WP 4: Evaluation of drug activity against multiple life cycle stages of malaria parasites

Overview

Overview
Related items

LEADER: prof. L-M. Birkholtz

PARTNERS: UP & WITS & SU & StU

OBJECTIVES:

• Evaluation of the ability of the novel polymer-drug systems to kill the transmissible gametocytes.

• Validation using treatment of anopheline mosquitoes in a membrane feeding assay.

DELIVERABLES

01.2022 D 4.1

Antimalarial drug candidates identified and prioritised for inclusion in the nanoencapsulation based on efficacy evaluated against both asexual and sexual stages of the human malaria parasite P. falciparum: 1-3 lead compounds with dual activity against bothasexual and sexual stages. 1-2 lead compounds with preferential activity against specific stages (UP)

10.2022 D 4.2

Evaluation of toxicity of polymer matrices against malaria parasites and hemolytic activity. Polymer formulations without toxicity to malaria parasites or hemolytic activity identified (UP)

01.2023 D 4.3

Evaluation of toxicity of polymers to mosquito vector. Polymer formulations without toxicity to mosquito vector identified (WITS)

04.2023 M 4.1

Confirmed transmission-blocking activity of lead compounds via gamete formation and in mosquito feeding assays

10.2023 M 4.2

Polymer formulations without toxicity to malaria parasites and to mosquito vector identified

04.2024 D 4.6

Adjusted chemical composition, particle morphology and drug loading for effective transmission-blocking activity against gamete formation. (StU)

07.2024 D 4.4

Evaluation of asexual and sexual stage activity of nanoparticle encapsulated compounds on control antimalarials with required dynamic parameters. (UP)

07.2024 D4.5

Evaluation of transmission-blocking activity of polymer encapsulated compounds against gamete formation and mosquito feeding assays. (WITS)

07.2024 D 4.7

Adjusted chemical composition, particle morphology and drug loading of lipid nanoparticles for effective stage specific activity. (SU)

Programme: M-era.Net 3D4D2

SEEK ID: https://fairdomhub.org/projects/264

Public web page: Not specified

Organisms: No Organisms specified

FAIRDOM PALs: No PALs for this Project

Project start date: 1st Jul 2021

Project end date: 30th Jun 2024

Related items

Advanced People list for this Project with search and filtering

Lyn-Marie Birkholtz

Projects: WP 4: Evaluation of drug activity against multiple life cycle stages of malaria parasites, Project Coordination

Institutions: University of Pretoria

https://orcid.org/0000-0001-5888-2905

Dina Coertzen

Projects: WP 4: Evaluation of drug activity against multiple life cycle stages of malaria parasites, Project Coordination

Institutions: University of Pretoria

https://orcid.org/0000-0002-8408-244X

Stefaniya Gaydarova

Projects: WP 2: Antimalarial drug encapsulation, WP 4: Evaluation of drug activity against multiple life cycle stages of malaria parasites, WP 5: Intradermal 3D drug device administration, WP 3: Drug release kinetics study

Institutions: Sofia University

Bert Klumperman

Projects: WP 2: Antimalarial drug encapsulation, Project Coordination, WP 5: Intradermal 3D drug device administration, WP 4: Evaluation of drug activity against multiple life cycle stages of malaria parasites, Unshackling Membrane Protein Research: New Amphiphilic Copolymers for Extraction of Stable, Active Membrane Proteins, WP1 - Structure-activity relationships of amphiphilic copolymers, WP2.1 - Mono-chain-end functional amphiphilic copolymers, WP2.2 - Hetero di-chain-end functional amphiphilic copolymers, WP2.4 - Block copolymers for tethering to surfaces, WP2.3 - Meta-stable amphiphilic copolymers, WP2.5 - Fusion of SMALPs, WP2.6 - SMALPs for photosynthetic research, WP3 - Scalability of polymer production process, WP4 - Community engagement and technical advice

Institutions: University of Stellenbosch, Stellenbosch University

https://orcid.org/0000-0003-1561-274X

Lizette Koekemoer

Projects: Project Coordination, WP 4: Evaluation of drug activity against multiple life cycle stages of malaria parasites

Institutions: University of the Witwatersrand

https://orcid.org/0000-0003-4236-6345

Albena Lederer

Projects: WP 3: Drug release kinetics study, WP 4: Evaluation of drug activity against multiple life cycle stages of malaria parasites, WP 5: Intradermal 3D drug device administration, WP 2: Antimalarial drug encapsulation, WP 1: Biodegradable and responsive polymer matrix, Project Coordination

Institutions: Leibniz-Institut für Polymerforschung Dresden e. V.

https://orcid.org/0000-0002-1760-6426

Martha Muruya

Projects: WP 4: Evaluation of drug activity against multiple life cycle stages of malaria parasites

Institutions: University of Pretoria

Christo Tzachev

Projects: Project Coordination, WP 2: Antimalarial drug encapsulation, WP 5: Intradermal 3D drug device administration, WP 4: Evaluation of drug activity against multiple life cycle stages of malaria parasites, WP 3: Drug release kinetics study

Institutions: Sofia University

Zanelle Viktor

Projects: WP 1: Biodegradable and responsive polymer matrix, WP 2: Antimalarial drug encapsulation, WP 4: Evaluation of drug activity against multiple life cycle stages of malaria parasites, Project Coordination, WP 3: Drug release kinetics study, WP 5: Intradermal 3D drug device administration

Institutions: Leibniz-Institut für Polymerforschung Dresden e. V.

Advanced Programmes list for this Project with search and filtering

M-era.Net 3D4D2

No description specified

Projects: WP 1: Biodegradable and responsive polymer matrix, WP 2: Antimalarial drug encapsulation, WP 3: Drug release kinetics study, WP 4: Evaluation of drug activity against multiple life cycle stages of malaria parasites, WP 5: Intradermal 3D drug device administration, Project Coordination

Web page: Not specified

Advanced Institutions list for this Project with search and filtering

Leibniz-Institut für Polymerforschung Dresden e. V.

Country: Germany

City: Dresden

Web page: https://www.ipfdd.de/de/ueber-uns/

Sofia University

Country: Bulgaria

City: Sofia

Web page: https://www.uni-sofia.bg/eng

University of Pretoria

Country: South Africa

City: Pretoria

Web page: https://www.up.ac.za/

University of Stellenbosch

Country: South Africa

City: Stellenbosch

Web page: Not specified

University of the Witwatersrand

Country: South Africa

City: Johannesburg

Web page: http://www.wits.ac.za

Advanced Publications list for this Project with search and filtering

Toward New Transmission-Blocking Combination Therapies: Pharmacokinetics of 10-Amino-Artemisinins and 11-Aza-Artemisinin and Comparison with Dihydroartemisinin and Artemether

WP 4: Evaluation of drug activity against multiple life cycle stages of malaria parasites

Abstract (Expand)

As artemisinin combination therapies (ACTs) are compromised by resistance, we are evaluating triple combination therapies (TACTs) comprising an amino-artemisinin, a redox drug, and a third drug with …

Authors: Daniel J. Watson, Lizahn Laing, Liezl Gibhard, Ho Ning Wong, Richard K. Haynes, Lubbe Wiesner

Date Published: 16th Jul 2021

Publication Type: Journal

DOI: 10.1128/AAC.00990-21

Citation: Antimicrob Agents Chemother 65(8),e00990-21

Created: 9th Jan 2023 at 09:19, Last updated: 9th Jan 2023 at 09:26

A Phase 1, Placebo-controlled, Randomized, Single Ascending Dose Study and a Volunteer Infection Study to Characterize the Safety, Pharmacokinetics, and Antimalarial Activity of the Plasmodium Phosphatidylinositol 4-Kinase Inhibitor MMV390048

WP 4: Evaluation of drug activity against multiple life cycle stages of malaria parasites

Abstract (Expand)

Abstract Background MMV390048 is the first Plasmodium phosphatidylinositol 4-kinase inhibitor to reach clinical development as a new antimalarial. We aimed to characterize the safety, pharmacokinetics, …

Authors: James S McCarthy, Cristina Donini, Stephan Chalon, John Woodford, Louise Marquart, Katharine A Collins, Felix D Rozenberg, David A Fidock, Mohammed H Cherkaoui-Rbati, Nathalie Gobeau, Jörg J Möhrle

Date Published: 15th Nov 2020

Publication Type: Journal

DOI: 10.1093/cid/ciaa368

Citation: Clinical Infectious Diseases 71(10):e657-e664

Created: 9th Jan 2023 at 09:30, Last updated: 9th Jan 2023 at 09:30

Safety, Tolerability, Pharmacokinetics, and Antimalarial Activity of the Novel Plasmodium Phosphatidylinositol 4-Kinase Inhibitor MMV390048 in Healthy Volunteers

WP 4: Evaluation of drug activity against multiple life cycle stages of malaria parasites

Abstract (Expand)

MMV390048 is a novel antimalarial compound that inhibits Plasmodium phosphatidylinositol-4-kinase. The safety, tolerability, pharmacokinetic profile, and antimalarial activity of MMV390048 were determined …

Authors: Phumla Sinxadi, Cristina Donini, Hilary Johnstone, Grant Langdon, Lubbe Wiesner, Elizabeth Allen, Stephan Duparc, Stephan Chalon, James S. McCarthy, Ulrike Lorch, Kelly Chibale, Jörg Möhrle, Karen I. Barnes

Date Published: 24th Mar 2020

Publication Type: Journal

DOI: 10.1128/AAC.01896-19

Citation: Antimicrob Agents Chemother 64(4),e01896-19

Created: 9th Jan 2023 at 09:45, Last updated: 9th Jan 2023 at 09:46

Comparison of in vitro/in vivo blood distribution and pharmacokinetics of artemisinin, artemether and dihydroartemisinin in rats

WP 4: Evaluation of drug activity against multiple life cycle stages of malaria parasites

Abstract

Not specified

Authors: Tianming Dai, Weifan Jiang, Zizheng Guo, Yanxiang Xie, Renke Dai

Date Published: 2019

Publication Type: Journal

DOI: 10.1016/j.jpba.2018.09.024

Citation: Journal of Pharmaceutical and Biomedical Analysis 162:140-148

Created: 9th Jan 2023 at 09:28, Last updated: 9th Jan 2023 at 09:29

Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase

WP 4: Evaluation of drug activity against multiple life cycle stages of malaria parasites

Abstract (Expand)

MMV390048, a member of a new class of inhibitors of the Plasmodium phosphatidylinositol 4-kinase, shows potential for both treatment and prophylaxis. …

Authors: Tanya Paquet, Claire Le Manach, Diego González Cabrera, Yassir Younis, Philipp P. Henrich, Tara S. Abraham, Marcus C. S. Lee, Rajshekhar Basak, Sonja Ghidelli-Disse, María José Lafuente-Monasterio, Marcus Bantscheff, Andrea Ruecker, Andrew M. Blagborough, Sara E. Zakutansky, Anne-Marie Zeeman, Karen L. White, David M. Shackleford, Janne Mannila, Julia Morizzi, Christian Scheurer, Iñigo Angulo-Barturen, María Santos Martínez, Santiago Ferrer, Laura María Sanz, Francisco Javier Gamo, Janette Reader, Mariette Botha, Koen J. Dechering, Robert W. Sauerwein, Anchalee Tungtaeng, Pattaraporn Vanachayangkul, Chek Shik Lim, Jeremy Burrows, Michael J. Witty, Kennan C. Marsh, Christophe Bodenreider, Rosemary Rochford, Suresh M. Solapure, María Belén Jiménez-Díaz, Sergio Wittlin, Susan A. Charman, Cristina Donini, Brice Campo, Lyn-Marie Birkholtz, Kirsten K. Hanson, Gerard Drewes, Clemens H. M. Kocken, Michael J. Delves, Didier Leroy, David A. Fidock, David Waterson, Leslie J. Street, Kelly Chibale

Date Published: 26th Apr 2017

Publication Type: Journal

DOI: 10.1126/scitranslmed.aad9735

Citation: Sci. Transl. Med. 9(387),eaad9735

Created: 9th Jan 2023 at 09:35

Review of the clinical pharmacokinetics of artesunate and its active metabolite dihydroartemisinin following intravenous, intramuscular, oral or rectal administration

WP 4: Evaluation of drug activity against multiple life cycle stages of malaria parasites

Abstract (Expand)

Abstract Artesunate (AS) is a clinically versatile artemisinin derivative utilized for the treatment of mild to severe malaria infection. Given the therapeutic significance of AS and the necessity of …of AS and the necessity of appropriate AS dosing, substantial research has been performed investigating the pharmacokinetics of AS and its active metabolite dihydroartemisinin (DHA). In this article, a comprehensive review is presented of AS clinical pharmacokinetics following administration of AS by the intravenous (IV), intramuscular (IM), oral or rectal routes. Intravenous AS is associated with high initial AS concentrations which subsequently decline rapidly, with typical AS half-life estimates of less than 15 minutes. AS clearance and volume estimates average 2 - 3 L/kg/hr and 0.1 - 0.3 L/kg, respectively. DHA concentrations peak within 25 minutes post-dose, and DHA is eliminated with a half-life of 30 - 60 minutes. DHA clearance and volume average between 0.5 - 1.5 L/kg/hr and 0.5 - 1.0 L/kg, respectively. Compared to IV administration, IM administration produces lower peaks, longer half-life values, and higher volumes of distribution for AS, as well as delayed peaks for DHA; other parameters are generally similar due to the high bioavailability, assessed by exposure to DHA, associated with IM AS administration (> 86%). Similarly high bioavailability of DHA (> 80%) is associated with oral administration. Following oral AS, peak AS concentrations (Cmax) are achieved within one hour, and AS is eliminated with a half-life of 20 - 45 minutes. DHA Cmax values are observed within two hours post-dose; DHA half-life values average 0.5 - 1.5 hours. AUC values reported for AS are often substantially lower than those reported for DHA following oral AS administration. Rectal AS administration yields pharmacokinetic results similar to those obtained from oral administration, with the exceptions of delayed AS Cmax and longer AS half-life. Drug interaction studies conducted with oral AS suggest that AS does not appreciably alter the pharmacokinetics of atovaquone/proguanil, chlorproguanil/dapsone, or sulphadoxine/pyrimethamine, and mefloquine and pyronaridine do not alter the pharmacokinetics of DHA. Finally, there is evidence suggesting that the pharmacokinetics of AS and/or DHA following AS administration may be altered by pregnancy and by acute malaria infection, but further investigation would be required to define those alterations precisely.

Authors: Carrie A Morris, Stephan Duparc, Isabelle Borghini-Fuhrer, Donald Jung, Chang-Sik Shin, Lawrence Fleckenstein

Date Published: 1st Dec 2011

Publication Type: Journal

DOI: 10.1186/1475-2875-10-263

Citation: Malar J 10(1),263

Created: 9th Jan 2023 at 09:32, Last updated: 9th Jan 2023 at 09:32

Pharmacokinetics of Artemisinin-Type Compounds

WP 4: Evaluation of drug activity against multiple life cycle stages of malaria parasites