Ewerling Sonja

Actelion (Switzerland)

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Didier Leroy

Medicines for Malaria Venture

Rintis Noviyanti

Eijkman Institute for Molecular Biology

Sergio Wittlin

University of Basel

Grennady Wirjanata

Charles Darwin University

Andrea Ruecker

Mahidol Oxford Tropical Medicine Research Unit

Fidock David A.

Ferrer Santiago

Hospital Universitario La Paz

Schleiferboeck Sarah

University of Basel

Sanz Laura María

Martínez Maria Santos

Universidade Federal do Rio de Janeiro

Cooperative Institutions

Actelion (Switzerland)

Ludwig-Maximilians-Universität München

University of Basel

Swiss Tropical and Public Health Institute

GlaxoSmithKline (Spain)

Medicines for Malaria Venture

Columbia University Irving Medical Center

GlaxoSmithKline (United Kingdom)

Idorsia (Switzerland)

Roche (Switzerland)

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Ex vivo drug susceptibility.

Le Bihan Amélie Kanter Ruben de Íñigo Angulo‐Barturen Binkert Christoph Boss Christoph

Ex vivo

10.1371/journal.pmed.1002138.g002

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149 LAPAROSCOPIC EMBRYO TRANSFER IN PIGS

Reproduction Fertility and Development (2008)

S.L. Terlouw Ewerling Sonja B.A. Didion J.R. Dobrinsky

In an effort to optimize the number of live offspring from cloned and transgenic pig embryos, embryos are surgically transferred into the isthmus region of the oviduct soon after micromanipulation. Surgical embryo transfer in pigs is successful but still an invasive process. Laparoscopic embryo transfer (Besenfelder et al. 1997 Theriogenology 47, 1051–1060) is much less invasive than surgery and is more adaptable to a variety of commercial embryo transfer conditions. Our goal was to develop the use the laparoscope as an alternative method of embryo transfer for micromanipulated embryos. Naturally cycling maternal white line donor and recipient females were used for laparoscopic embryo transfer. Donors were selected to be in estrus 0 to 24 h before recipients. Two- to four-cell embryos were surgically recovered via mid-ventral laparotomy and immediately prepared for laparoscopic transfer into the oviduct through the infundibulum or through puncture of the oviduct into the ampulla. Sixty-nine embryos (range, 13–20) were transferred into the oviduct via the infundibulum of four recipients. Two recipients farrowed (50%), one recipient spontaneously aborted on Day 27, and one returned to estrus on Day 25 of the estrous cycle. Twenty-one pigs were born (10.5 pigs/farrowed sow) resulting in 30% (21/69) of transferred embryos becoming live offspring. Ninety-seven embryos (range, 10-21) were transferred into the ampulla of the oviduct of six recipients. Four recipients farrowed (67%) and 2 returned to estrus on Day 20 and Day 28. Thirty-nine pigs were born (9.5/sow farrowed) resulting in 39% (38/97) of transferred embryos becoming live offspring. Observations indicate that it is much easier to find the oviduct and deliver embryos via puncture into the ampulla than find and insert the transfer catheter into the infundibulum. Using the efficiencies generated from these data, 1.1 more pigs can be expected per transfer by transferring embryos to the oviduct via puncture than into the oviduct via the infundibulum. These data demonstrate the effective use of the laparoscope for oviductal embryo transfer. Further work is needed to determine if the laparoscope improves the production of live offspring compared to surgical embryo transfer.

Oviduct

Infundibulum

Ampulla

10.1071/rdv20n1ab149

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PK/PD strategy.

Le Bihan Amélie Kanter Ruben de Íñigo Angulo‐Barturen Binkert Christoph Boss Christoph

10.1371/journal.pmed.1002138.g009

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In vitro activity against a panel of resistant and sensitive strains of P. falciparum.

Le Bihan Amélie Kanter Ruben de Íñigo Angulo‐Barturen Binkert Christoph Christoph Boss

10.1371/journal.pmed.1002138.t001

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Parameterization of the pharmacokinetic model.

Le Bihan Amélie Kanter Ruben de Íñigo Angulo‐Barturen Binkert Christoph Boss Christoph

10.1371/journal.pmed.1002138.t003

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P. falciparum dual gamete formation assay.

Le Bihan Amélie Kanter Ruben de Íñigo Angulo‐Barturen Binkert Christoph Christoph Boss

Gamete

10.1371/journal.pmed.1002138.g007

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Correlation of the observed survival or antimalarial activity versus modeled maximal effect relationship.

Le Bihan Amélie Kanter Ruben de Íñigo Angulo‐Barturen Binkert Christoph Christoph Boss

10.1371/journal.pmed.1002138.t005

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Time-, stage-, and concentration-dependent effects of ACT-451840 on synchronous cultures of P. falciparum NF54 in vitro.

Le Bihan Amélie Kanter Ruben de Íñigo Angulo‐Barturen Binkert Christoph Christoph Boss

10.1371/journal.pmed.1002138.g004

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Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose–Efficacy Modeling

PLoS Medicine (2016)

Amélie Le Bihan Ruben de Kanter Íñigo Angulo‐Barturen Christoph A. Binkert Christoph Boss

Background Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented. Method and Findings The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3–4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11–16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23–39). The compound’s preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as survival) in relation to area under the concentration versus time curve (AUC), maximum observed plasma concentration (Cmax), and time above a threshold concentration. The determination of the dose–efficacy relationship of ACT-451840 under curative conditions in rodent malaria models allowed prediction of the human efficacious exposure. Conclusion The dual activity of ACT-451840 against asexual and sexual stages of P. falciparum and the activity on P. vivax have the potential to meet the specific profile of a target compound that could replace the fast-acting artemisinin component and harbor additional gametocytocidal activity and, thereby, transmission-blocking properties. The fast parasite reduction ratio (PRR) and gametocytocidal effect of ACT-451840 were recently also confirmed in a clinical proof-of-concept (POC) study.

Plasmodium berghei

Primaquine

10.1371/journal.pmed.1002138

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ACT-451840 blocking transmission.

Le Bihan Amélie Kanter Ruben de Angulo-Barturen Iñigo Binkert Christoph Christoph Boss

Blocking (statistics)

10.1371/journal.pmed.1002138.g008

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