and this contributes the majority of antimalarial activity. For DHA, a one-compartment model assuming complete conversion from artesunate and first-order appearance and elimination kinetics gave the best fit to the data. The mean population estimate of apparent clearance (CL/F) was 2.64 (l/kg/h) with 66% inter-individual variability. The apparent volume of distribution (V/F) was 2.75 (l/kg) with 96% inter-individual variability. The estimated DHA population mean elimination half-life was 43 min. Gender was associated with increased mean CL/F by 1.14 (95% CI: 0.36-1.92) (l/kg/h) for a male compared with a female, and weight was positively associated with V/F. Larger V/Fs were observed for the patients requiring early rescue treatment compared with the remainder, independent of any confounders. No associations between the parasitological responses and the posterior individual estimates of V/F, CL/F, and AUC0-6h were observed. CONCLUSIONS: The pharmacokinetic properties of DHA were affected only by gender and body weight. Patients with the lowest area under the DHA concentration curve did not have slower parasite clearance, suggesting that rectal artesunate is well absorbed in most patients with moderately severe malaria. However, a number of modelling assumptions were required due to the large intra- and inter-individual variability of the DHA concentrations.

Administration, Rectal↗
PubMed2005

Efficacy of artesunate plus amodiaquine versus that of artemether-lumefantrine for the treatment of uncomplicated childhood Plasmodium falciparum malaria in Zanzibar, Tanzania.

BACKGROUND: This is the first clinical trial comparing the efficacy of artesunate plus amodiaquine (ASAQ) and artemether-lumefantrine (AL)--the major artemisinin-based combination therapy (ACT) candidates for treatment of malaria in Africa--that involved an extended, 42-day follow-up period, polymerase chain reaction-adjusted parasitological cure rates (PCR APCRs), and systematic analyses of genetic markers related to quinoline resistance. METHODS. A total of 408 children with uncomplicated Plasmodium falciparum malaria in Zanzibar, Tanzania, were enrolled. Children who were 6-8 months of age and/or who weighed 6-8 kg were assigned to receive ASAQ for 3 days. Children who were 9-59 months of age and who weighted > or =9 kg were randomly assigned to receive either ASAQ or AL for 3 days in standard doses. Intention-to-treat analyses were performed. RESULTS: Age- and weight-adjusted PCR-APCRs by follow-up day 42 were 91% (188 of 206 patients) in the ASAQ group and 94% (185 of 197 patients) in the AL group (odds ratio [OR] for the likelihood of cure, 2.07; 95% confidence interval [CI], 0.84-5.10; P=.115). A total of 5 and 7 recrudescences occurred after day 28 in the ASAQ and AL groups, respectively. On the assumption that 10 malaria episodes with uncertain PCR results were recrudescences, PCR-APCRs decreased to 88% in the ASAQ group and to 92% in the AL group. Unadjusted cure rates by day 42 were 56% (116 of 206 patients) in the ASAQ group versus 77% (151 of 197 patients) in the AL group (OR, 2.55; 95% CI, 1.66-3.91; P<.001). Rates of reinfection by day 42 were 36% (65 of 181 patients) in the ASAQ arm versus 17% (31 of 182 patients) in the AL arm (OR, 0.37; 95% CI, 0.22-0.60; P<.001). A significant selection of P. falciparum multidrug resistance gene 1 allele 86N was found in isolates associated with reinfection after AL treatment, compared with isolates at baseline (2.2-fold increase; P<.001). CONCLUSIONS: Both treatments were highly efficacious, but AL provided stronger prevention against reinfection. The high proportion of recrudescences found after day 28 and the genetic selection by the long-acting partner drug underlines the importance of long follow-up periods in clinical trials. A long follow-up duration and performance of PCR genotyping should be implemented in programmatic surveillance of antimalarial drugs.

Amodiaquine↗
PubMed2005

Drug resistance hampers our capacity to roll back malaria.

Widespread drug resistance in parasites aggravates the burden of malaria. The extent of the problem is due mainly to the limited armamentarium of drugs used thus far to treat malaria and to policies and practices constrained by limited resources. All drugs in use are affected except, thus far, artemisinin derivatives. The scale and impact of resistance has been underestimated, leading to the continued use of failing drugs, which contributes to the rise in resistance and increased morbidity and mortality due to malaria. Pharmacological, epidemiological, and operational aspects factor the development and spread of resistance. Although the problem is complex, much can be done to reverse the course of events: adopt adequate tests to assess resistance, encourage and sustain development of new drugs, protect drugs against resistance through use of combinations, expand access to prompt and effective treatment, and promote evidence-based policies and sensible practices. The current situation favors the development of sensible strategies to restrain resistance.

Animals↗
PubMed2005

Effects of the antimalarial drug dihydroartemisinin (DHA) on rat embryos in vitro.

Artemisinin derivatives are not currently recommended for use during the first trimester of pregnancy because they cause embryo death and some abnormalities in early pregnancy in animals. We studied the effects of dihydroartemisinin (DHA) in rat whole embryo cultures (WEC). DHA was added to the culture medium for the entire 48-h culture, 1.5 h at the beginning or at the end of the culture at 0.01-2 microg/mL. DHA affected primarily red blood cells during yolk sac hematopoiesis. Higher concentrations and longer exposure inhibited angiogenesis. Tissue damage (cell deaths) and effects on embryo morphology (neural tube, branchial arches, somites and caudal region defects) were attributed to these events. The viability of severely affected embryos beyond the 48-h assay is uncertain. These results help explain findings from animal data and provide evidence that the yolk sac is highly susceptible to artemisinin compounds. Extrapolating results to pregnant women exposed in the first trimester remains difficult. Pharmacovigilance and further studies of the mechanism of damage are needed.

Animals↗
PubMed2004

Plasmodium berghei: dehydroepiandrosterone sulfate reverses chloroquino-resistance in experimental malaria infection; correlation with glucose 6-phosphate dehydrogenase and glutathione synthesis pathway.

In Plasmodium falciparum-infected cells or in P. berghei infected mice, increase of reduced glutathione (GSH) levels confers resistance to chloroquine (CQ). GSH is synthesized within the cells through a complex biochemical pathway composed of several well known enzymes, in which glucose-6-phosphate dehydrogenase (G6PD) plays an important role. The physiological hormone dehydroepiandrosterone sulfate (DHEAS) is a potent inhibitor of G6PD activity, and G6PD deficiency is known to exert antimalaria protection. This study aimed to investigate the ability of DHEAS to enhance the antimalarial activity of CQ, via an inhibition of G6PD activity and GSH synthesis. Two P. berghei CQ resistant strains (CQR6 and CQR30) were selected in vivo from the sensitive strain NK65. Drug effects were checked both by monitoring the evolution of parasitaemia and by the survival of infected mice. In addition, intra-parasite levels of GSH and G6PD activity were measured before and after the treatment. Results demonstrate that acquisition of CQ resistance in P. berghei is associated with a significant increase in parasite G6PD activity and GSH level. Combination of CQ with DHEAS or buthionin sulfoximin (BSO, a specific inhibitor of GSH synthesis) significantly increased sensitivity of resistant parasites to CQ and increased the survival period of the infected mice. This reduction of parasitaemia and improvement of the survival of infected mice were associated with intra-parasite depletion of GSH and inhibition of G6PD activity due to DHEAS action. This experimental study suggests that DHEAS could be used to potentiate antimalarial action of CQ, particularly on CQ resistant strains.

Animals↗
PubMed2004

Evidence that haem iron in the malaria parasite is not needed for the antimalarial effects of artemisinin.

The role of haem iron (II) and oxidative stress in the activation and antimalarial activity of artemisinin is unclear. Thus, we submitted malaria parasite to modified culture conditions: artemisinin activity increased by 20-30% under an oxygen-rich atmosphere (20% O2 instead of "standard" 1% O2), and by 40-50% in the presence of carboxy-haemoglobin, and 2% carbon monoxide, conditions which inhibit haem iron (II) reactivity. In all cases, parasite growth and chloroquine activity were unaffected. We conclude that in the malaria parasite artemisinin is not activated by haem iron and that free radicals are not needed for its toxicity.

Animals↗
PubMed2004

In vivo assessment of drug efficacy against Plasmodium falciparum malaria: duration of follow-up.

To determine the optimum duration of follow-up for the assessment of drug efficacy against Plasmodium falciparum malaria, 96 trial arms from randomized controlled trials (RCTs) with follow-up of 28 days or longer that were conducted between 1990 and 2003 were analyzed. These trials enrolled 13,772 patients, and participating patients comprised 23% of all patients enrolled in RCTs over the past 40 years; 61 (64%) trial arms were conducted in areas where the rate of malaria transmission was low, and 58 (50%) trial arms were supported by parasite genotyping to distinguish true recrudescences from reinfections. The median overall failure rate reported was 10% (range, 0 to 47%). The widely used day 14 assessment had a sensitivity of between 0 and 37% in identifying treatment failures and had no predictive value. Assessment at day 28 had a sensitivity of 66% overall (28 to 100% in individual trials) but could be used to predict the true failure rate if either parasite genotyping was performed (r(2) = 0.94) or if the entomological inoculation rate was known. In the assessment of drug efficacy against falciparum malaria, 28 days should be the minimum period of follow-up.

Algorithms↗
PubMed2004

The European and developing countries clinical trails partnership.

The European and Developing Countries Clinical Trials Partnership (EDCTP) is a new venture between 14 states of the European Union (EU) and Norway to support the conduct of clinical trials of drugs and vaccines (and microbicides) against HIV/AIDS, malaria and tuberculosis in Africa, to develop the capacity to conduct such trials in African institutions, and to promote a more integrated approach to health research amongst European countries. It is funded for 5 years with a contribution of euros 200 million from the European Commission, matched by an equivalent sum that is spent directly by national research programmes of EU member states and Norway on activities that fall under the EDCTP remit. EDCTP seeks to be synergistic with other funding bodies supporting research on these diseases and will promote collaborative research, involving support from multiple funding agencies and harnessing and networking expertise across different African and European countries.

Africa South of the Sahara↗
PubMed2003

Accelerated senescence of human erythrocytes cultured with Plasmodium falciparum.

Red blood cells infected withPlasmodium falciparum(IRBCs) undergo changes primarily in their membrane composition that contribute to malaria pathogenesis. However, all manifestations (eg, anemia) cannot be accounted for by IRBCs alone. Uninfected erythrocytes (URBCs) may play a role, but they have been under-researched. We wanted to document changes in the erythrocyte membrane that could contribute to URBC reduced life span and malaria-associated anemia. Human erythrocytes were cultured withP falciparumand washed at the trophozoite stage. IRBCs and URBCs were separated on Percoll density gradient, thus obtaining erythrocyte fractions of different densities/ages. IRBC- and URBC-purified membranes were analyzed and compared with control normal erythrocytes (NRBCs) of the same age, from the same donor, kept in the same conditions.P falciparumaccelerated aging of both IRBCs and URBCs, causing a significant shift in the cell population toward the denser (old) fraction. Protein, phospholipid, and cholesterol content were reduced in IRBCs and young URBCs. Young and medium uninfected fractions had higher levels of lipid peroxidation and phospholipid saturation (because of the loss of polyunsaturated fatty acids, PUFAs) and lower phosphatidylserine. In IRBCs, thiobarbituric reactive substances (TBARSs) were higher, and PUFAs and phosphatidylserine lower than in NRBCs and URBCs. In comparison, trophozoite membranes had lower phospholipid (particularly sphingomyelin and phosphatidylserine) and cholesterol content and a higher degree of saturation. Parasite-induced peroxidative damage might account for these modifications. In summary, we demonstrated that membrane damage leading to accelerated senescence of both infected and uninfected erythrocytes will likely contribute to malaria anemia.

Animals↗