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P L Olliaro

Publications and source records attributed to P L Olliaro.

15 recordsLinked to original sources
PubMed2005

A new and simple solid-phase extraction method for LC determination of pyronaridine in human plasma.

A new approach using a simple solid-phase extraction technique has been developed for the determination of pyronaridine (PND), an antimalarial drug, in human plasma. After extraction with C18 solid-phase sorbent, PND was analyzed using a reverse phase chromatographic method with fluorescence detection (at lambda(ex)=267 nm and lambda(em)=443 nm). The mean extraction recovery for PND was 95.2%. The coefficient of variation for intra-assay precision, inter-assay precision and accuracy was less than 10%. The quantification limit with fluorescence detection was 0.010 microg/mL plasma. The method described herein has several advantages over other published methods since it is easy to perform and rapid. It also permits reducing both, solvent use and sample preparation time. The method has been used successfully to assay plasma samples from clinical pharmacokinetic studies.

Administration, Oral↗
PubMed2001

Pharmacokinetics of artesunate after single oral administration to rats.

BACKGROUND: Artesunate is a commonly used antimalarial drug derived from artemisinin. It is rapidly converted to dihydroartemisinin. Little is known on this conversion in the GI tract and blood, and how this influences absorption. In order to study the absorption phase of the kinetics of artesunate following oral administration in rats, samples were collected at baseline, and then 0.5, 2, 5, 10, 15, 30, 45, 60 and 120 minutes after a single dose of 150 mg. RESULTS: Peak concentration of parent artesunate and dihydroartemisinin was achieved within 5 and 37.5 +/- 8.7 min, respectively of start of administration through gavage. The half lives of absorption were 2.73 +/- 0.85 and 12.49 +/- 2.49 min, respectively. CONCLUSIONS: These times were considerably shorter for artesunate than those found in studies which start sampling later. The profiles of parent compound and metabolite result from a complex equation dictated by the pH-dependent rates of hydroxylation of artesunate to dihydroartemisinin, the different rates at which either compounds are absorbed, and the catalytic hydroxylation by esterases. The rate of chemical oxidation of artesunate is pH dependent; this explains its rapid conversion to dihydroartemisinin in the stomach, as compared to its greater stability in other compartments at higher pH and in plasma. We propose that variable proportions of absorption take place in the stomach, and conclude that parent artesunate reaches an early peak within minutes of dosing, and that the early dihydroartemisinin levels result primarily from the absorption of the metabolite as such.

Administration, Oral↗
PubMed2001

Possible modes of action of the artemisinin-type compounds.

Artemisinin-type compounds are used for the treatment of uncomplicated and severe forms of malaria. They reduce parasitaemia more rapidly than any other antimalarial compound known, and are effective against multidrug-resistant parasites. However, uncertainties remain as to how they act on the parasite and cause toxicity. In this review, we summarize current ideas.

Animals↗
PubMed1999

An overview of chemotherapeutic targets for antimalarial drug discovery.

The need for new antimalarials comes from the widespread resistance to those in current use. New antimalarial targets are required to allow the discovery of chemically diverse, effective drugs. The search for such new targets and new drug chemotypes will likely be helped by the advent of functional genomics and structure-based drug design. After validation of the putative targets as those capable of providing effective and safe drugs, targets can be used as the basis for screening compounds in order to identify new leads, which, in turn, will qualify for lead optimization work. The combined use of combinatorial chemistry--to generate large numbers of structurally diverse compounds--and of high throughput screening systems--to speed up the testing of compounds--hopefully will help to optimize the process. Potential chemotherapeutic targets in the malaria parasite can be broadly classified into three categories: those involved in processes occurring in the digestive vacuole, enzymes involved in macromolecular and metabolite synthesis, and those responsible for membrane processes and signalling. The processes occurring in the digestive vacuole include haemoglobin digestion, redox processes and free radical formation, and reactions accompanying haem release followed by its polymerization into haemozoin. Many enzymes in macromolecular and metabolite synthesis are promising potential targets, some of which have been established in other microorganisms, although not yet validated for Plasmodium, with very few exceptions (such as dihydrofolate reductase). Proteins responsible for membrane processes, including trafficking and drug transport and signalling, are potentially important also to identify compounds to be used in combination with antimalarial drugs to combat resistance.

Antimalarials↗
PubMed1998

Clinical recovery and limited cure in canine visceral leishmaniasis treated with aminosidine (paromomycin).

Three groups of three, six, and 12 dogs with parasitologically proven clinical visceral leishmaniasis (Leishmania chagasi infection) were treated with intramuscular aminosidine sulfate at doses of 20 mg/kg/day for 15 days; 80 mg/kg/day for 20 days, and 40 mg/kg/day for 30 days, respectively. Follow-up was by parasitologic examination of bone marrow and skin, serology using the indirect immunofluorescent antibody test, and clinical examination for signs of visceral leishmaniasis or adverse effects of treatment. In animals treated with 20 mg/kg/day, for 15 days, there was dramatic clinical improvement with disappearance of conjunctivitis, increase in appetite, weight gain, and recovery of normal skin condition and a healthy coat, but parasitologic relapse occurred between 50 and 100 days after initiation of treatment. Adverse effects were seen with treatment with 80 mg/kg/day for 20 days; three dogs died during or just after treatment, two showed temporary recovery, and one showed total clinical and parasitologic cure that was maintained for four years. Although adverse effects and relapses were seen in some dogs treated with 40 mg/kg/day for 30 days, three of 12 dogs showed complete parasitologic and clinical cure that was sustained for at least four years. Aminosidine treatment cannot be recommended as an alternative to the humane destruction of dogs for the control of canine visceral leishmaniasis because ineffective treatment may prolong carrier status or encourage development of drug resistance. This drug may be a therapeutic option if there is no danger of a dog acting as a reservoir of infection. Achievement of clinical recovery and limited cure with aminosidine suggests that further trials would be of value, possibly in combination with other anti-leishmanial drugs and with supportive measures to reduce adverse effects.

Animals↗
PubMed1996

Strategies for the prevention of antimalarial drug resistance: rationale for combination chemotherapy for malaria.

Among the several 'tropical' diseases that affect humans, malarin poses special control problems due to the increasing population at risk from the disease, the difficulties in eradicating the mosquito vector in the tropics and the emergence and spread of parasite resistance to commonly used antimalarial drugs. There is both clinical experience and experimental evidence that, however effective when first introduced, the lifespan of drugs is inevitably curtailed by the emergence of resistant parasites. Resistance is the most important factor in determining the useful lifespan of antimalarial drugs. In this review, Nick White and Piero Olliaro discuss the rationale for combination chemotherapy.

Journal Article↗
PubMed1995

The plasmodium digestive vacuole: metabolic headquarters and choice drug target.

The Plasmodium digestive (food) vacuole is an acidic proteolytic compartment central to the metabolism of the parasite. Here haemoglobin is degraded, haem is polymerized, amino acid are transported, oxygen radicals are detoxified, drugs are accumulated, acidification is maintained and free iron may be generated. Despite these crucial roles in parasite development, a number of questions about the digestive vacuole and the haemoglobin ingestion pathway remain unanswered; in consequence, a number of attractive drug targets remain to be exploited. Piero Olliaro and Daniel Goldberg here review the morphology, metabolism and pharmacological disruption of this specialized organelle.

Journal Article↗
PubMed1995

A randomized, placebo-controlled trial in Tunisia treating cutaneous leishmaniasis with paromomycin ointment.

A randomized, placebo-controlled, double-blind trial was carried out in 1992 in central Tunisia to assess the tolerability and efficacy of paromomycin ointment against zoonotic cutaneous leishmaniasis caused by Leishmania major. One hundred fifteen patients, 2--60 years of age, with a single lesion of parasitologically confirmed cutaneous leishmaniasis, were included in the trial. The ointment was applied twice a day from day 1 through day 14. Clinical and parasitologic evaluations of lesions were done at days 0, 15, 45, and 105. Fifty-seven patients were allocated the treatment and 58 the placebo. Based on local toxicity and laboratory evaluation, there was no difference in tolerability between the two groups. Parasitologic evaluation at day 15 showed that 74.5% of the treated group had negative smears compared with 56.4% among controls (P = 0.06). This difference was no longer apparent at days 45 and 105. Clinical evaluation at days 15, 45, and 105 did not indicate any difference between the two groups. The clinical evaluation at day 15 was a good predictor of the final prognosis of the lesion in the two groups when analyzed separately, suggesting no clinical relapse in either group. These findings suggest that paromomycin ointment should not be used in the present formulation as a treatment for zoonotic cutaneous leishmaniasis in Tunisia.

Adolescent↗
PubMed1995

Status of antimalarial drugs under development.

Despite the urgent need of a new antimalarial drugs, particularly those against multiresistant falciparum malaria, only a limited number of drugs are now at an advanced stage of preclinical or clinical development. They include artemisinin derivatives, pyronaridine and benflumetol (all originally developed in China), as well as new antifolate combinations, the hydroxynaphoquinone atovaquone which has a novel mode of action, and a new 8-aminoquinoline which appears more active and less toxic than primaquine. Some of these drugs may become available in the next few years. It is therefore essential to find mechanisms to ensure that they are made available at an affordable price to the populations that really need them.

Antimalarials↗
PubMed1993

Practical progress and new drugs for changing patterns of leishmaniasis.

The problems surrounding leishmaniasis are changing. An increase in travel, the Indian and Sudanese epidemics of visceral leishmaniasis, parasite resistance to antimony and the emergence of AIDS-related leishmaniasis have all increased the urgency for new drugs, and led to reappraisals of the old ones, as discussed here by Piero Olliaro and Anthony Bryceson.

Journal Article↗
PubMedDate not supplied

Developing artemisinin based drug combinations for the treatment of drug resistant falciparum malaria: A review.

The emergence and spread of drug resistant malaria represents a considerable challenge to controlling malaria. To date, malaria control has relied heavily on a comparatively small number of chemically related drugs, belonging to either the quinoline or the antifolate groups. Only recently have the artemisinin derivatives been used but mostly in south east Asia. Experience has shown that resistance eventually curtails the life-span of antimalarial drugs. Controlling resistance is key to ensuring that the investment put into developing new antimalarial drugs is not wasted. Current efforts focus on research into new compounds with novel mechanisms of action, and on measures to prevent or delay resistance when drugs are introduced. Drug discovery and development are long, risky and costly ventures. Antimalarial drug development has traditionally been slow but now various private and public institutions are at work to discover and develop new compounds. Today, the antimalarial development pipeline is looking reasonably healthy. Most development relies on the quinoline, antifolate and artemisinin compounds. There is a pressing need to have effective, easy to use, affordable drugs that will last a long time. Drug combinations that have independent modes of action are seen as a way of enhancing efficacy while ensuring mutual protection against resistance. Most research work has focused on the use of artesunate combined with currently used standard drugs, namely, mefloquine, amodiaquine, sulfadoxine/pyrimethamine, and chloroquine. There is clear evidence that combinations improve efficacy without increasing toxicity. However, the absolute cure rates that are achieved by combinations vary widely and depend on the level of resistance of the standard drug. From these studies, further work is underway to produce fixed dose combinations that will be packaged in blister packs. This review will summarise current antimalarial drug developments and outline recent clinical research that aims to bring artemisinin based combinations to those that need them most.

Animals↗