Congenital toxoplasmosis.
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Antiprotozoal Agents↗
Biomedical subjects
Piero Olliaro
Publications and source records attributed to Piero Olliaro.
Does chloroquine really act through oxidative stress?
To assess whether molecular oxygen and oxidative stress contribute to chloroquine activity, we cultivated strains of Plasmodium falciparum in erythrocytes with carboxyhemoglobin and an atmosphere containing 2% CO, 5% CO(2) and 93% N(2). Results indicate that, contrary to common belief, oxygen is not involved in the activity of chloroquine. Reactive radicals formation is suggested.
Animals↗
Drug development for neglected diseases: a deficient market and a public-health policy failure.
There is a lack of effective, safe, and affordable pharmaceuticals to control infectious diseases that cause high mortality and morbidity among poor people in the developing world. We analysed outcomes of pharmaceutical research and development over the past 25 years, and reviewed current public and private initiatives aimed at correcting the imbalance in research and development that leaves diseases that occur predominantly in the developing world largely unaddressed. We compiled data by searches of Medline and databases of the US Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products, and reviewed current public and private initiatives through an analysis of recently published studies. We found that, of 1393 new chemical entities marketed between 1975 and 1999, only 16 were for tropical diseases and tuberculosis. There is a 13-fold greater chance of a drug being brought to market for central-nervous-system disorders or cancer than for a neglected disease. The pharmaceutical industry argues that research and development is too costly and risky to invest in low-return neglected diseases, and public and private initiatives have tried to overcome this market limitation through incentive packages and public-private partnerships. The lack of drug research and development for "non-profitable" infectious diseases will require new strategies. No sustainable solution will result for diseases that predominantly affect poor people in the South without the establishment of an international pharmaceutical policy for all neglected diseases. Private-sector research obligations should be explored, and a public-sector not-for-profit research and development capacity promoted.
Anti-Infective Agents↗
Visceral leishmaniasis: current status of control, diagnosis, and treatment, and a proposed research and development agenda.
Visceral leishmaniasis is common in less developed countries, with an estimated 500000 new cases each year. Because of the diversity of epidemiological situations, no single diagnosis, treatment, or control will be suitable for all. Control measures through case finding, treatment, and vector control are seldom used, even where they could be useful. There is a place for a vaccine, and new imaginative approaches are needed. HIV co-infection is changing the epidemiology and presents problems for diagnosis and case management. Field diagnosis is difficult; simpler, less invasive tests are needed. Current treatments require long courses and parenteral administration, and most are expensive. Resistance is making the mainstay of treatment, agents based on pentavalent antimony, useless in northeastern India, where disease incidence is highest. Second-line drugs (pentamidine and amphotericin B) are limited by toxicity and availability, and newer formulations of amphotericin B are not affordable. The first effective oral drug, miltefosine, has been licensed in India, but the development of other drugs in clinical phases (paromomycin and sitamaquine) is slow. No novel compound is in the pipeline. Drug combinations must be developed to prevent drug resistance. Despite these urgent needs, research and development has been neglected, because a disease that mainly affects the poor ranks as a low priority in the private sector, and the public sector currently struggles to undertake the development of drugs and diagnostics in the absence of adequate funds and infrastructure. This article reviews the current situation and perspectives for diagnosis, treatment, and control of visceral leishmaniasis, and lists some priorities for research and development.
Aminoquinolines↗
Malaria: current status of control, diagnosis, treatment, and a proposed agenda for research and development.
Rolling back malaria is possible. Tools are available but they are not used. Several countries deploy, as their national malaria control treatment policy, drugs that are no longer effective. New and innovative methods of vector control, diagnosis, and treatment should be developed, and work towards development of new drugs and a vaccine should receive much greater support. But the pressing need, in the face of increasing global mortality and general lack of progress in malaria control, is research into the best methods of deploying and using existing approaches, particularly insecticide-treated mosquito nets, rapid methods of diagnosis, and artemisinin-based combination treatments. Evidence on these approaches should provide national governments and international donors with the cost-benefit information that would justify much-needed increases in global support for appropriate and effective malaria control.
Animals↗
Developments in the treatment of leishmaniasis and trypanosomiasis.
The leishmaniases and trypanosomiases are diseases caused by related parasites belonging to the kinetoplastidae family. They share common biological traits, which are comparatively better known than for other parasites, and which would favour the identification of common targets. Yet, very few new drugs are on the horizon and treatment relies on old, often toxic and ineffective drugs. Miltefosine may soon become the first oral drug registered for Leishmaniasis. Other compounds in clinical trials are paromomycin, sitamquine and lipid formulations of amphotericin B. For African trypanosomiasis old drugs primarily indicated for Chagas disease are being considered (nifurtimox, megazole). Earlier projects are berenil, bisamidines and triazines for African trypanosomiasis, and novel azoles and cruzipain inhibitors for Chagas disease.
Journal Article↗
Congenital toxoplasmosis.
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Coccidiostats↗
Congenital toxoplasmosis.
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Coccidiostats↗
Artesunate plus sulfadoxine-pyrimethamine for uncomplicated malaria in Kenyan children: a randomized, double-blind, placebo-controlled trial.
Plasmodium falciparum has developed resistance to almost all routinely used antimalarial drugs. Sulfadoxine-pyrimethamine (SP) has replaced chloroquine as first-line treatment of uncomplicated malaria infection in Kenya but resistance to SP is already reported. The addition of artemisinin derivatives to SP may delay the development of drug resistance, improve cure rates, and reduce transmission. The efficacy and safety of artesunate plus SP in the treatment of uncomplicated P. falciparum malaria was evaluated in a randomized trial of 600 children at Siaya District Hospital, western Kenya between October 1999 and March 2000. Children aged < 5 years were randomly assigned to receive SP alone (1.25 mg/kg based on pyrimethamine), or in combination with artesunate (4 mg/kg/d) for either 1 or 3 d. Parasitological failure by days 14 and 28 (polymerase chain reaction [PCR]-corrected for new infections) were the primary endpoints. Treatment failure rates by day 14 were 25.5% in the SP alone group, 16.2% (risk difference [delta]-9.3%, 95% CI -17.3 to -1.2%, P= 0.027) in the 1-dose artesunate group, and 9.4% (delta-16.2%, 95% CI -23.6 to -8.7%, P< 0.001) in the 3-dose artesunate group. Corresponding rates by day 28 were 46.0% in the SP alone group, 38.2% (delta-7.8%, 95% CI -17.7 to 2.1%, P= 0.16) in the 1-dose artesunate group, and 26.0% (delta-20.0%, 95% CI -29.4 to -10.6%, P < 0.001) in the 3-dose artesunate group. The artesunate and SP combination was well tolerated. There were no serious drug-related adverse events. Parasite clearance and gametocyte carriage were reduced significantly in both combination groups compared with SP alone. Three days of artesunate were required to reduce significantly the risk of treatment failure by day 28. However, the high background rate of parasitological failure with SP may make this combination unsuitable for widespread use in Kenya.
Antimalarials↗
The effect of mass administration of sulfadoxine-pyrimethamine combined with artesunate on malaria incidence: a double-blind, community-randomized, placebo-controlled trial in The Gambia.
A double-blind, community-randomized, placebo-controlled trial was conducted in a rural area of The Gambia between June and December 1999 to test whether a reduction in the infectious reservoir can reduce malaria transmission. Overall 14,017 (85%) individuals living in the study area were treated with either placebo or sulfadoxine-pyrimethamine (SP) combined with a single dose of artesunate (AS). Following the mass drug administration (MDA) 1375 children aged 6 months to 10 years were kept under surveillance for clinical malaria in 18 villages throughout the 1999 malaria transmission season. During a 20-week surveillance period 637 episodes of malaria were detected. The mean incidence rate was 2.5/100 child-weeks in the placebo villages, and 2.3/100 child-weeks in villages that received SP + AS. The mean rate ratio, adjusted for individual and village-level covariates, was 0.91 (95% CI 0.68-1.22, P = 0.49). During the first 2 months of surveillance, the malaria incidence was lower in treated villages. After 2 months the incidence was slightly higher in the MDA group but this was not statistically significant. Overall, no benefit of the MDA could be detected. The reason for the absence of an impact on malaria transmission is probably the very high basic reproductive number of malaria, and the persistence of mature gametocytes, which are not affected by AS treatment.
Adult↗
Artesunate and sulfadoxine-pyrimethamine combinations for the treatment of uncomplicated Plasmodium falciparum malaria in Uganda: a randomized, double-blind, placebo-controlled trial.
Drug-resistant malaria is spreading in Africa. The few available drugs might be safeguarded if combined with an artemisinin derivative. We investigated the efficacy, safety, and tolerability of 2 combinations of artesunate with sulfadoxine-pyrimethamine (SP) in a mesoendemic region in Uganda with SP resistance, from September 1999 to June 2000. In a randomized, double-blind, placebo-controlled trial, 420 children aged 6-59 months with uncomplicated Plasmodium falciparum malaria were assigned SP alone (25 mg/kg sulfadoxine, 1.25 mg/kg pyrimethamine) or combined with artesunate (AS; 4 mg/kg/d) for either 1 d (SPAS1) or 3 d (SPAS3). Children were followed-up for 28 d. Day 14 cure rates were 84.6% (99/117) with SPAS3 and 61.9% (73/118) with SPAS1 compared with 55.8% (86/154) with SP. Corresponding day 28 results were 74.4% (87/117) and 45.2% (52/115) compared with 40.5% (62/153). A significant improvement was obtained with the addition of 3 d, but not 1 d, of artesunate (risk ratio [RR] = 1.5, 95% CI 1.3-1.8 at 14 d and RR = 1.8, 95% CI 1.5-2.3 at 28 d). Both AS regimens achieved significantly faster parasite clearance and lower gametocyte carriage. All drug regimens were well tolerated, but SP alone was ineffective. Treatment efficacy improved with SPAS3 but the cure rate at day 28 was modest. The combinations were well tolerated and safe. In areas where SP resistance is prevalent other combinations should be considered.
Antimalarials↗
Insights into the mechanism of action of ferroquine. Relationship between physicochemical properties and antiplasmodial activity.
Ferroquine (FQ) is a 4-aminoquinoline antimalarial which contains a quinoline nucleus similar to chloroquine, but a novel ferrocenic group in its side chain. Previous work has demonstrated that this compound has excellent activity against malaria parasites, both in vitro and in vivo, with especially good activity against chloroquine-resistant parasites, but details of its mechanism of action have not previously been reported. In this study, we have investigated the physicochemical properties of FQ for comparison with chloroquine (CQ). Like CQ, FQ forms complexes with hematin in solution (log K = 4.95 +/- 0.05). FQ is an even stronger inhibitor of beta-hematin formation than CQ (IC(50) = 0.78 equiv relative to hematin for FQ vs 1.9 for CQ). These data suggest that the mechanism of action of FQ is likely to be similar to that of CQ and probably involves hematin as the drug target and inhibition of hemozoin formation. However, both the basicity and lipophilicity of FQ are significantly different from those of CQ. The lipophilicity of FQ and CQ are similar when protonated at the putative food vacuole pH of 5.2 (log D = -0.77 and -1.2 respectively), but differ markedly at pH 7.4 (log D = 2.95 and 0.85 respectively). In addition, the pK(a) values of FQ are lower (pK(a1) = 8.19 and pK(a2) = 6.99) than those of CQ (10.03 and 7.94, respectively). This suggests that there will be somewhat less vacuolar accumulation of FQ compared with CQ. Single crystal structure determination of FQ shows the presence of a strong internal hydrogen bond between the 4-amino group and the terminal N atom. This, together with the electron donating properties of the ferrocene moiety, probably explains the decreased pK(a). Interestingly, the decreased accumulation arising from the less basic behavior of this compound is partly compensated for by its stronger beta-hematin inhibition. Increased lipophilicity, differences in geometric and electronic structure, and changes in the N-N distances in FQ compared to CQ probably explain its activity against CQ-resistant parasites.
Aminoquinolines↗