Karina Claassen (1), Stefan Willmann (2), Tobias Preusser (1, 3), Michael Block (2)
(1) Jacobs University Bremen, School of Engineering and Science, Campus Ring 1, 28759 Bremen, Germany; (2) Bayer Technology Services GmbH, Technology Development, Enabling Technologies, Computational Systems Biology, Building 9115, 51368 Leverkusen, Germany; (3) Fraunhofer MEVIS, Universitätsallee 29, 28359 Bremen, Germany
Objectives: Jellyfish stings in northern Australia cause significant morbidity and mortality [1]. One of the most popular jellyfishes, Carukia barnesi (CB) is a small and extremely venomous jellyfish whose sting causes Irukandji syndrome [2]. During envenomation a two phasic reaction takes place. The initial phase is dependent on severity of envenomation and culminates in hypertension and tachycardia. In mild envenomation a prolonged hypertension can be found. In severe syndromic cases hypotension and pulmonary oedema occur, caused by life threatening cardiac failure. Large knowledge gaps exist in the toxin’s mechanisms of actions [2]. This work is aimed to show the effects of CB venom on the cardiovascular system (CVS) in a newly developed physiologically based pharmacodynamical (PD) model for the CVS. Several hypotheses of toxin mode of actions are discussed.
Methods: The physiologically based PD model was established by usage of PK-Sim® and MoBi® based on data for physiological factors determining the blood pressure (BP) and the circulation in human. CV relevant data of human CB envenoming have been collected for both phases [1, 3-7]. These data were used to establish a proof of concept study. Different possible mechanisms of action causing hypertension (sympathetic and vagal influence, even as changes in resistances) and hypotension (heart failure causing changes in elastance, resistance or pump function) were investigated and simulated with the presented model. Finally both effects were combined to simulate the full CV changes of jellyfish envenomation. Effects on the mean arterial blood pressure, the sympathetic and parasympathetic activity even as the dynamic changes in heart rate will be shown in detail.
Results: The results show different possible modes of action of CB toxin, causing hypertension and hypotension. The CV model is able to describe and explain the cardiovascular effects of the toxin with sufficient agreement to experimental data.
Conclusions: The physiologically based PD model of the CVS is able to represent the pharmacodynamics of CB toxin sufficiently well, indicating a reasonable description of the underlying physiological processes. Furthermore, the accurate prediction of the BP, HR and activity of the autonomic nervous system are shown. This provides a proof of concept of how CB envenomation causes CV effects.
References:
[1] Huynh TT, Seymour J, Pereira P, et al.: Severity of Irukandji syndrome and nematocyst identification from skin scrapings. Med J Aust. 2003;178(1):38-41.
[2] Tibballs J, Li R, Tibballs HA, Gershwin LA, Winkel KD: Australian carybdeid jellyfish causing “Irukandji syndrome”. Toxicon. 2012;59(6):617-25.
[3] de Pender AM, Winkel KD, Ligthelm RJ: A probable case of Irukandji syndrome in Thailand. J Travel Med. 2006;13(4):240-3.
[4] Ramasamy S, Isbister GK, Seymour JE, Hodgson WC: The in vivo cardiovascular effects of an Australasian box jellyfish (Chiropsalmus sp.) venom in rats. Toxicon. 2005;45(3):321-7.
[5] Ramasamy S, Isbister GK, Seymour JE, Hodgson WC: Pharmacologically distinct cardiovascular effects of box jellyfish (Chironex fleckeri) venom and a tentacle-only extract in rats. Toxicol Lett. 2005;155(2):219-26.
[6] Winkel KD, Tibballs J, Molenaar P, et al.: Cardiovascular actions of the venom from the Irukandji (Carukia barnesi) jellyfish: effects in human, rat and guinea-pig tissues in vitro and in pigs in vitro. Clin Exp Pharmacol Physiol. 2005;32(9):777-88.
[7] Li R, Wright CE, Winkel KD, Gershwin LA, Angus JA: The pharmacology of Malo maxima jellyfish venom extract in isolated cardiovascular tissues: A probable cause of the Irukandji syndrome in Western Australia. Toxicol Lett. 2011;201(3):221-9.
Reference: PAGE 22 (2013) Abstr 2773 [www.page-meeting.org/?abstract=2773]
Poster: Other Drug/Disease Modelling