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Biomedical subjects

P Olliaro

Publications and source records attributed to P Olliaro.

At least 19 recordsLinked to original sources
PubMed1999

A novel endogenous antimalarial: Fe(II)-protoporphyrin IX alpha (heme) inhibits hematin polymerization to beta-hematin (malaria pigment) and kills malaria parasites.

The polymerization of hemoglobin-derived ferric-protoporphyrin IX [Fe(III)PPIX] to inert hemozoin (malaria pigment) is a crucial and unique process for intraerythrocytic plasmodia to prevent heme toxicity and thus a good target for new antimalarials. Quinoline drugs, i.e., chloroquine, and non-iron porphyrins have been shown to block polymerization by forming electronic pi-pi interactions with heme monomers. Here, we report the identification of ferrous-protoporphyrin IX [Fe(II)PPIX] as a novel endogenous anti-malarial. Fe(II)PPIX molecules, released from the proteolysis of hemoglobin, are first oxidized and then polymerized to hemozoin. We obtained Fe(II)PPIX on preparative scale by electrochemical reduction of Fe(III)PPIX, and the reaction was monitored by cyclic voltammetry. Polymerization assays at acidic pH were conducted with the resulting Fe(II)PPIX using a spectrophotometric microassay of heme polymerization adapted to anaerobic conditions and the products characterized by infrared spectroscopy. Fe(II)PPIX (a) did not polymerize and (b) produced a dose-dependent inhibition of Fe(III)PPIX polymerization (IC(50) = 0.4 molar equiv). Moreover, Fe(II)PPIX produced by chemical reduction with thiol-containing compounds gave similar results: a dose-dependent inhibition of heme polymerization was observed using either L-cysteine, N-acetylcysteine, or DL-homocysteine, but not with L-cystine. Cyclic voltammetry confirmed that the inhibition of heme polymerization was due to the Fe(II)PPIX molecules generated by the thiol-mediated reduction of Fe(III)PPIX. These results point to Fe(II)PPIX as a potential endogenous antimalarial and to Fe(III)PPIX reduction as a potential new pharmacological target.

Animals↗
PubMed1999

Rapid absorption and clinical effectiveness of intragastric mefloquine in the treatment of cerebral malaria in African children.

To obviate the lack of injectable quinine in a hospital in rural Burundi, mefloquine, only available as an oral formulation, was administered (25 mg/kg bodyweight) as a single dose by nasogastric tube to four small children with cerebral malaria. All patients recovered uneventfully after a mean coma duration of 20.5 h. Mefloquine was rapidly absorbed and therapeutic serum concentrations were achieved within a few hours in all subjects, with parasite reduction ratios after 48 h within the expected range for drug-sensitive parasites. These findings suggest that intragastric mefloquine deserves consideration whenever parenteral drugs are not available for the treatment of cerebral malaria.

Absorption↗
PubMed1999

Tolerability of twice-weekly rifabutin-isoniazid combinations versus daily isoniazid for latent tuberculosis in HIV-infected subjects: a pilot study.

The tolerability of and adherence to intermittent short-term rifabutin-isoniazid preventive treatment was assessed in subjects dually infected with Mycobacterium tuberculosis and the human immunodeficiency virus (HIV). In a randomised, open-label, phase II pilot study, 44 subjects received either rifabutin 300 mg and isoniazid 750 mg twice weekly for 3 months (group A, n = 16) or the same regimen with rifabutin at 600 mg (group B, n = 14), or isoniazid 300 mg/day for 6 months (group C, n = 14). Three, two and four subjects in groups A, B, and C, respectively, did not complete their treatment (one case of flu-like syndrome in group B; one methadone withdrawal syndrome in group A; and patient decision in two cases in group A and four in group C). Overall, adverse events were reported by four, nine, and seven subjects in groups A, B and C, respectively. Intermittent combined rifabutin + isoniazid for 3 months had lower default rates than daily standard isoniazid for 6 months. The regimen with rifabutin at 300 mg dose compared favourably to standard isoniazid, and warrants larger efficacy studies to assess its role for the prevention of latent tuberculosis in HIV-infected subjects.

AIDS-Related Opportunistic Infections↗
PubMed1998

Macrophage populations of different origins have distinct susceptibilities to lipid peroxidation induced by beta-haematin (malaria pigment).

We investigated the susceptibility of peritoneal mouse macrophages and macrophage and microglia cell lines to the peroxidative activity of beta-haematin, the synthetic polymer identical to native malaria pigment. The extent of lipid peroxidation, measured as production of thiobarbituric acid reactive substances (TBARS), was greater for peritoneal macrophages than for cell lines and microglia cells. TBARS production apparently was not attributable to the release of free iron from the protoporphyrin moiety, but related to lower glutathione content and different lipid composition of the cell membrane. These findings offer a new interpretation for the contentious immunomodulatory effects of beta-haematin reported for phagocytes of different origins.

Animals↗
PubMed1998

Response of uncomplicated falciparum malaria to oral chloroquine and quinine in Burundi highlands.

The in vivo response of falciparum malaria to oral chloroquine and quinine was evaluated in two identical hospital-based, comparative open trials carried out 2 years apart in the same seasonal period at a hospital located in the highlands of Northern Burundi. Children aged 0-14 with uncomplicated falciparum malaria were administered either chloroquine, at 25 mg/kg over 3 days, or quinine, at 10 mg/kg per 8 hourly for 5 days (alternate allocation) and treatment response was evaluated by the WHO 7-day test. In the first study (1992/1993) 472 patients qualified for analyses (211 in the chloroquine and 261 in the quinine group), as compared to 249 subjects in the second study (1994/1995). In each study, the response to quinine was significantly higher than that to chloroquine (P = 0.004 and < 0.001, respectively). While the response to quinine showed insignificant changes over time (95.8 vs. 92.9%), chloroquine was found to be significantly less effective in the second study as compared to the first (77.8 vs. 63.1%; OR (95% CI) 2.04 (1.21-3.43)). Such decline in chloroquine efficacy was attributable to the age group < 5 years of age, where response to chloroquine decreased from 72.9% in 1992/93 to 56% in 1994/1995. Uncontrolled chloroquine use, which spread after the onset in late 1993 of the still ongoing ethnic fighting, appears to be the most likely reason for such a decrease in chloroquine efficacy. Chloroquine resistance has long been known to be present in the hyperendemic lowlands of Burundi, but no data have so far been reported on the response to antimalarials in the highlands of the country. These findings should be considered when deciding on drug policies for the treatment of falciparum malaria in Burundi.

Administration, Oral↗
PubMed1998

Randomised controlled trial of aminosidine (paromomycin) v sodium stibogluconate for treating visceral leishmaniasis in North Bihar, India.

OBJECTIVES: To assess the efficacy and tolerability of aminosidine compared with sodium stibogluconate for treating visceral leishmaniasis. DESIGN: Randomised, unblinded, controlled trial with 180 day follow up. SETTING: Kala-Azar Research Centre, Brahmpura, Muzaffarpur, Bihar, India. SUBJECTS: People of either sex aged 6-50 years with symptoms and signs suggestive of visceral leishmaniasis (fever, loss of appetite, enlarged spleen) with leishmania amastigotes detected in Giemsa stained aspirates of spleen or bone marrow. INTERVENTIONS: Aminosidine at three daily doses (12, 16, and 20 mg/kg) for 21 days and sodium stibogluconate 20 mg/kg/day for 30 days. MAIN OUTCOME MEASURES: Laboratory measures of efficacy: parasite count, haemoglobin concentration, white cell count, platelet count, serum albumin concentration. Clinical measures of efficacy: spleen size, fever, body weight, and liver size. Measures of safety: liver and renal function tests, reports of adverse events. RESULTS: Of the 120 patients enrolled (30 per treatment arm), 119 completed treatment and follow up. Cure at end of follow up was achieved in 23 (77%), 28 (93%), and 29 (97%) patients treated with 12, 16, and 20 mg aminosidine/kg/day respectively, and in 19 (63%) patients given sodium stibogluconate. At 16 and 20 mg/kg/day, aminosidine was significantly more active than sodium stibogluconate in both clinical and laboratory measures of efficacy. No significant clinical or laboratory toxicity occurred in any treatment group. CONCLUSIONS: A 21 day course of aminosidine 16 or 20 mg/kg/day should be considered as first line treatment for visceral leishmaniasis in Bihar.

Adolescent↗
PubMed1998

A microtitre-based method for measuring the haem polymerization inhibitory activity (HPIA) of antimalarial drugs.

The malaria parasite metabolizes haemoglobin and detoxifies the resulting haem by polymerizing it to form haemozoin (malaria pigment). A polymer identical to haemozoin, beta-haematin, can be obtained in vitro from haematin at acidic pH. Quinoline-containing anti-malarials (e.g. chloroquine) inhibit the formation of either polymer. Haem polymerization is an essential and unique pharmacological target. To identify molecules with haem polymerization inhibitory activity (HPIA) and quantify their potency, we developed a simple, inexpensive, quantitative in-vitro spectrophotometric microassay of haem polymerization. The assay uses 96-well U-bottomed polystyrene microplates and requires 24 h and a microplate reader. The relative amounts of polymerized and unpolymerized haematin are determined, based on solubility in DMSO, by measuring absorbance at 405 nm in the presence of test compounds as compared with untreated controls. The final product (a solid precipitate of polymerized haematin) was validated using infrared spectroscopy and the assay proved reproducible; in this assay, activity could be partly predicted based on the compound's chemical structure. Both water-soluble and water-insoluble compounds can be quantified by this method. Although the throughput of this assay is lower than that of radiometric methods, the assay is easier to set up and cheaper, and avoids the problems related to radioactive waste disposal.

Analysis of Variance↗
PubMed1998

Safety of artemisinin and its derivatives. A review of published and unpublished clinical trials.

The preliminary results of a clinical safety review that partly used the Cochrane methodology are presented. Despite methodological limitations including incomplete databases, this review collated evidence corroborating the benign safety profile of the artemisinin type of compounds. No difference was apparent amongst the various derivatives. At the time the workshop was held, 188 studies had been identified of which 108 (enrolling 9,241 patients) fulfilled criteria for analyses. These included both uncomplicated and severe malaria patients enrolled in either controlled and non-controlled studies as well as healthy volunteers. Safety was assessed by analysing adverse events, as well as clinical laboratory (haematology assessed in 4,062, blood chemistry in 3,893 patients), electrocardiographic (2638 patients) and neurological assessments as reported in the papers. No serious adverse event or severe significant toxicity was reported. Overall, the most commonly reported adverse experiences were gastro-intestinal. Occasional neutropenia (1.3%), reticulocytopenia (0.6%), elevated liver enzymes (0.9%) were reported. Transient bradycardia and prolonged QT interval were reported in circa 1.1% of patients monitored. A neurological assessment was performed primarily in the severe malaria patients. No difference was apparent with respect to quinine. In addition, four cases of neuropsychiatric adverse events were reported in patients receiving concomitant mefloquine.

Adverse Drug Reaction Reporting Systems↗
PubMed1998

Artemisinin and derivatives in the treatment of uncomplicated malaria.

Artemisinin and its derivatives are the most rapidly acting antimalarials known to-date and are well-tolerated. All derivatives in use today are produced by semi-synthesis from artemisinin: dihydroartemisinin is the product of the first step; more synthetic steps give rise to artesunate, artemether and arteether which are metabolised back to dihydroartemisinin in the body. Although their residence in the body after oral administration is very short (with half-lives of < 2 hours), they can be administered once daily. By acting on ring stages, they clear peripheral parasitaemia more quickly than other antimalarial drugs and prevent the development into mature sequestering blood stages. They are effective against all human malaria parasites, notably multidrug-resistant Plasmodium falciparum. They have anti-transmission properties, too. So far, resistance to this class of compounds has not been reported. However, when used alone, they require long treatment courses (7 days). So, combination with long-half life drugs such as mefloquine appears to be the best approach to mutually protect both drugs against resistance. While reported in experimental animals, there is no evidence neurotoxicity in human beings. Whether such event could occur after continuous or discontinuous use is not clear.

Administration, Oral↗
PubMed1998

Treatment of uncomplicated malaria with artemisinin derivatives. A systematic review of randomised controlled trials.

This systematic review of randomised or pseudorandomised trials was aimed at summarising the effectiveness and safety of artemisinin drugs for treating uncomplicated falciparum malaria. Ninety-three potentially eligible studies were identified and 38 met the inclusion criteria. Most data are from Southeast Asian areas of mefloquine-resistant falciparum malaria, Thailand in particular. Artemisinin drugs achieve high cure rates at follow-up in all endemic areas represented by the studies included provided that the duration of treatment is adequate. Combination with mefloquine improves sustained parasite clearance and is effective in multidrug resistant areas. Provided the dose of both drugs is adequate, the combination can shorten the duration of treatment. There is no evidence from randomised trials that any artemisinin derivative is better than the others. Data from just over 4,300 patients are included for analysis in this review. Despite the large amount of clinical research that has been done, variation in study design, quality and comparisons make synthesis of the data problematic. It is extremely difficult to draw clear conclusions from the existing database.

Adult↗
PubMed1998

Treatment of severe malaria with artemisinin derivatives. A systematic review of randomised controlled trials.

This systematic review of randomised or pseudorandomised trials aimed at summarising the effectiveness and safety of artemisinin drugs for treating severe falciparum malaria in adults and children. Survival was better with artemisinin drugs in 1.265 patients compared with 1.183 treated with quinine (OR: 0.68; 95% CI: 0.55-0.84). However, the difference is barely significant when only studies with adequate concealment of allocation at enrolment are included in the analysis (OR: 0.77; 95% CI: 0.61-0.98). In 1784 patients with cerebral malaria, mortality was also lower with artemisinin drugs overall (OR: 0.70; 95% CI: 0.55-0.90), but not significantly better than quinine in studies reporting adequate concealment of allocation. No difference in neurological sequelae has been demonstrated. Artemisinin drugs clear parasites from the blood faster than quinine. Adverse effects are similarly common with artemisinin drugs and quinine, although reporting varies between trials. There is no evidence from this review that any one artemisinin derivative is better than the others, but comparative studies are few, small and heterogeneous.

Adult↗
PubMed1998

What role can public health institutions play in drug development for the poor? A case study of artesunate.

Although the strategy of artesunate development was orchestrated from within WHO's Special Programme for Research and Training in Tropical Diseases, it relies heavily upon an alliance of scientist, laboratories, industry, regulators and ministries of health to ensure the public health outcome. This development strategy has transformed the way in which WHO does business, both within and outside the Organization. In essence, each and every player has rallied in the challenge to reduce the discrepancy between need and availability of a drug that can has the potential to reduce mortality form the disease.

Africa↗
PubMed1997

Non-iron porphyrins inhibit beta-haematin (malaria pigment) polymerisation.

Infrared spectroscopy was used to evaluate the effect of non-iron porphyrins (protoporphyrin IX and haematoporphyrin) on haematin polymerisation to beta-haematin at acidic pH. Both molecules effectively inhibited the reaction, with haematoporphyrin 6 times as active as protoporphyrin IX. We postulated that the interaction between the pi electron system of porphyrin rings leads to the formation of pi-pi adducts, which inhibit polymer elongation in the same way as antimalarial drugs (e.g., chloroquine); the presence of hydroxyl groups able to bind haem iron enhances activity.

Antimalarials↗
PubMed1997

Plasmodium falciparum: an electronmicroscopy study of caveolae and trafficking between the parasite and the extracellular medium.

Caveolae containing grape-like tubulovesicular structures were observed in the cytoplasm and in the parasitophorous vacuole of ring- and trophozoite-stage Plasmodium falciparum parasites. In appliqué-forms intact caveolae and free vesicles were also seen to bud off the surface of infected erythrocytes directly from the parasitophorous vacuole where the parasite was in close vicinity to the host cell membrane. The mean vesicle diameter was 0.08-0.1 micron. No such structure was observed in schizonts, segmenters or in the cytoplasm of infected or uninfected erythrocytes. These structures may represent morphological evidence in P. falciparum of a "window" through which the parasite would have direct access to the extracellular milieu. They may constitute carrier vesicles containing parasite membrane transport molecules possibly involved in malaria pathogenesis and/or immunity.

Animals↗