- Email: [email protected]
Evaluation of activated charcoal and lipid emulsion treatment in model of acute rivaroxaban toxicity
Accepted Manuscript Evaluation of activated charcoal and lipid emulsion treatment in model of acute rivaroxaban toxicity
Sinan Cem Uzunget, Togay Evrin, Sezen Baglan Uzunget, Zamir Kemal Ertürk, Egemen Akıncıoğlu, Saffet Özdemir, Atila Korkmaz PII: DOI: Reference:
S0735-6757(17)31041-0 https://doi.org/10.1016/j.ajem.2017.12.039 YAJEM 57179
To appear in: Received date: Revised date: Accepted date:
19 June 2017 13 December 2017 13 December 2017
Please cite this article as: Sinan Cem Uzunget, Togay Evrin, Sezen Baglan Uzunget, Zamir Kemal Ertürk, Egemen Akıncıoğlu, Saffet Özdemir, Atila Korkmaz , Evaluation of activated charcoal and lipid emulsion treatment in model of acute rivaroxaban toxicity. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Yajem(2017), https://doi.org/10.1016/j.ajem.2017.12.039
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ACCEPTED MANUSCRIPT Evaluatıon of actıvated charcoal and lıpıd emulsıon treatment ın model of acute rıvaroxaban toxıcıty 1. Sinan Cem Uzunget, MD, [email protected] 2. Togay Evrin , MD, [email protected] 3. Sezen Baglan Uzunget, MD, [email protected]
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4. Zamir Kemal Ertürk, MD,[email protected]
6.Saffet Özdemir, MD, [email protected]
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7.Atila Korkmaz, MD, [email protected]
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5.Egemen Akıncıoğlu, MD, [email protected]
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1. Department of Emergency Medicine, Ufuk University Faculty of Medicine
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2. Department of Emergency Medicine, Ufuk University Faculty of Medicine 3. Department of Cardiology, Ufuk University Faculty of Medicine
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4. Department of Emergency Medicine, Ufuk University Faculty of Medicine
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5.Department of Pathology, Ufuk University Faculty of Medicine 6. Department of Emergency Medicine, Ufuk University Faculty of Medicine
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7. Department of Emergency Medicine, Ufuk University Faculty of Medicine
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Corresponding author: Sinan Cem Uzunget MD, Department of Emergency Medicine, Ufuk University Faculty of Medicine Mevlana Bulvarı No:86-88, 06520 Balgat - ANKARA TURKEY
Tel: 05077079909 Fax : +90 312 287 2390. [email protected]
ACCEPTED MANUSCRIPT EVALUATION OF ACTIVATED CHARCOAL AND LIPID EMULSION TREATMENT IN MODEL OF ACUTE RIVAROXABAN TOXICITY
INTRODUCTION
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Acute intoxications are a major public health problem across the world. There are
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numerous applications to hospitals due to suicide, accidental exposure, and overdose of drugs
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or other chemicals. Although many life-saving attempts have been made in poisonings, basic
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treatment has been limited to evacuation of the stomach , supportive care and activated
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carbon treatment even , indications for these treatments have been significantly deemphasized and are now uncommonly used or indicated [1].
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Activated charcoal (AC) is an effective adsorbent for many drugs and toxic substances [2] AC, which is defined as universal antidote, is the most commonly used method for
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gastrointestinal decontamination [3]. The use of AC alone or in combination with evacuation
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of the stomach is effective for gastric decontamination in many oral poisonings But in recent years, its use has decreased substantially [3].
Today, parenteral treatments are being investigated to reduce or reverse the effects of overdose or toxicity. The general strategy in this approach is to reduce the concentration of the drug or toxin in blood or tissue by injecting a colloid forming a compartment that the drug or toxin exhibits affinity, and thus to protect organ function and maintain endogenous
ACCEPTED MANUSCRIPT metabolism [4]. Lipid emulsions (LE), produced solutions used for total parenteral nutrition as a source of calories in the malnutrition, have been used in recent years as an effective antidote in lipophilic drug intoxications, primarily local anesthetic toxicity[4], and in the
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resuscitation of the hemodynamically unstable patients. Currently, it is suggested that lipid emulsions should be given to patients in drug poisonings that cannot be treated with the
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standard resuscitation approaches (5).
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New oral anticoagulants are increasingly replacing vitamin K antagonists because they have advantages such as short half-lives, less drug interaction, no need for monitoring, and
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better pharmacokinetic profile [6, 7]. Rivaroxaban, one of the these drugs, is lipophilic and
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also is an oxazolidinone derivative that selectively binds to factor Xa and acts as an inhibitor
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[8]. In case of rivaroxaban toxicity or side effects, preventing the absorption of rivaroxaban
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and increasing its elimination can reduce the toxic effects and mortality of this agent.
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In this study, the effects of activated charcoal and lipid emulsion treatment in the treatment of acute rivaroxaban toxicity were evaluated.
MATERIALS AND METHODS
This experimental study was carried out in Gazi University Laboratory Animal Breeding and Experimental Research Center in November 2016. The study was approved by Gazi University Experimental Animal Ethics Committee. A total of 42 adult male Balb/c mice
ACCEPTED MANUSCRIPT weighing 30 grams were used in the study. Experimental animals were maintained in a 12 h light/12 h dark cycle at room temperature (24±2ºC). They were allowed to reach the standard mouse diet and the water without restriction. 6 mice were placed in one cage.
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The mice were randomly divided into 7 groups (n= 6):
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EXPERIMENTAL GROUPS
Group 1: Rivaroxaban (Vega Pharma Limited, Zhejiang, China) was orally
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Group 2: 20% LE (Intralipid
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administered at 300 mg/kg.
20 % Fresenius Kabi AB, Uppsala, Sweden) was
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administered intraperitoneally at 15 ml/kg.
Group 3: AC (Aqua-Carbo® 50 g/240 ml, Avicenna Farma, Istanbul, Turkey) was orally
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administered at 1 g/kg.
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Group 4: Rivaroxaban was orally administered at 300 mg/kg, and then 20% LE was administered intraperitoneally at 1st hour.
Group 5: Rivaroxaban was orally administered at 300 mg/kg, and then 20% LE was administered intraperitoneally at 3rd hour.
ACCEPTED MANUSCRIPT Group 6: Rivaroxaban was orally administered at 300 mg/kg, and then AC was orally administered at 1 g/kg at 1st hour.
Group 7: Rivaroxaban was orally administered at 300 mg/kg, and then AC was orally
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administered at 1 g/kg at 1st hour and 20% LE was administered intraperitoneally at 3rd
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hour.
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While rivaroxaban and AC were given with orogastric tube, LE was administered
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intraperitoneally. 300mg/ kg rivaroxaban was administered according to previously defined
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LD 50 dose in mice[9]. One study conducted by Perez et al. demonstrated that survival rose after 18,6 ml/ kg LE in rodents [10] but because of poor solubility and lower blood volume in
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mice , we applied 15 ml / kg LE and 300 mg/ kg rivoraxaban each mouse.
No deaths were observed in the groups during the experiment. All experimental
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animals were anesthetized with 50 mg/kg IM ketamine (Ketamine hydrochloride, Ketalar®,
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Pfizer, Istanbul, Turkey) 5 hours after first drug administration. They were sacrificed by the cardiac puncture blood collection method.
The brain(cerebrum and cerebellum), stomach, and small and large bowel tissues were appropriately obtained from the sacrificed subjects for pathological examination. The samples was examined by the same pathologist who was blinded to the groups of samples. Specimens were fixed in 10% of formalin solution. After obtaining slices of 4 to 5mm of
ACCEPTED MANUSCRIPT thickness from the paraffin embedded specimen, they were stained with hematoxylin and eosin. The samples were evaluated for hemorrhage under light microscope. The criteria for the minor hemorrhage in the gastrointestinal tract (stomach, small intestine and large
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bowel) was extravasation of blood into the mucosa, muscularis mucosa, submucosa,
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was extravasation of blood into the brain parenchyma.
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muscularis propria and serosa. Also the criteria for intracerebral haemorrhage
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The blood samples from mice were transferred to 3.2% (109 mmol/L) sodium citrate tubes at an appropriate dose. Prothrombin time (PT) and anti-factor Xa (Anti-FXa) activity
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were examined.
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STATISTICAL METHOD
Statistical analyzes were performed with the SPSS for Windows Version 20.0 package
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program. Numerical variables were expressed as mean±standard deviation and median
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[minimum-maximum] values. The Kruskal-Wallis test was used whether there was a difference between the groups in terms of PT and Anti-FXa activity. P<0.05 was considered statistically significant. Power analyse was performed and 6 animals for each group were determined.
ACCEPTED MANUSCRIPT RESULTS:
PT and Anti-FXa values of the groups not receiving rivaroxaban (Groups 2 and 3) were compared with those of the rivaroxaban group and the rivaroxaban+treatment groups.
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Another experimental group in which no substance was used was not created in order not to
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increase animal sacrifice. The group receiving only AC was defined as the control group
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(Table 1, 2).
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Although there were some small decreases in mean PT and Anti-FXa levels as the
these results
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control group and four rivaroxaban+treatment groups ( group 4,5,6,7) were compared , were statistically insignificant. (Group 4 PT:32.07±9.31 Anti-FXa:
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1320.33±275.61, Group 5 PT:31.25±12.15 Anti-FXa 1708.67±482,20, Group 6 PT 26.13±7.60
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Anti-FXa 1237.67±344.95, Group 7 PT:22.33±7.95 Anti-FXa:760.33±166.95). (Figure 1,2)
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Also, the statistical analyze showed that there were no discrimination in mean PT and
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Anti-FXa levels between given LE in the first hour and in the third hour.
PATHOLOGICAL EXAMINATION
There was no macroscopic and microscopic hemorrhage in all samples of groups.
DISCUSSION
ACCEPTED MANUSCRIPT The use of rivaroxaban at very high doses leads to deterioration in coagulation tests. It is known that particularly a massive rivaroxaban overdose prolongs the PT [9]. [11]. The concentration of rivaroxaban cannot be assessed by routine coagulation tests, but it is known
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that an increase in rivaroxaban concentration prolongs the PT and aPTT [7, 10]. [7, 8, 11, 12]. In a study conducted on healthy volunteers by Eerenberg et al. [11], [13], they found that the
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PT was prolonged. Although it was reported that the PT was prolonged when rivaroxaban
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was used at high doses, its use is not recommended in clinical evaluation. The chromogenic
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anti-factor Xa assay is recommended as a routine monitoring method for factor Xa inhibitors
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[7, 11, 12, 14].
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In our study, it was found that the mean PT was prolonged in mice receiving
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rivaroxaban. In our study, it was found that the mean PT was prolonged and anti-factor Xa activity increased in mice receiving rivaroxaban. When the rivaroxaban group was compared
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with the groups not receiving rivaroxaban, the PT was increased and there was a statistically
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significant difference (p<0.001).
AC Activated charcoal used to prevent drug absorption from the gastrointestinal tract after drug overdose may also be useful for overdose of factor Xa inhibitors [9] [11]. In a study performed on healthy volunteers by Wang et al. [12], [15], AC was given following administration of apixaban at toxic dose, and the concentration of apixaban was found to be
ACCEPTED MANUSCRIPT decreased. Except for a case report who used rivaroxaban due to pulmonary thromboembolism and received a high dose of rivaroxaban due to wrong order and then was treated with AC [13], [16]. The idea that lipid emulsions are used as lipophilic drug
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during intoxication has existed for a long time. It was studied on gluthemid for lipid emulsions to be used as dialysate in lipophilic drug toxication [17]. In an animal experiment,
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intravenous fat emulsion was used to reduce the effect of chlorpromazine [18]. A study
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conducted in 1998 found that lipid therapy is a useful treatment for local anesthetic systemic
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toxicity [19]. Scientists who have been studying in this regard have thought that intravenous
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lipid emulsion therapy may be beneficial in lipophilic drugs and have achieved various results. There are studies about its use in the toxicity of many lipophilic substances, primarily the
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toxicity of local anesthetics such as bupivacaine [20], lidocaine [21], and ropivacaine [22]. Currently, the use of lipid emulsion therapy in resuscitation attempts after local anesthetic
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toxicity and in situations where drug toxicity cannot be resolved with the standard
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resuscitation approaches is recommended in 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care [5].
there are no studies in the literature on the use of AC in rivaroxaban toxicity. In the literature, there is no study on the use of lipid emulsion and/or activated charcoal in rivaroxaban toxicity.
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In our study,
the control group and the rivaroxaban+treatment groups were
compared in terms of PT and anti-factor Xa levels, it was seen that the mean PT and anti-
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factor Xa levels increased in the groups receiving rivaroxaban+LE at 1 hour, rivaroxaban+LE
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at 3 hour, rivaroxaban+activated charcoal at 1 hour and rivaroxaban+activated charcoal at 1
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hour+LE at 3 hour. However, there was no statistically significant difference between these
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groups (respectively, p=1.00, p=0.06; p=1.00, p=0.20; p=1.00, p=0.11 and p=0.95, p=0.83)
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In our experimental study, the intraperitoneal route was preferred because LE should be given in the amount that we cannot give intravenously to mice. LE was given
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intraperitoneally in some previous studies, and it is known that intraperitoneal absorption
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occurs from the first hour [36, 37]. [23, 24]. However, in our study, it is considered that LE
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did not completely pass into the systemic circulation because it was planned to see its effect
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within the first 6 hours and that the optimal LE levels in the plasma could not be reached because no a further infusion of LE was given. However, the decrease in PT value is thought to be clinically important.
The general approach in acute drug intoxications is decontamination of the substance and supportive care [39, 40]. [25, 26]. Moreover, the use of the antidote can be a solution. Therefore, it is thought that new and more effective medical treatment methods for
ACCEPTED MANUSCRIPT detoxification are needed [41]. [27]. New treatments in toxicology are being investigated with original methods such as radioligand binding, use of nanobodies, protein-protein interaction inhibitors, aptamers, antisense oligonucleotides, and protein-selective small
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molecules [1, 42-47]. [1, 28-33]. However, considering the factors such as cost and accessibility, a general antidote application would be cheaper and accessible rather than a
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special antidote to each poison. The fact that There was a 61% decrease in the mean Anti-
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FXa levels in the group receiving AC at 1st hour and LE at 3rd hour after rivaroxaban
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compared to the rivaroxaban group in our study suggests that it may be useful in the
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treatment of intoxication. However, this should be supported by further studies. that the use of AC and LE would be beneficial in the early period of rivaroxaban toxicity in clinic, further
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studies are required to recommend its routine use.
Spiller et al. [9] [11] reported that no bleeding was observed in acute rivaroxaban
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toxicity and that bleeding was more associated with long-term treatment. Replinger et al.
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[48] [34] reported that there was no bleeding after acute rivaroxaban overdose. No bleeding was observed in a case receiving 1960 mg rivaroxaban who was reported by Lehman et al. [49] [35] and in a case receiving 1400 mg rivaroxaban who was reported by Linkins et al. [50]. [36]. The fact that being no macroscopic or microscopic hemorrhage in any of 30 mice given a massive dose of rivaroxaban in our study supports this finding.
ACCEPTED MANUSCRIPT LIMITATIONS OF THE STUDY
The toxic effect of rivaroxaban is observed mostly in chronic use. In our experiment, the subjects were sacrificed at the 5th hour following a high dose of rivaroxaban. There was no
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bleeding or death in the group receiving only a high dose of rivaroxaban. Therefore, the
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effects of AC and LE at these outcome points could not be assessed. LE could not be applied
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optimally in experimental animals. Since intravenous administration is not possible in mice,
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intraperitoneal administration was performed, and no intravenous infusion was given after bolus administration. Lipid emulsion was observed in the peritoneum after sacrification in all
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experimental animals given LE. It is thought that LE might have not been given at effective
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doses and therefore sufficient effect could might have not been achieved. Also, the number
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COMPETING INTERESTS
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of animals were smallrestricted with 42 subjects in order not to increase animal sacrifice.
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The authors declared that they have no competing interests.
ACKNOWLEDGEMENTS
This study received funding from Ufuk University research funds.
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35. Weinberg, G.L., Lipid emulsion infusion: resuscitation for local anesthetic and other drug overdose. Anesthesiology, 2012. 117 (1): p. 1807. 36. Mahedero, G., et al., Absorption of Intralipid and interferences from nutrients infused into the peritoneal cavity of the rat. Am.J.Surg, 1992. 164:p. 45-50 37. Moran, J., et al., Transperitoneal absorption of intralipid in rats: total serum fatty acids and triglyceride after absorption. JPEN J Parenter Enteral Nutr. 1986.10 (6):604-8. 38. Douxfils, J., et al., Non-VKA Oral Anticoagulants: Accurate Measurement of Plasma Drug Concentrations. Biomed Res Int, 2015. 2015: p. 345138. 39. Ferner, R.E., Our poisoned patients. Qjm, 2001. 94 (3): p. 117-20. 40. Larsen, L.C. and D.M. Cummings, Oral poisonings: guidelines for initial evaluation and treatment. Am Fam Physician, 1998. 57 (1): p. 85-92. 41. Zhang, L. and J.C. Leroux, Current and forthcoming approaches for systemic detoxification. Adv Drug Deliv Rev, 2015. 90: p. 1-2. 42. Insel, P.A., et al., Introduction to the Theme "New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology". Annu Rev Pharmacol Toxicol, 2016. 43. Bondeson, D.P. and C.M. Crews, Targeted Protein Degradation by Small Molecules. Annu Rev Pharmacol Toxicol, 2016. 44. Forster, V. and J.C. Leroux, Nano-antidotes for drug overdose and poisoning. Sci Transl Med, 2015. 7 (290): p. 290ps14. 45. Oney, S., et al., Development of universal antidotes to control aptamer activity. Nat Med, 2009. 15 (10): p. 1224-8. 46. Forster, V., P. Luciani, and J.C. Leroux, Treatment of calcium channel blocker-induced cardiovascular toxicity with drug scavenging liposomes. Biomaterials, 2012. 33 (13): p. 3578-85. 47. Zhu, Y., et al., Engineering Factor Xa Inhibitor with Multiple PlateletBinding Sites Facilitates its Platelet Targeting. Sci Rep, 2016. 6: p. 29895. 48. Repplinger, D.J., et al., Lack of significant bleeding despite large acute rivaroxaban overdose confirmed with whole blood concentrations. Clin Toxicol (Phila), 2016. 54 (8): p. 647-9. 49. Lehmann, T., et al., Massive human rivaroxaban overdose. Thromb Haemost, 2014. 112 (4): p. 834-6. 50. Linkins, L.A. and K. Moffat, Monitoring the anticoagulant effect after a massive rivaroxaban overdose. J Thromb Haemost, 2014. 12 (9): p. 1570-1.
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ACCEPTED MANUSCRIPT Table 1: All groups descriptive values
1929,83 ± 344,18
10,50 ± 0,33
<25
10,07 ± 0,40
<25
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1708,67 ± 482,20
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31,25 ± 12,15
1320,33 ± 275,61
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32,07 ± 9,31
PT
38,93 ± 9,13
26,13 ± 7,60
1237,67 ± 344,95
22,33 ± 7,95
760,33 ± 166,95
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Group 7 (Rivaroxaban+AC+LE)
Anti-Fxa (ng/ml) (Mean±SD)
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Group 1 (Rivaroxaban) Group 2 (LE) Group 3 (AC) Group 4 (Rivaroxaban+LE 1st hour) Group 5 (Rivaroxaban+LE 3rd hour) Group 6 (Rivaroxaban+AC)
PT (second) (Mean±SD)
PT: Prothrombin Time, SD: Standard Deviation, Anti-FXa: Antifactor Xa , LE: Lipid Emulsion, AC:
AC
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Activated Charcoal
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Table 2: P value comparison between groups
PT (p value)
Anti FXa (p value)
Groups
PT (p value)
Anti FXa (p value)
Group 1 - Group 2
0,004*
0,002*
Group 3 - Group 4
0,01*
0,06*
Group 1 - Group 3
0,001*
0,002*
Group 3 - Group 5
0,02*
0,06*
Group 1 - Group 4
1
1
Group 3 - Group 6
0,10
0,11
Group 1 - Group 5
1
1
Group 3 - Group 7
0,46
0,83
Group 1 - Group 6
1
1
Group 4 - Group 5
1
1
Group 1 - Group 7
0,94
1
Group 4 - Group 6
1
1
Group 2 - Group 3
1
1
Group 4 - Group 7
1
1
Group 2 - Group 4
0,06
0,06
Group 5 - Group 6
1
1
Group 2 - Group 5
0,14
0,02*
Group 5 - Group 7
1
1
Group 2 - Group 6
0,48
0,11
Group 6 - Group 7
1
1
Group 2 - Group 7
1
0,83
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Group 1 : Rivaroxaban Group 2 : LE Group 3 : AC Group 4 : Rivaroxaban + LE 1 st hour Group 5 : Rivaroxaban + LE 3 st hour Group 6 : Rivaroxaban + AC Group 7 : Rivaroxaban + AC + LE
PT
Groups
AC
PT: Prothrombin Time, Anti-Fxa: Antifactor Xa, LE: Lipid Emulsion, AC: Activated Charcoal, * p<0,05
Figure 1
Figure 2
Sinan Cem Uzunget, Togay Evrin, Sezen Baglan Uzunget, Zamir Kemal Ertürk, Egemen Akıncıoğlu, Saffet Özdemir, Atila Korkmaz PII: DOI: Reference:
S0735-6757(17)31041-0 https://doi.org/10.1016/j.ajem.2017.12.039 YAJEM 57179
To appear in: Received date: Revised date: Accepted date:
19 June 2017 13 December 2017 13 December 2017
Please cite this article as: Sinan Cem Uzunget, Togay Evrin, Sezen Baglan Uzunget, Zamir Kemal Ertürk, Egemen Akıncıoğlu, Saffet Özdemir, Atila Korkmaz , Evaluation of activated charcoal and lipid emulsion treatment in model of acute rivaroxaban toxicity. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Yajem(2017), https://doi.org/10.1016/j.ajem.2017.12.039
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ACCEPTED MANUSCRIPT Evaluatıon of actıvated charcoal and lıpıd emulsıon treatment ın model of acute rıvaroxaban toxıcıty 1. Sinan Cem Uzunget, MD, [email protected] 2. Togay Evrin , MD, [email protected] 3. Sezen Baglan Uzunget, MD, [email protected]
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4. Zamir Kemal Ertürk, MD,[email protected]
6.Saffet Özdemir, MD, [email protected]
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7.Atila Korkmaz, MD, [email protected]
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5.Egemen Akıncıoğlu, MD, [email protected]
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1. Department of Emergency Medicine, Ufuk University Faculty of Medicine
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2. Department of Emergency Medicine, Ufuk University Faculty of Medicine 3. Department of Cardiology, Ufuk University Faculty of Medicine
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4. Department of Emergency Medicine, Ufuk University Faculty of Medicine
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5.Department of Pathology, Ufuk University Faculty of Medicine 6. Department of Emergency Medicine, Ufuk University Faculty of Medicine
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7. Department of Emergency Medicine, Ufuk University Faculty of Medicine
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Corresponding author: Sinan Cem Uzunget MD, Department of Emergency Medicine, Ufuk University Faculty of Medicine Mevlana Bulvarı No:86-88, 06520 Balgat - ANKARA TURKEY
Tel: 05077079909 Fax : +90 312 287 2390. [email protected]
ACCEPTED MANUSCRIPT EVALUATION OF ACTIVATED CHARCOAL AND LIPID EMULSION TREATMENT IN MODEL OF ACUTE RIVAROXABAN TOXICITY
INTRODUCTION
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Acute intoxications are a major public health problem across the world. There are
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numerous applications to hospitals due to suicide, accidental exposure, and overdose of drugs
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or other chemicals. Although many life-saving attempts have been made in poisonings, basic
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treatment has been limited to evacuation of the stomach , supportive care and activated
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carbon treatment even , indications for these treatments have been significantly deemphasized and are now uncommonly used or indicated [1].
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Activated charcoal (AC) is an effective adsorbent for many drugs and toxic substances [2] AC, which is defined as universal antidote, is the most commonly used method for
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gastrointestinal decontamination [3]. The use of AC alone or in combination with evacuation
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of the stomach is effective for gastric decontamination in many oral poisonings But in recent years, its use has decreased substantially [3].
Today, parenteral treatments are being investigated to reduce or reverse the effects of overdose or toxicity. The general strategy in this approach is to reduce the concentration of the drug or toxin in blood or tissue by injecting a colloid forming a compartment that the drug or toxin exhibits affinity, and thus to protect organ function and maintain endogenous
ACCEPTED MANUSCRIPT metabolism [4]. Lipid emulsions (LE), produced solutions used for total parenteral nutrition as a source of calories in the malnutrition, have been used in recent years as an effective antidote in lipophilic drug intoxications, primarily local anesthetic toxicity[4], and in the
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resuscitation of the hemodynamically unstable patients. Currently, it is suggested that lipid emulsions should be given to patients in drug poisonings that cannot be treated with the
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standard resuscitation approaches (5).
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New oral anticoagulants are increasingly replacing vitamin K antagonists because they have advantages such as short half-lives, less drug interaction, no need for monitoring, and
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better pharmacokinetic profile [6, 7]. Rivaroxaban, one of the these drugs, is lipophilic and
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also is an oxazolidinone derivative that selectively binds to factor Xa and acts as an inhibitor
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[8]. In case of rivaroxaban toxicity or side effects, preventing the absorption of rivaroxaban
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and increasing its elimination can reduce the toxic effects and mortality of this agent.
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In this study, the effects of activated charcoal and lipid emulsion treatment in the treatment of acute rivaroxaban toxicity were evaluated.
MATERIALS AND METHODS
This experimental study was carried out in Gazi University Laboratory Animal Breeding and Experimental Research Center in November 2016. The study was approved by Gazi University Experimental Animal Ethics Committee. A total of 42 adult male Balb/c mice
ACCEPTED MANUSCRIPT weighing 30 grams were used in the study. Experimental animals were maintained in a 12 h light/12 h dark cycle at room temperature (24±2ºC). They were allowed to reach the standard mouse diet and the water without restriction. 6 mice were placed in one cage.
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The mice were randomly divided into 7 groups (n= 6):
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EXPERIMENTAL GROUPS
Group 1: Rivaroxaban (Vega Pharma Limited, Zhejiang, China) was orally
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Group 2: 20% LE (Intralipid
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administered at 300 mg/kg.
20 % Fresenius Kabi AB, Uppsala, Sweden) was
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administered intraperitoneally at 15 ml/kg.
Group 3: AC (Aqua-Carbo® 50 g/240 ml, Avicenna Farma, Istanbul, Turkey) was orally
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administered at 1 g/kg.
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Group 4: Rivaroxaban was orally administered at 300 mg/kg, and then 20% LE was administered intraperitoneally at 1st hour.
Group 5: Rivaroxaban was orally administered at 300 mg/kg, and then 20% LE was administered intraperitoneally at 3rd hour.
ACCEPTED MANUSCRIPT Group 6: Rivaroxaban was orally administered at 300 mg/kg, and then AC was orally administered at 1 g/kg at 1st hour.
Group 7: Rivaroxaban was orally administered at 300 mg/kg, and then AC was orally
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administered at 1 g/kg at 1st hour and 20% LE was administered intraperitoneally at 3rd
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hour.
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While rivaroxaban and AC were given with orogastric tube, LE was administered
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intraperitoneally. 300mg/ kg rivaroxaban was administered according to previously defined
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LD 50 dose in mice[9]. One study conducted by Perez et al. demonstrated that survival rose after 18,6 ml/ kg LE in rodents [10] but because of poor solubility and lower blood volume in
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mice , we applied 15 ml / kg LE and 300 mg/ kg rivoraxaban each mouse.
No deaths were observed in the groups during the experiment. All experimental
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animals were anesthetized with 50 mg/kg IM ketamine (Ketamine hydrochloride, Ketalar®,
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Pfizer, Istanbul, Turkey) 5 hours after first drug administration. They were sacrificed by the cardiac puncture blood collection method.
The brain(cerebrum and cerebellum), stomach, and small and large bowel tissues were appropriately obtained from the sacrificed subjects for pathological examination. The samples was examined by the same pathologist who was blinded to the groups of samples. Specimens were fixed in 10% of formalin solution. After obtaining slices of 4 to 5mm of
ACCEPTED MANUSCRIPT thickness from the paraffin embedded specimen, they were stained with hematoxylin and eosin. The samples were evaluated for hemorrhage under light microscope. The criteria for the minor hemorrhage in the gastrointestinal tract (stomach, small intestine and large
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bowel) was extravasation of blood into the mucosa, muscularis mucosa, submucosa,
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was extravasation of blood into the brain parenchyma.
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muscularis propria and serosa. Also the criteria for intracerebral haemorrhage
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The blood samples from mice were transferred to 3.2% (109 mmol/L) sodium citrate tubes at an appropriate dose. Prothrombin time (PT) and anti-factor Xa (Anti-FXa) activity
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were examined.
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STATISTICAL METHOD
Statistical analyzes were performed with the SPSS for Windows Version 20.0 package
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program. Numerical variables were expressed as mean±standard deviation and median
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[minimum-maximum] values. The Kruskal-Wallis test was used whether there was a difference between the groups in terms of PT and Anti-FXa activity. P<0.05 was considered statistically significant. Power analyse was performed and 6 animals for each group were determined.
ACCEPTED MANUSCRIPT RESULTS:
PT and Anti-FXa values of the groups not receiving rivaroxaban (Groups 2 and 3) were compared with those of the rivaroxaban group and the rivaroxaban+treatment groups.
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Another experimental group in which no substance was used was not created in order not to
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increase animal sacrifice. The group receiving only AC was defined as the control group
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(Table 1, 2).
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Although there were some small decreases in mean PT and Anti-FXa levels as the
these results
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control group and four rivaroxaban+treatment groups ( group 4,5,6,7) were compared , were statistically insignificant. (Group 4 PT:32.07±9.31 Anti-FXa:
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1320.33±275.61, Group 5 PT:31.25±12.15 Anti-FXa 1708.67±482,20, Group 6 PT 26.13±7.60
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Anti-FXa 1237.67±344.95, Group 7 PT:22.33±7.95 Anti-FXa:760.33±166.95). (Figure 1,2)
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Also, the statistical analyze showed that there were no discrimination in mean PT and
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Anti-FXa levels between given LE in the first hour and in the third hour.
PATHOLOGICAL EXAMINATION
There was no macroscopic and microscopic hemorrhage in all samples of groups.
DISCUSSION
ACCEPTED MANUSCRIPT The use of rivaroxaban at very high doses leads to deterioration in coagulation tests. It is known that particularly a massive rivaroxaban overdose prolongs the PT [9]. [11]. The concentration of rivaroxaban cannot be assessed by routine coagulation tests, but it is known
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that an increase in rivaroxaban concentration prolongs the PT and aPTT [7, 10]. [7, 8, 11, 12]. In a study conducted on healthy volunteers by Eerenberg et al. [11], [13], they found that the
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PT was prolonged. Although it was reported that the PT was prolonged when rivaroxaban
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was used at high doses, its use is not recommended in clinical evaluation. The chromogenic
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anti-factor Xa assay is recommended as a routine monitoring method for factor Xa inhibitors
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[7, 11, 12, 14].
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In our study, it was found that the mean PT was prolonged in mice receiving
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rivaroxaban. In our study, it was found that the mean PT was prolonged and anti-factor Xa activity increased in mice receiving rivaroxaban. When the rivaroxaban group was compared
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with the groups not receiving rivaroxaban, the PT was increased and there was a statistically
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significant difference (p<0.001).
AC Activated charcoal used to prevent drug absorption from the gastrointestinal tract after drug overdose may also be useful for overdose of factor Xa inhibitors [9] [11]. In a study performed on healthy volunteers by Wang et al. [12], [15], AC was given following administration of apixaban at toxic dose, and the concentration of apixaban was found to be
ACCEPTED MANUSCRIPT decreased. Except for a case report who used rivaroxaban due to pulmonary thromboembolism and received a high dose of rivaroxaban due to wrong order and then was treated with AC [13], [16]. The idea that lipid emulsions are used as lipophilic drug
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during intoxication has existed for a long time. It was studied on gluthemid for lipid emulsions to be used as dialysate in lipophilic drug toxication [17]. In an animal experiment,
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intravenous fat emulsion was used to reduce the effect of chlorpromazine [18]. A study
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conducted in 1998 found that lipid therapy is a useful treatment for local anesthetic systemic
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toxicity [19]. Scientists who have been studying in this regard have thought that intravenous
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lipid emulsion therapy may be beneficial in lipophilic drugs and have achieved various results. There are studies about its use in the toxicity of many lipophilic substances, primarily the
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toxicity of local anesthetics such as bupivacaine [20], lidocaine [21], and ropivacaine [22]. Currently, the use of lipid emulsion therapy in resuscitation attempts after local anesthetic
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toxicity and in situations where drug toxicity cannot be resolved with the standard
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resuscitation approaches is recommended in 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care [5].
there are no studies in the literature on the use of AC in rivaroxaban toxicity. In the literature, there is no study on the use of lipid emulsion and/or activated charcoal in rivaroxaban toxicity.
ACCEPTED MANUSCRIPT
In our study,
the control group and the rivaroxaban+treatment groups were
compared in terms of PT and anti-factor Xa levels, it was seen that the mean PT and anti-
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factor Xa levels increased in the groups receiving rivaroxaban+LE at 1 hour, rivaroxaban+LE
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at 3 hour, rivaroxaban+activated charcoal at 1 hour and rivaroxaban+activated charcoal at 1
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hour+LE at 3 hour. However, there was no statistically significant difference between these
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groups (respectively, p=1.00, p=0.06; p=1.00, p=0.20; p=1.00, p=0.11 and p=0.95, p=0.83)
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In our experimental study, the intraperitoneal route was preferred because LE should be given in the amount that we cannot give intravenously to mice. LE was given
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intraperitoneally in some previous studies, and it is known that intraperitoneal absorption
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occurs from the first hour [36, 37]. [23, 24]. However, in our study, it is considered that LE
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did not completely pass into the systemic circulation because it was planned to see its effect
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within the first 6 hours and that the optimal LE levels in the plasma could not be reached because no a further infusion of LE was given. However, the decrease in PT value is thought to be clinically important.
The general approach in acute drug intoxications is decontamination of the substance and supportive care [39, 40]. [25, 26]. Moreover, the use of the antidote can be a solution. Therefore, it is thought that new and more effective medical treatment methods for
ACCEPTED MANUSCRIPT detoxification are needed [41]. [27]. New treatments in toxicology are being investigated with original methods such as radioligand binding, use of nanobodies, protein-protein interaction inhibitors, aptamers, antisense oligonucleotides, and protein-selective small
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molecules [1, 42-47]. [1, 28-33]. However, considering the factors such as cost and accessibility, a general antidote application would be cheaper and accessible rather than a
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special antidote to each poison. The fact that There was a 61% decrease in the mean Anti-
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FXa levels in the group receiving AC at 1st hour and LE at 3rd hour after rivaroxaban
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compared to the rivaroxaban group in our study suggests that it may be useful in the
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treatment of intoxication. However, this should be supported by further studies. that the use of AC and LE would be beneficial in the early period of rivaroxaban toxicity in clinic, further
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studies are required to recommend its routine use.
Spiller et al. [9] [11] reported that no bleeding was observed in acute rivaroxaban
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toxicity and that bleeding was more associated with long-term treatment. Replinger et al.
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[48] [34] reported that there was no bleeding after acute rivaroxaban overdose. No bleeding was observed in a case receiving 1960 mg rivaroxaban who was reported by Lehman et al. [49] [35] and in a case receiving 1400 mg rivaroxaban who was reported by Linkins et al. [50]. [36]. The fact that being no macroscopic or microscopic hemorrhage in any of 30 mice given a massive dose of rivaroxaban in our study supports this finding.
ACCEPTED MANUSCRIPT LIMITATIONS OF THE STUDY
The toxic effect of rivaroxaban is observed mostly in chronic use. In our experiment, the subjects were sacrificed at the 5th hour following a high dose of rivaroxaban. There was no
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bleeding or death in the group receiving only a high dose of rivaroxaban. Therefore, the
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effects of AC and LE at these outcome points could not be assessed. LE could not be applied
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optimally in experimental animals. Since intravenous administration is not possible in mice,
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intraperitoneal administration was performed, and no intravenous infusion was given after bolus administration. Lipid emulsion was observed in the peritoneum after sacrification in all
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experimental animals given LE. It is thought that LE might have not been given at effective
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doses and therefore sufficient effect could might have not been achieved. Also, the number
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COMPETING INTERESTS
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of animals were smallrestricted with 42 subjects in order not to increase animal sacrifice.
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The authors declared that they have no competing interests.
ACKNOWLEDGEMENTS
This study received funding from Ufuk University research funds.
References:
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35. Weinberg, G.L., Lipid emulsion infusion: resuscitation for local anesthetic and other drug overdose. Anesthesiology, 2012. 117 (1): p. 1807. 36. Mahedero, G., et al., Absorption of Intralipid and interferences from nutrients infused into the peritoneal cavity of the rat. Am.J.Surg, 1992. 164:p. 45-50 37. Moran, J., et al., Transperitoneal absorption of intralipid in rats: total serum fatty acids and triglyceride after absorption. JPEN J Parenter Enteral Nutr. 1986.10 (6):604-8. 38. Douxfils, J., et al., Non-VKA Oral Anticoagulants: Accurate Measurement of Plasma Drug Concentrations. Biomed Res Int, 2015. 2015: p. 345138. 39. Ferner, R.E., Our poisoned patients. Qjm, 2001. 94 (3): p. 117-20. 40. Larsen, L.C. and D.M. Cummings, Oral poisonings: guidelines for initial evaluation and treatment. Am Fam Physician, 1998. 57 (1): p. 85-92. 41. Zhang, L. and J.C. Leroux, Current and forthcoming approaches for systemic detoxification. Adv Drug Deliv Rev, 2015. 90: p. 1-2. 42. Insel, P.A., et al., Introduction to the Theme "New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology". Annu Rev Pharmacol Toxicol, 2016. 43. Bondeson, D.P. and C.M. Crews, Targeted Protein Degradation by Small Molecules. Annu Rev Pharmacol Toxicol, 2016. 44. Forster, V. and J.C. Leroux, Nano-antidotes for drug overdose and poisoning. Sci Transl Med, 2015. 7 (290): p. 290ps14. 45. Oney, S., et al., Development of universal antidotes to control aptamer activity. Nat Med, 2009. 15 (10): p. 1224-8. 46. Forster, V., P. Luciani, and J.C. Leroux, Treatment of calcium channel blocker-induced cardiovascular toxicity with drug scavenging liposomes. Biomaterials, 2012. 33 (13): p. 3578-85. 47. Zhu, Y., et al., Engineering Factor Xa Inhibitor with Multiple PlateletBinding Sites Facilitates its Platelet Targeting. Sci Rep, 2016. 6: p. 29895. 48. Repplinger, D.J., et al., Lack of significant bleeding despite large acute rivaroxaban overdose confirmed with whole blood concentrations. Clin Toxicol (Phila), 2016. 54 (8): p. 647-9. 49. Lehmann, T., et al., Massive human rivaroxaban overdose. Thromb Haemost, 2014. 112 (4): p. 834-6. 50. Linkins, L.A. and K. Moffat, Monitoring the anticoagulant effect after a massive rivaroxaban overdose. J Thromb Haemost, 2014. 12 (9): p. 1570-1.
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ACCEPTED MANUSCRIPT Table 1: All groups descriptive values
1929,83 ± 344,18
10,50 ± 0,33
<25
10,07 ± 0,40
<25
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1708,67 ± 482,20
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31,25 ± 12,15
1320,33 ± 275,61
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32,07 ± 9,31
PT
38,93 ± 9,13
26,13 ± 7,60
1237,67 ± 344,95
22,33 ± 7,95
760,33 ± 166,95
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Group 7 (Rivaroxaban+AC+LE)
Anti-Fxa (ng/ml) (Mean±SD)
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Group 1 (Rivaroxaban) Group 2 (LE) Group 3 (AC) Group 4 (Rivaroxaban+LE 1st hour) Group 5 (Rivaroxaban+LE 3rd hour) Group 6 (Rivaroxaban+AC)
PT (second) (Mean±SD)
PT: Prothrombin Time, SD: Standard Deviation, Anti-FXa: Antifactor Xa , LE: Lipid Emulsion, AC:
AC
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Activated Charcoal
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Table 2: P value comparison between groups
PT (p value)
Anti FXa (p value)
Groups
PT (p value)
Anti FXa (p value)
Group 1 - Group 2
0,004*
0,002*
Group 3 - Group 4
0,01*
0,06*
Group 1 - Group 3
0,001*
0,002*
Group 3 - Group 5
0,02*
0,06*
Group 1 - Group 4
1
1
Group 3 - Group 6
0,10
0,11
Group 1 - Group 5
1
1
Group 3 - Group 7
0,46
0,83
Group 1 - Group 6
1
1
Group 4 - Group 5
1
1
Group 1 - Group 7
0,94
1
Group 4 - Group 6
1
1
Group 2 - Group 3
1
1
Group 4 - Group 7
1
1
Group 2 - Group 4
0,06
0,06
Group 5 - Group 6
1
1
Group 2 - Group 5
0,14
0,02*
Group 5 - Group 7
1
1
Group 2 - Group 6
0,48
0,11
Group 6 - Group 7
1
1
Group 2 - Group 7
1
0,83
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Group 1 : Rivaroxaban Group 2 : LE Group 3 : AC Group 4 : Rivaroxaban + LE 1 st hour Group 5 : Rivaroxaban + LE 3 st hour Group 6 : Rivaroxaban + AC Group 7 : Rivaroxaban + AC + LE
PT
Groups
AC
PT: Prothrombin Time, Anti-Fxa: Antifactor Xa, LE: Lipid Emulsion, AC: Activated Charcoal, * p<0,05
Figure 1
Figure 2