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1. Randomized, open-label, phase 2a study to evaluate the contribution of artefenomel to the clinical and parasiticidal activity of artefenomel plus ferroquine in African patients with uncomplicated Plasmodium falciparum malaria

Author

Gansane, Adama, Lingani, Moussa, Yeka, Adoke, Nahum, Alain, Bouyou-Akotet, Marielle, Mombo-Ngoma, Ghyslain, Kaguthi, Grace, Barceló, Catalina, Laurijssens, Bart, Cantalloube, Cathy, Macintyre, Fiona, Djeriou, Elhadj, Jessel, Andreas, Bejuit, Raphaël, Demarest, Helen, Marrast, Anne Claire, Debe, Siaka, Tinto, Halidou, Kibuuka, Afizi, Nahum, Diolinda, Mawili-Mboumba, Denise Patricia, Zoleko-Manego, Rella, Mugenya, Irene, Olewe, Frederick, Duparc, Stephan, and Ogutu, Bernhards

Published
2023
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5. Additional file 1 of Randomized, open-label, phase 2a study to evaluate the contribution of artefenomel to the clinical and parasiticidal activity of artefenomel plus ferroquine in African patients with uncomplicated Plasmodium falciparum malaria

Author

Gansane, Adama, Lingani, Moussa, Yeka, Adoke, Nahum, Alain, Bouyou-Akotet, Marielle, Mombo-Ngoma, Ghyslain, Kaguthi, Grace, Barceló, Catalina, Laurijssens, Bart, Cantalloube, Cathy, Macintyre, Fiona, Djeriou, Elhadj, Jessel, Andreas, Bejuit, Raphaël, Demarest, Helen, Marrast, Anne Claire, Debe, Siaka, Tinto, Halidou, Kibuuka, Afizi, Nahum, Diolinda, Mawili-Mboumba, Denise Patricia, Zoleko-Manego, Rella, Mugenya, Irene, Olewe, Frederick, Duparc, Stephan, and Ogutu, Bernhards

Abstract

Additional file 1: Study protocol.

Published
2023
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6. Additional file 2 of Randomized, open-label, phase 2a study to evaluate the contribution of artefenomel to the clinical and parasiticidal activity of artefenomel plus ferroquine in African patients with uncomplicated Plasmodium falciparum malaria

Author

Gansane, Adama, Lingani, Moussa, Yeka, Adoke, Nahum, Alain, Bouyou-Akotet, Marielle, Mombo-Ngoma, Ghyslain, Kaguthi, Grace, Barceló, Catalina, Laurijssens, Bart, Cantalloube, Cathy, Macintyre, Fiona, Djeriou, Elhadj, Jessel, Andreas, Bejuit, Raphaël, Demarest, Helen, Marrast, Anne Claire, Debe, Siaka, Tinto, Halidou, Kibuuka, Afizi, Nahum, Diolinda, Mawili-Mboumba, Denise Patricia, Zoleko-Manego, Rella, Mugenya, Irene, Olewe, Frederick, Duparc, Stephan, and Ogutu, Bernhards

Abstract

Additional file 2: Clinical trial simulation to determine the dose and sample sizes.

Published
2023
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7. Additional file 5 of Randomized, open-label, phase 2a study to evaluate the contribution of artefenomel to the clinical and parasiticidal activity of artefenomel plus ferroquine in African patients with uncomplicated Plasmodium falciparum malaria

Author

Gansane, Adama, Lingani, Moussa, Yeka, Adoke, Nahum, Alain, Bouyou-Akotet, Marielle, Mombo-Ngoma, Ghyslain, Kaguthi, Grace, Barceló, Catalina, Laurijssens, Bart, Cantalloube, Cathy, Macintyre, Fiona, Djeriou, Elhadj, Jessel, Andreas, Bejuit, Raphaël, Demarest, Helen, Marrast, Anne Claire, Debe, Siaka, Tinto, Halidou, Kibuuka, Afizi, Nahum, Diolinda, Mawili-Mboumba, Denise Patricia, Zoleko-Manego, Rella, Mugenya, Irene, Olewe, Frederick, Duparc, Stephan, and Ogutu, Bernhards

Abstract

Additional file 5. Supplementary tables and figures.

Published
2023
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8. Additional file 4 of Randomized, open-label, phase 2a study to evaluate the contribution of artefenomel to the clinical and parasiticidal activity of artefenomel plus ferroquine in African patients with uncomplicated Plasmodium falciparum malaria

Author

Gansane, Adama, Lingani, Moussa, Yeka, Adoke, Nahum, Alain, Bouyou-Akotet, Marielle, Mombo-Ngoma, Ghyslain, Kaguthi, Grace, Barceló, Catalina, Laurijssens, Bart, Cantalloube, Cathy, Macintyre, Fiona, Djeriou, Elhadj, Jessel, Andreas, Bejuit, Raphaël, Demarest, Helen, Marrast, Anne Claire, Debe, Siaka, Tinto, Halidou, Kibuuka, Afizi, Nahum, Diolinda, Mawili-Mboumba, Denise Patricia, Zoleko-Manego, Rella, Mugenya, Irene, Olewe, Frederick, Duparc, Stephan, and Ogutu, Bernhards

Abstract

Additional file 4: Exposure–response pharmacokinetic/pharmacodynamic analysis.

Published
2023
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12. Additional file 1 of A randomized, double-blind, phase 2b study to investigate the efficacy, safety, tolerability and pharmacokinetics of a single-dose regimen of ferroquine with artefenomel in adults and children with uncomplicated Plasmodium falciparum malaria

Author

Adoke, Yeka, Zoleko-Manego, Rella, Ouoba, Serge, Tiono, Alfred B., Kaguthi, Grace, Juvêncio Eduardo Bonzela, Duong, Tran Thanh, Nahum, Alain, Bouyou-Akotet, Marielle, Bernhards Ogutu, Ouedraogo, Alphonse, Macintyre, Fiona, Jessel, Andreas, Laurijssens, Bart, Cherkaoui-Rbati, Mohammed H., Cantalloube, Cathy, Marrast, Anne Claire, Bejuit, Raphaël, White, David, Wells, Timothy N. C., Wartha, Florian, Leroy, Didier, Afizi Kibuuka, Mombo-Ngoma, Ghyslain, Ouattara, Daouda, Mugenya, Irène, Bui Quang Phuc, Bohissou, Francis, Mawili-Mboumba, Denise P., Olewe, Fredrick, Issiaka Soulama, and Halidou Tinto

Abstract

Additional file 1. Study methods. Supplementary information regarding enrolment procedures, randomization, administration of study treatments, justification of the doses of ferroquine and artefenomel, dose adjustment to body weight, use of rescue treatment and definition of treatment failure.

Published
2021
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13. Additional file 2 of A randomized, double-blind, phase 2b study to investigate the efficacy, safety, tolerability and pharmacokinetics of a single-dose regimen of ferroquine with artefenomel in adults and children with uncomplicated Plasmodium falciparum malaria

Author

Adoke, Yeka, Zoleko-Manego, Rella, Ouoba, Serge, Tiono, Alfred B., Kaguthi, Grace, Juvêncio Eduardo Bonzela, Duong, Tran Thanh, Nahum, Alain, Bouyou-Akotet, Marielle, Bernhards Ogutu, Ouedraogo, Alphonse, Macintyre, Fiona, Jessel, Andreas, Laurijssens, Bart, Cherkaoui-Rbati, Mohammed H., Cantalloube, Cathy, Marrast, Anne Claire, Bejuit, Raphaël, White, David, Wells, Timothy N. C., Wartha, Florian, Leroy, Didier, Afizi Kibuuka, Mombo-Ngoma, Ghyslain, Ouattara, Daouda, Mugenya, Irène, Bui Quang Phuc, Bohissou, Francis, Mawili-Mboumba, Denise P., Olewe, Fredrick, Issiaka Soulama, and Halidou Tinto

Abstract

Additional file 2. Study results. Supplementary data regarding patient demographics, baseline characteristics, compliance/exposure, as well as further efficacy and safety data.

Published
2021
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14. Additional file 4 of A randomized, double-blind, phase 2b study to investigate the efficacy, safety, tolerability and pharmacokinetics of a single-dose regimen of ferroquine with artefenomel in adults and children with uncomplicated Plasmodium falciparum malaria

Author

Adoke, Yeka, Zoleko-Manego, Rella, Ouoba, Serge, Tiono, Alfred B., Kaguthi, Grace, Juvêncio Eduardo Bonzela, Duong, Tran Thanh, Nahum, Alain, Bouyou-Akotet, Marielle, Bernhards Ogutu, Ouedraogo, Alphonse, Macintyre, Fiona, Jessel, Andreas, Laurijssens, Bart, Cherkaoui-Rbati, Mohammed H., Cantalloube, Cathy, Marrast, Anne Claire, Bejuit, Raphaël, White, David, Wells, Timothy N. C., Wartha, Florian, Leroy, Didier, Afizi Kibuuka, Mombo-Ngoma, Ghyslain, Ouattara, Daouda, Mugenya, Irène, Bui Quang Phuc, Bohissou, Francis, Mawili-Mboumba, Denise P., Olewe, Fredrick, Issiaka Soulama, and Halidou Tinto

Abstract

Additional file 4. Exposure–response analysis details. Supplementary document including tables and figures to provide further methodological details and results on the exposure–response analysis.

Published
2021
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15. Additional file 3 of A randomized, double-blind, phase 2b study to investigate the efficacy, safety, tolerability and pharmacokinetics of a single-dose regimen of ferroquine with artefenomel in adults and children with uncomplicated Plasmodium falciparum malaria

Author

Adoke, Yeka, Zoleko-Manego, Rella, Ouoba, Serge, Tiono, Alfred B., Kaguthi, Grace, Juvêncio Eduardo Bonzela, Duong, Tran Thanh, Nahum, Alain, Bouyou-Akotet, Marielle, Bernhards Ogutu, Ouedraogo, Alphonse, Macintyre, Fiona, Jessel, Andreas, Laurijssens, Bart, Cherkaoui-Rbati, Mohammed H., Cantalloube, Cathy, Marrast, Anne Claire, Bejuit, Raphaël, White, David, Wells, Timothy N. C., Wartha, Florian, Leroy, Didier, Afizi Kibuuka, Mombo-Ngoma, Ghyslain, Ouattara, Daouda, Mugenya, Irène, Bui Quang Phuc, Bohissou, Francis, Mawili-Mboumba, Denise P., Olewe, Fredrick, Issiaka Soulama, and Halidou Tinto

Abstract

Additional file 3. Pharmacokinetic analysis details. Supplementary document including tables and figures to provide further methodological details and results on the pharmacokinetic analysis.

Published
2021
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16. Additional file 5 of A randomized, double-blind, phase 2b study to investigate the efficacy, safety, tolerability and pharmacokinetics of a single-dose regimen of ferroquine with artefenomel in adults and children with uncomplicated Plasmodium falciparum malaria

Author

Adoke, Yeka, Zoleko-Manego, Rella, Ouoba, Serge, Tiono, Alfred B., Kaguthi, Grace, Juvêncio Eduardo Bonzela, Duong, Tran Thanh, Nahum, Alain, Bouyou-Akotet, Marielle, Bernhards Ogutu, Ouedraogo, Alphonse, Macintyre, Fiona, Jessel, Andreas, Laurijssens, Bart, Cherkaoui-Rbati, Mohammed H., Cantalloube, Cathy, Marrast, Anne Claire, Bejuit, Raphaël, White, David, Wells, Timothy N. C., Wartha, Florian, Leroy, Didier, Afizi Kibuuka, Mombo-Ngoma, Ghyslain, Ouattara, Daouda, Mugenya, Irène, Bui Quang Phuc, Bohissou, Francis, Mawili-Mboumba, Denise P., Olewe, Fredrick, Issiaka Soulama, and Halidou Tinto

Subjects
cardiovascular diseases
Abstract

Additional file 5. Electrocardiogram (ECG) exposure–response analysis details. Supplementary document including tables and figures to provide further methodological details and results on the ECG exposure–response analysis.

Published
2021
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19. Unanticipated CNS Safety Signal in a Placebo‐Controlled, Randomized Trial of Co‐Administered Atovaquone‐Proguanil and Amodiaquine.

Author

Chalon, Stephan, Chughlay, M. Farouk, Abla, Nada, Marie Tchouatieu, Andre, Haouala, Amina, Hutter, Ben, Lorch, Ulrike, and Macintyre, Fiona

Subjects
CYTOCHROME P-450, AFRICANS, BLACK Africans, MALARIA, CHEMOPREVENTION, DENTAL prophylaxis
Abstract

Atovaquone‐proguanil (ATV‐PG) plus amodiaquine (AQ) has been considered as a potential replacement for sulfadoxine‐pyrimethamine plus AQ for seasonal malaria chemoprevention in African children. This randomized, double‐blind, placebo‐controlled, parallel group study assessed the safety, tolerability, and pharmacokinetics (PKs) of ATV‐PG plus AQ in healthy adult males and females of Black sub‐Saharan African origin. Participants were randomized to four treatment groups: ATV‐PG/AQ (n = 8), ATV‐PG/placebo (n = 12), AQ/placebo (n = 12), and placebo/placebo (n = 12). Treatments were administered orally once daily for 3 days (days 1–3) at daily doses of ATV‐PQ 1000/400 mg and AQ 612 mg. Co‐administration of ATV‐PG/AQ had no clinically relevant effect on PK parameters for ATV, PG, the PG metabolite cycloguanil, AQ, or the AQ metabolite N‐desethyl‐amodiaquine. Adverse events occurred in 8 of 8 (100%) of participants receiving ATV‐PG/AQ, 11 of 12 (91.7%) receiving ATV‐PG, 11 of 12 (91.7%) receiving AQ, and 3 of 12 (25%) receiving placebo. The safety and tolerability profiles of ATV‐PG and AQ were consistent with previous reports. In the ATV‐PG/AQ group, 2 of 8 participants experienced extrapyramidal adverse effects (EPAEs) on day 3, both psychiatric and physical, which appeared unrelated to drug plasma PKs or cytochrome P450 2C8 phenotype. Although rare cases are reported with AQ administration, the high incidence of EPAE was unexpected in this small study. Owing to the unanticipated increased frequency of EPAE observed, the combination of ATV‐PQ plus AQ is not recommended for further evaluation in prophylaxis of malaria in African children. [ABSTRACT FROM AUTHOR]

Published
2022
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20. Cyclosporine and drug metabolism

Author

Macintyre, Fiona

Subjects
615.1
Abstract

Cyclosporine (CsA) (50mg/kg daily) for 0 - 14 days caused reductions in cytochrome p-450-dependent monooxygenase activities, phase II drug metabolising enzyme activities and non-drug metabolising enzyme activities in male Sprague-Dawley rats, which appeared to be self-limiting. The chronologies and extents of these reductions varied. Decreased monooxygenase activities were accompanied by decreased NADPH-cytochrome c-reductase activities. No isozyme-specific effect was evident and there was no direct correlation of drug metabolising activities with nephrotoxicity (which was progressive). The wide-ranging effects of CsA on membrane-bound drug and non-drug metabolising enzyme activities suggests an effect on membrane properties may be responsible. CsA did not decrease cytochrome P-450-dependent monooxygenase activities in female rats, nor was there any visual signs of CsA toxicity. A method for in vitro generation of CsA metabolites, a solvent extraction system and an HPLC system for separation of the metabolites was undertaken. The metabolite profiles produced on incubation of CsA with liver microsomes prepared from untreated and CsA-pretreated rats, rats pretreated with inducers of cytochrome P-450 (Phenobarbitone (PB), 3-methylcholanthrene (3-MC) and pregnenelone 16 -carbonitrile (PCN)) and human microsomes were compared. Michaelis-Menten kinetics for CsA disappearance were calculated. All microsome types metabolised CsA with the exception of CsA-pretreated rats. Biphasic kinetics were produced by orally dosed PB-induced microsomes, PCN-induced, control rat microsomes and human microsomes. Monophasic kinetics were obtained for a further orally dosed PB-induced microsome sample and PB (80mg/kg ip). CsA metabolism was induced 2.5 - 3.0 fold by PB and PCN microsomes compared with control rat microsomes. Human microsomes metabolised CsA faster than all rat microsomes. Metabolite 1 was the major metabolite produced by all microsome types. Only low levels of secondary and tertiary metabolites were produced by rat microsomes, even when sufficient levels of primary metabolites were present, suggesting that CsA and its metabolites may be metabolised by the same enzyme. Metabolites 17 and 18 were produced by all microsome types. Metabolites B and 21 were produced only by PB and PCN-induced rat microsomes and by human microsomes.

Published
1988

21. A randomized, double-blind, phase 2b study to investigate the efficacy, safety, tolerability and pharmacokinetics of a single-dose regimen of ferroquine with artefenomel in adults and children with uncomplicated Plasmodium falciparum malaria.

Author

Adoke, Yeka, Zoleko-Manego, Rella, Ouoba, Serge, Tiono, Alfred B., Kaguthi, Grace, Bonzela, Juvêncio Eduardo, Duong, Tran Thanh, Nahum, Alain, Bouyou-Akotet, Marielle, Ogutu, Bernhards, Ouedraogo, Alphonse, Macintyre, Fiona, Jessel, Andreas, Laurijssens, Bart, Cherkaoui-Rbati, Mohammed H., Cantalloube, Cathy, Marrast, Anne Claire, Bejuit, Raphaël, White, David, and Wells, Timothy N. C.

Subjects
PLASMODIUM falciparum, MALARIA, AFRICANS, PHARMACOKINETICS, CONFIDENCE intervals
Abstract

Background: For uncomplicated Plasmodium falciparum malaria, highly efficacious single-dose treatments are expected to increase compliance and improve treatment outcomes, and thereby may slow the development of resistance. The efficacy and safety of a single-dose combination of artefenomel (800 mg) plus ferroquine (400/600/900/1200 mg doses) for the treatment of uncomplicated P. falciparum malaria were evaluated in Africa (focusing on children ≤ 5 years) and Asia. Methods: The study was a randomized, double-blind, single-dose, multi-arm clinical trial in patients aged > 6 months to < 70 years, from six African countries and Vietnam. Patients were followed up for 63 days to assess treatment efficacy, safety and pharmacokinetics. The primary efficacy endpoint was the polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response (ACPR) at Day 28 in the Per-Protocol [PP] Set comprising only African patients ≤ 5 years. The exposure–response relationship for PCR-adjusted ACPR at Day 28 and prevalence of kelch-13 mutations were explored. Results: A total of 373 patients were treated: 289 African patients ≤ 5 years (77.5%), 64 African patients > 5 years and 20 Asian patients. None of the treatment arms met the target efficacy criterion for PCR-adjusted ACPR at Day 28 (lower limit of 95% confidence interval [CI] > 90%). PCR-adjusted ACPR at Day 28 [95% CI] in the PP Set ranged from 78.4% [64.7; 88.7%] to 91.7% [81.6; 97.2%] for the 400 mg to 1200 mg ferroquine dose. Efficacy rates were low in Vietnamese patients, ranging from 20 to 40%. A clear relationship was found between drug exposure (artefenomel and ferroquine concentrations at Day 7) and efficacy (primary endpoint), with higher concentrations of both drugs resulting in higher efficacy. Six distinct kelch-13 mutations were detected in parasite isolates from 10/272 African patients (with 2 mutations known to be associated with artemisinin resistance) and 18/20 Asian patients (all C580Y mutation). Vomiting within 6 h of initial artefenomel administration was common (24.6%) and associated with lower drug exposures. Conclusion: The efficacy of artefenomel/ferroquine combination was suboptimal in African children aged ≤ 5 years, the population of interest, and vomiting most likely had a negative impact on efficacy. Trial registration ClinicalTrials.gov, NCT02497612. Registered 14 Jul 2015, https://clinicaltrials.gov/ct2/show/NCT02497612?term=NCT02497612&draw=2&rank=1 [ABSTRACT FROM AUTHOR]

Published
2021
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22. A randomised, double-blind clinical phase II trial of the efficacy, safety, tolerability and pharmacokinetics of a single dose combination treatment with artefenomel and piperaquine in adults and children with uncomplicated Plasmodium falciparum malaria

Author

Macintyre, Fiona, Adoke, Yeka, Tiono, Alfred B., Duong, Tran T., Mombo-Ngoma, Ghyslain, Bouyou-Akotet, Marielle, Tinto, Halidou, Bassat Orellana, Quique, Issifou, Saadou, Adamy, Marc, Demarest, Helen, Duparc, Stephan, Leroy, Didier, Laurijssens, Bart E., Biguenet, Sophie, Kibuuka, Afizi, Tshefu, Antoinette, Smith, Melnick, Foster, Chanelle, Leipoldt, Illse, Kremsner, Peter G., Phuc, Bui Q., Ouedraogo, Alphonse, Ramharter, Michael, and OZ-Piperaquine Study Group

Subjects
Male, Artefenomel, lcsh:Medicine, modelling and simulation, Pharmacokinetics, Phase II B, Tratamiento médico, 0302 clinical medicine, 030212 general & internal medicine, Malaria, Falciparum, Young adult, Child, Children, Enfermedades infecciosas en niños, education.field_of_study, biology, General Medicine, Middle Aged, OZ439, Artemisinins, 3. Good health, Piperaquine, Treatment Outcome, Tolerability, Child, Preschool, Quinolines, Drug Therapy, Combination, Female, Uncomplicated Plasmodium falciparum malaria, Research Article, Adult, medicine.medical_specialty, Adolescent, Plasmodium falciparum, 030231 tropical medicine, Population, Malària, Paludismo, Antimalarials, Young Adult, 03 medical and health sciences, Asian People, Double-Blind Method, Internal medicine, parasitic diseases, medicine, Humans, Single dose combination treatment, education, Antipalúdicos--Ensayos clínicos, Dose-Response Relationship, Drug, business.industry, lcsh:R, Infant, medicine.disease, biology.organism_classification, Surgery, Malaria, Africa, Dose–response, business
Abstract

Background The clinical development of a single encounter treatment for uncomplicated malaria has the potential to significantly improve the effectiveness of antimalarials. Exploratory data suggested that the combination of artefenomel and piperaquine phosphate (PQP) has the potential to achieve satisfactory cure rates as a single dose therapy. The primary objective of the study was to determine whether a single dose of artefenomel (800 mg) plus PQP in ascending doses is an efficacious treatment for uncomplicated Plasmodium falciparum malaria in the 'target' population of children ≤ 5 years of age in Africa as well as Asian patients of all ages. Methods Patients in six African countries and in Vietnam were randomised to treatment with follow-up for 42–63 days. Efficacy, tolerability, safety and pharmacokinetics were assessed. Additional key objectives were to characterise the exposure–response relationship for polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response at day 28 post-dose (ACPR28) and to further investigate Kelch13 mutations. Patients in Africa (n = 355) and Vietnam (n = 82) were included, with 85% of the total population being children 95% PCR-adjusted ACPR at day 28. Achieving very high efficacy following single dose treatment is challenging, since > 95% of the population must have sufficient concentrations to achieve cure across a range of parasite sensitivities and baseline parasitaemia levels. While challenging, the development of tools suitable for deployment as single encounter curative treatments for adults and children in Africa and to support elimination strategies remains a key development goal. Trial registration ClinicalTrials.gov, NCT02083380. Registered on 7 March 2014. Electronic supplementary material The online version of this article (doi:10.1186/s12916-017-0940-3) contains supplementary material, which is available to authorized users.

Published
2017

23. Additional file 2: S2. of A randomised, double-blind clinical phase II trial of the efficacy, safety, tolerability and pharmacokinetics of a single dose combination treatment with artefenomel and piperaquine in adults and children with uncomplicated Plasmodium falciparum malaria

Author

Macintyre, Fiona, Yeka Adoke, Tiono, Alfred, Duong, Tran, Mombo-Ngoma, Ghyslain, Bouyou-Akotet, Marielle, Halidou Tinto, Bassat, Quique, Saadou Issifou, Adamy, Marc, Demarest, Helen, Duparc, Stephan, Leroy, Didier, Laurijssens, Bart, Biguenet, Sophie, Afizi Kibuuka, Tshefu, Antoinette, Melnick Smith, Foster, Chanelle, Illse Leipoldt, Kremsner, Peter, Bui Phuc, Ouedraogo, Alphonse, and Ramharter, Michael

Abstract

Statistical analysis plan. (PDF 1515 kb)

Published
2017
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24. Additional file 3: S3. of A randomised, double-blind clinical phase II trial of the efficacy, safety, tolerability and pharmacokinetics of a single dose combination treatment with artefenomel and piperaquine in adults and children with uncomplicated Plasmodium falciparum malaria

Author

Macintyre, Fiona, Yeka Adoke, Tiono, Alfred, Duong, Tran, Mombo-Ngoma, Ghyslain, Bouyou-Akotet, Marielle, Halidou Tinto, Bassat, Quique, Saadou Issifou, Adamy, Marc, Demarest, Helen, Duparc, Stephan, Leroy, Didier, Laurijssens, Bart, Biguenet, Sophie, Afizi Kibuuka, Tshefu, Antoinette, Melnick Smith, Foster, Chanelle, Illse Leipoldt, Kremsner, Peter, Bui Phuc, Ouedraogo, Alphonse, and Ramharter, Michael

Abstract

Pharmacokinetic analysis details. (DOCX 689 kb)

Published
2017
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25. Additional file 4: S4. of A randomised, double-blind clinical phase II trial of the efficacy, safety, tolerability and pharmacokinetics of a single dose combination treatment with artefenomel and piperaquine in adults and children with uncomplicated Plasmodium falciparum malaria

Author

Macintyre, Fiona, Yeka Adoke, Tiono, Alfred, Duong, Tran, Mombo-Ngoma, Ghyslain, Bouyou-Akotet, Marielle, Halidou Tinto, Bassat, Quique, Saadou Issifou, Adamy, Marc, Demarest, Helen, Duparc, Stephan, Leroy, Didier, Laurijssens, Bart, Biguenet, Sophie, Afizi Kibuuka, Tshefu, Antoinette, Melnick Smith, Foster, Chanelle, Illse Leipoldt, Kremsner, Peter, Bui Phuc, Ouedraogo, Alphonse, and Ramharter, Michael

Abstract

Exposureâ response analysis details. (DOCX 269 kb)

Published
2017
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29. Antimalarial activity of artefenomel (OZ439), a novel synthetic antimalarial endoperoxide, in patients with Plasmodium falciparum and Plasmodium vivax malaria: an open-label phase 2 trial

Author

Phyo, Aung Pyae, primary, Jittamala, Podjanee, additional, Nosten, François H, additional, Pukrittayakamee, Sasithon, additional, Imwong, Mallika, additional, White, Nicholas J, additional, Duparc, Stephan, additional, Macintyre, Fiona, additional, Baker, Mark, additional, and Möhrle, Jörg J, additional

Published
2016
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30. SAR of a series of inhaled A2A agonists and comparison of inhaled pharmacokinetics in a preclinical model with clinical pharmacokinetic data

Author

Mantell, Simon J., Stephenson, Peter T., Monaghan, Sandra M., Maw, Graham N., Trevethick, Michael A., Yeadon, Michael, Walker, Don K., Selby, Matthew D., Batchelor, David V., Rozze, Stuart, Chavaroche, Helene, Lemaitre, Arnaud, Wright, Karen N., Whitlock, Lynsey, Stuart, Emilio F., Wright, Patricia A., and Macintyre, Fiona

Published
2009
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35. Wrong comparison at Ebury

Author

MacIntyre, Fiona

Subjects
Lonely Planet, Ebury Press, Book publishing -- Analysis, Publishing industry -- Analysis, Business, international, Publishing industry, Retail industry, Analysis
Abstract

Last Friday's Bookseller quoted Stephen Mesquita stating: 'Some publishers are much more lavish on discounting than others. Berlitz's average discounting was just 2% compared to 20% at Ebury'. The Ebury [...]

Published
2009

37. Synthesis of Ultrahigh Surface Area Monodisperse Porous Polymer Nanospheres

Author

S. Macintyre, Fiona, C. Sherrington, David, and Tetley, Laurence

Abstract

Synthesis of vinyl benzyl chloride (VBC)/divinylbenzene (DVB) copolymers via surfactant-free emulsion polymerization yields near monodisperse chloromethylated polystyrene precursor nanospheres ∼400 nm in diameter. These are analogous to gel-type suspension polymerized particles typically of ∼100−500 m in diameter and are essentially nonporous in the dry state having only a very nominal surface area (∼10 m2g-1). Cross-linking of appropriate dichloroethane swollen precursors with a high content of VBC residues in the presence of FeCl3(i.e., using a Davankov-type strategy) yields near monodisperse porous hyper-cross-linked nanoparticles with extremely high surface areas up to ∼1200 m2g-1. The latter display all the characteristics of Davakov-type resins in terms of their ability to sorb both thermodynamically “poor” and “good” solvents and in particular despite their superficial hydrophobic makeup are able to sorb significant quantities of water (up to ∼2.5 g/g). By adjusting the content of VBC in the precursor particles, the surface area of the near monodisperse nanoparticles can be adjusted in the range ∼15−1300 m2g-1.

Published
2006
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38. Control of Porous Morphology in Suspension Polymerized Poly(divinylbenzene) Resins Using Oligomeric Porogens

Author

S. Macintyre, Fiona and C. Sherrington, David

Abstract

Porous poly(divinylbenzene) (DVB) resins have been prepared using suspension polymerization with toluene and an oligomer as coporogens. The oligomers investigated were poly(propylene glycol) 1000 (PPG 1000), poly(propylene glycol) 4000 (PPG 4000), and poly(dimethylsiloxane) (PDMS). The porogen was used in a 1/1 vol/vol ratio with DVB, and with each oligomeric coporogen the full compositional range 100 vol % toluene to 100 vol % oligomer was examined. As predicted from previous knowledge of the effect of different solvent porogens, toluene yielded a highly microporous resin with a large dry state surface area (∼650 m2g-1), whereas each oligomeric porogen yielded a highly macroporous resin with rather low surface area ∼15−50 m2g-1. Using mixtures of toluene and oligomer as coporogens, we speculated that it might be possible to produce a resin with a strongly bimodal pore size distribution with one population of pores in the micropore region, and one in the macropore region. This proved to be the case with a mixture 80 vol % toluene and 20 vol % PDMS. Unexpectedly, however, the surface area of the poly(DVB) resins was found to rise significantly (∼100 m2g-1) in shifting from toluene as sole porogen to a mixture with a low level of oligomeric coporogen (∼4−6 vol %). Further increase in the level of oligomer led to the predicted fall in surface area. Overall, therefore, it is clear that use of oligomers, particularly as coporogens with solvent porogens, provides a valuable methodology for fine-tuning the porous morphology of poly(DVB) resins.

Published
2004
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39. Additional file 3: S3. of A randomised, double-blind clinical phase II trial of the efficacy, safety, tolerability and pharmacokinetics of a single dose combination treatment with artefenomel and piperaquine in adults and children with uncomplicated Plasmodium falciparum malaria

Author

Macintyre, Fiona, Yeka Adoke, Tiono, Alfred, Duong, Tran, Mombo-Ngoma, Ghyslain, Bouyou-Akotet, Marielle, Halidou Tinto, Bassat, Quique, Saadou Issifou, Adamy, Marc, Demarest, Helen, Duparc, Stephan, Leroy, Didier, Laurijssens, Bart, Biguenet, Sophie, Afizi Kibuuka, Tshefu, Antoinette, Melnick Smith, Foster, Chanelle, Illse Leipoldt, Kremsner, Peter, Bui Phuc, Ouedraogo, Alphonse, and Ramharter, Michael

Subjects
3. Good health
Abstract

Pharmacokinetic analysis details. (DOCX 689 kb)

40. Additional file 2: S2. of A randomised, double-blind clinical phase II trial of the efficacy, safety, tolerability and pharmacokinetics of a single dose combination treatment with artefenomel and piperaquine in adults and children with uncomplicated Plasmodium falciparum malaria

Author

Macintyre, Fiona, Yeka Adoke, Tiono, Alfred, Duong, Tran, Mombo-Ngoma, Ghyslain, Bouyou-Akotet, Marielle, Halidou Tinto, Bassat, Quique, Saadou Issifou, Adamy, Marc, Demarest, Helen, Duparc, Stephan, Leroy, Didier, Laurijssens, Bart, Biguenet, Sophie, Afizi Kibuuka, Tshefu, Antoinette, Melnick Smith, Foster, Chanelle, Illse Leipoldt, Kremsner, Peter, Bui Phuc, Ouedraogo, Alphonse, and Ramharter, Michael

Subjects
3. Good health
Abstract

Statistical analysis plan. (PDF 1515 kb)

41. Additional file 1: S1. of A randomised, double-blind clinical phase II trial of the efficacy, safety, tolerability and pharmacokinetics of a single dose combination treatment with artefenomel and piperaquine in adults and children with uncomplicated Plasmodium falciparum malaria

Author

Macintyre, Fiona, Yeka Adoke, Tiono, Alfred, Duong, Tran, Mombo-Ngoma, Ghyslain, Bouyou-Akotet, Marielle, Halidou Tinto, Bassat, Quique, Saadou Issifou, Adamy, Marc, Demarest, Helen, Duparc, Stephan, Leroy, Didier, Laurijssens, Bart, Biguenet, Sophie, Afizi Kibuuka, Tshefu, Antoinette, Melnick Smith, Foster, Chanelle, Illse Leipoldt, Kremsner, Peter, Bui Phuc, Ouedraogo, Alphonse, and Ramharter, Michael

Subjects
3. Good health
Abstract

Study Protocol. (PDF 1822 kb)

42. Additional file 4: S4. of A randomised, double-blind clinical phase II trial of the efficacy, safety, tolerability and pharmacokinetics of a single dose combination treatment with artefenomel and piperaquine in adults and children with uncomplicated Plasmodium falciparum malaria

Author

Macintyre, Fiona, Yeka Adoke, Tiono, Alfred, Duong, Tran, Mombo-Ngoma, Ghyslain, Bouyou-Akotet, Marielle, Halidou Tinto, Bassat, Quique, Saadou Issifou, Adamy, Marc, Demarest, Helen, Duparc, Stephan, Leroy, Didier, Laurijssens, Bart, Biguenet, Sophie, Afizi Kibuuka, Tshefu, Antoinette, Melnick Smith, Foster, Chanelle, Illse Leipoldt, Kremsner, Peter, Bui Phuc, Ouedraogo, Alphonse, and Ramharter, Michael

Subjects
3. Good health
Abstract

Exposureâ response analysis details. (DOCX 269 kb)

44. SAR of a series of inhaled A2A agonists and comparison of inhaled pharmacokinetics in a preclinical model with clinical pharmacokinetic data

Author

Mantell, Simon J., Stephenson, Peter T., Monaghan, Sandra M., Maw, Graham N., Trevethick, Michael A., Yeadon, Michael, Walker, Don K., Selby, Matthew D., Batchelor, David V., Rozze, Stuart, Chavaroche, Helene, Lemaitre, Arnaud, Wright, Karen N., Whitlock, Lynsey, Stuart, Emilio F., Wright, Patricia A., and Macintyre, Fiona

Subjects
*STRUCTURE-activity relationship in pharmacology, *RESPIRATORY therapy complications, *OBSTRUCTIVE lung diseases, *PHARMACOKINETICS, *CLINICAL medicine research, *DISEASE risk factors, CARDIOVASCULAR disease related mortality
Abstract

Abstract: COPD is a major cause of mortality in the western world. A2A agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A2A agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. The pharmacological and pharmacokinetic SAR of a series of inhaled A2A agonists is described leading through to human pharmacokinetic data for a clinical candidate. [Copyright &y& Elsevier]

Published
2009
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45. A randomised, double-blind clinical phase II trial of the efficacy, safety, tolerability and pharmacokinetics of a single dose combination treatment with artefenomel and piperaquine in adults and children with uncomplicated Plasmodium falciparum malaria.

Author

Macintyre F, Adoke Y, Tiono AB, Duong TT, Mombo-Ngoma G, Bouyou-Akotet M, Tinto H, Bassat Q, Issifou S, Adamy M, Demarest H, Duparc S, Leroy D, Laurijssens BE, Biguenet S, Kibuuka A, Tshefu AK, Smith M, Foster C, Leipoldt I, Kremsner PG, Phuc BQ, Ouedraogo A, and Ramharter M

Subjects
Adolescent, Adult, Africa, Antimalarials administration & dosage, Artemisinins administration & dosage, Asian People, Child, Child, Preschool, Dose-Response Relationship, Drug, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Infant, Male, Middle Aged, Quinolines administration & dosage, Treatment Outcome, Young Adult, Antimalarials therapeutic use, Malaria, Falciparum drug therapy, Plasmodium falciparum genetics, Quinolines therapeutic use
Abstract

Background: The clinical development of a single encounter treatment for uncomplicated malaria has the potential to significantly improve the effectiveness of antimalarials. Exploratory data suggested that the combination of artefenomel and piperaquine phosphate (PQP) has the potential to achieve satisfactory cure rates as a single dose therapy. The primary objective of the study was to determine whether a single dose of artefenomel (800 mg) plus PQP in ascending doses is an efficacious treatment for uncomplicated Plasmodium falciparum malaria in the 'target' population of children ≤ 5 years of age in Africa as well as Asian patients of all ages., Methods: Patients in six African countries and in Vietnam were randomised to treatment with follow-up for 42-63 days. Efficacy, tolerability, safety and pharmacokinetics were assessed. Additional key objectives were to characterise the exposure-response relationship for polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response at day 28 post-dose (ACPR28) and to further investigate Kelch13 mutations. Patients in Africa (n = 355) and Vietnam (n = 82) were included, with 85% of the total population being children < 5 years of age., Results: ACPR28 in the per protocol population (95% confidence interval) was 70.8% (61.13-79.19), 68.4% (59.13-76.66) and 78.6% (70.09-85.67) for doses of 800 mg artefenomel with 640 mg, 960 mg and 1440 mg of PQP respectively. ACPR28 was lower in Vietnamese than in African patients (66.2%; 54.55-76.62 and 74.5%; 68.81-79.68) respectively. Within the African population, efficacy was lowest in the youngest age group of ≥ 0.5 to ≤ 2 years, 52.7% (38.80-66.35). Initial parasite clearance was twice as long in Vietnam than in Africa. Within Vietnam, the frequency of the Kelch13 mutation was 70.1% and was clearly associated with parasite clearance half-life (PCt1/2). The most significant tolerability finding was vomiting (28.8%)., Conclusions: In this first clinical trial evaluating a single encounter antimalarial therapy, none of the treatment arms reached the target efficacy of > 95% PCR-adjusted ACPR at day 28. Achieving very high efficacy following single dose treatment is challenging, since > 95% of the population must have sufficient concentrations to achieve cure across a range of parasite sensitivities and baseline parasitaemia levels. While challenging, the development of tools suitable for deployment as single encounter curative treatments for adults and children in Africa and to support elimination strategies remains a key development goal., Trial Registration: ClinicalTrials.gov, NCT02083380 . Registered on 7 March 2014.

Published
2017
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