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Effect of Intravenous Lipid Emulsion on Clozapine Acute Toxicity in Rats

Effect of Intravenous Lipid Emulsion on Clozapine Acute Toxicity in Rats administration causes pancreatitis and lung injury but Objectives: Many studies have been reported the effi - fat emulsion did not show an optimal eff ect on tissue cacy of intravenous lipid emulsion (ILE) as an antidote damages caused by clozapine toxicity. on acute lipophilic drug toxicity. Clozapine, highly li- pophilic dibenzodiazepine neuroleptics, is an impor- Conclusion: In conclusion, ILE can remove toxic signs tant medication in the schizophrenia therapy regimen. of clozapine same as other lipophilic medicines, how- Acute intoxication with antipsychotics is one of the ever, clinical uses of ILE for this intention requires main reasons for the referral of poisoned patients to more appraisement to determine the precise implica- the hospital. We expected that ILE could be used for the tion and safety. therapy of acute clozapine intoxicated patients. 1. Introduction Methods: We used two groups of consisting of six male rats. Both groups received a toxic dose of clozapine (40 AILE has been used to supply calories in the form of mg/kg) intravenously, via the tail vein. After 15 minutes, free fatty acids in patients who require parenteral nu- they were treated with intravenous infusion of 18.6 mg/ trition. Th ere are many reports on the effi cacy of intra- kg normal saline (NS group), or 18.6 mg/kg ILE 20% (ILE venous lipid emulsion (ILE) as an antidotal candidate group). We evaluated blood pressure (BP) and heart rate in intoxication with medications [1-3]. Investigations by power lab apparatus through the tail artery, ataxia by and case reports about this novel benefi t of ILE result a rat rotary circle, seizure scores and death in multiple in adding it into Guidelines for the Management of times after starting clozapine administration. For bio- Severe Local Anesthetic Toxicity [4-6]. ILE has been shown to have positive impacts toxicity resulted in li- pophilic drugs overdose through some case reports Received: Feb 02, 2019 Reviewed: Apr 15, 2019 Accepted: May 31, 2019 This is an Open-Access article distributed under the terms of the Creative Commons Corresponding Author Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad Univer- which permits unrestricted noncommercial use, distribution, and reproduction in any sity of Medical Sciences, Mashhad, Iran. medium, provided the original work is properly cited. Tel: +98-513-881-9042 Fax: +98-513-882-3251 E-mail: hosseinzadehh@mums.ac.ir This paper meets the requirements of KS X ISO 9706, ISO 9706-1994 and ANSI/NISO Z39.48-1992 (Permanence of Paper). ⓒ 2019 Korean Pharmacopuncture Institute http://www.journal.ac Journal of Pharmacopuncture 2019;22[3]:147-153 http://www.journal.ac and animal studies [7, 8]. Acute antipsychotic drug poison- 2.3.3. Evaluation of cardiovascular toxicity, ing is one of the most important reasons for referring to blood pressure, and heart rate measurement the hospital [9, 10]. Clozapine, highly lipophilic dibenzo- diazepine neuroleptics, is one of the most eff ective for the Blood pressure (BP) and heart rate were evaluated by therapy of schizophrenia and is increasingly being used to power lab apparatus (Data Acquisition Systems, US) treat aff ective disorders, some neurological disorders, and through the tail artery, in the conscious animals. For this aggression [11, 12]. Clozapine toxicity has been common- purpose, rats were restricted in the clear restraint tube. ly seen in psychotic patients [13, 14], especially in patients Th eir tails were warming up to 28-29°C. After allowing 15 who received diff erent drugs simultaneously [13, 15]. min for each animal to acclimatize in the tube, an 11-mm Clozapine toxicity like other antipsychotic toxicity causes cuff was placed around the tail. Th e pulses were recorded side eff ects in several organ systems that need emergency at a rate of 3 mm Hg/s. Th e systolic pressure was incorpo- evaluation and treatment, like serious cardiovascular side rated as the pressure at the point when the fi rst tail pulse eff ects include hypotension and myocarditis; the serious was discovered. By calculating the number of pulses reg- neurological side eff ects include seizures and ataxia; seri- istering over a 2-s period, the heart rate was calculated ous hematological side eff ect of agranulocytosis and tissue (beats/min). [25]. injuries [16-22] Th e primary objective of this study is to determine if ILE would have benefi cial eff ects in the setting of clozapine 2.4. Evaluation of neurotoxicity, ataxia, and toxicity. seizure 2. Materials and Methods: 2.4.1. Rotarod performance 2.1. Animals Rotarod test (Borj Sanat, Iran), as ataxic criteria, meas- ured the ability of the animal to maintain itself on the re- Adult male Wistar rats (Bu-Ali Research Institute, Mash- volving rod. Four days before the onset of tests, the rats had, I.R. Iran), weighing 250-300 g, were used for all ex- were trained (three 2-min trials/day). Only animals able periments. Th ese animals were housed in a pathogen-free for remaining 120 seconds on the rod without any fall, facility on a 12 hour light/dark schedule and with ad lib were selected for experiments [26]. access to food and water. All animal procedures were ap- proved by the ethics committee of MUMS (Mashhad Uni- 2.4.2. Seizure scores versity of Medical Sciences). Seizure scores were classifi ed according to a modifi ed 2.2. Preparation of clozapine intravenous scale [27]. solution 2.5. Biochemical and Histopathological Studies 5 mg of the clozapine powder (Exir Pharmaceutical Co., Iran) dissolved in HCl for preparing the clozapine intra- For biochemical and pathological evaluations the sam- venous (IV) solution. Th en, normal saline was used for ples of tissue and blood were taken from all animals after reaching working concentration. Th e neutralization was 24h or at the death point. All tests were blindly carried out done with NaCl solution [23]. Th e sterile pyrpgen free nor- with a single pathologist. mal saline (NS) and ILE (Fresenius Kabi AB, Spain) were also IV administered. 2.6. Statistical Analysis: Statistical analysis of all variables was performed using 2.3. Procedures Statistical Package for Social Sciences software version 2.3.1 Animal Groups 11.5 (SPSS Inc., Chicago, Illinois, USA). Two-way repeated measures analysis of variance (ANOVA) was used to evalu- We used two groups of consisting six male rats. Both ate the diff erences in BP of diff erent groups. Kruskal–Wal- groups received a toxic dose of clozapine, 40 mg/kg intra- lis ANOVA or Mann–Whitney test was used, if necessary. venously, through tail vein through 60 seconds (time 0). Th e alpha level was set at 0.05. After 15 minutes (time 1) the fi rst group received 18.6mg/ kg normal saline intravenously (NS group), and the sec- 3. Results ond group received 18.6 mg/kg ILE 20% intravenously (ILE group) [24]. 3.1. Survival 2.3.2. Animal Toxicity Tests After Clozapine administration, animals were assessed for their survival and 2 deaths were recorded in the NS All toxicological evaluations and survival observations group before 24 hours. were performed at 0, 15, 30, 45, 60, 180, 360, 720 and 1440 According to Fisher Exact test, there were no signifi cant minutes after starting clozapine administration. diff erences with regard to the number of deaths between the 2 groups receiving either NS or ILE. (P = 0.4545) Journal of Pharmacopuncture 2019;22[3]:147-153 http://www.journal.ac ed group become hypotensive again, while the BP of ILE 3.2. Seizur treated group remained near normal up to the end of measurement (P < 0.001). According to seizure assessment, seizure scores during a 24-hour observation were recorded. Seizures initiated as soon as Clozapine injection was completed in all groups. ILE signifi cantly decreased (P < 0.05) seizure scores in comparison with NS (Fig. 1). Figure 3 Eff ect of lipid emulsion on blood pressure after acute clozapine poisoning in diff erent groups of animals. Signifi cant diff erence *= (P < 0.05), **= (p < 0.01); ***= (p < 0.001), (N = 6) 3.5. Histopathological Studies Figure 1 Eff ect of infusion of 18.6 ml/kg intravenous lipid emul- sion (ILE) on seizure scores induced by acute clozapine (40 mg/ Th e histopathological evaluation of the lung of the rats kg) poisoning in comparing with normal saline (NS).* P < 0.5, ** showed similar educative secretions and alveolar wall In- P<0.01 data were reported by Mean ± SE, analyzed by ANOVA, fl ammation in both groups (Fig. 4). However, the conjuga- post test = Tuky, (N = 6) tion of vessels and fat necrosis of pancreatic tissue slides were reported equal in both groups, the scoring of pan- creatic parenchyma infl ammation in ILE group was lower 3.3. Ataxia than NS treated group (1 ± 0.089 and 1.67 ± 0.51; P < 0.05) (Fig. 5). ILE signifi cantly rectifi ed ataxia more rapid than NS, and ILE treated rats were able to stay and walk on the rat ro- tarod at the 3rd hour (P < 0.01), however, the NS-treated group was ataxic more than 24 hours (Fig. 2). Figure 4 Pancreas slides of rats treated by Clozapine and in- travenous lipid emulsion (ILE) or normal saline (NS). Magnifi - cation = ×400. (A) Moderate infl ammation: Clozapine+NS (B) Sever infl ammation: Clozapine+NS. (C) Mild infl ammation: Clozpine+ILE , (N=6) Figure 2 Eff ect of infusion of 18.6 ml/kg intravenous lipid emul- sion (ILE) on acute clozapine (40 mg/kg) induced an ataxia in comparing with normal salin (NS).**= (p < 0.01); ***= (p < 0 .001) data were reported by Mean ± SE, analyzed by ANOVA, post test Figure 5 Lung slides of rats treated by Clozapine and intravenous = Tuky, (N = 6) lipid emulsion (ILE) or normal saline (NS). (A) Magnifi cation = ×400, Infl ammation of the lining of the lung alveoli in both groups 3.4. Blood pressure (Clozapine+NS and Clozapine+ILE). (B) Magnifi cation = ×100 Pul- monary alveolar wall with hemorrhage, infl ammation and vessels As shown in fi gure 3, administration of 18.5 ml/kg of NS Conjugated in both groups (clozapine+NS and Clozapine+ILE). or ILE to clozapine poisoned hypotensive rats raised their (C) Magnifi cation = ×100 Exudative secretions and edematous wall blood pressure to near normal baseline, but NS-treat- of the alveoli in both groups (Clozapine+NS and Clozapine+ILE). Journal of Pharmacopuncture 2019;22[3]:147-153 http://www.journal.ac sink theory justifi es the failure of ILE to improve intoxica- 3.6. Biochemical tests tion of less lipid-soluble drugs such as nifedipine [31]. Clo- zapine volume of distribution is lower than that of other As demonstrated in table 1, following clozapine intoxi- antipsychotic drugs, but, is nonetheless considerable (2.0 cation, lipase and amylase increased in both groups, and – 5.1 L/kg) [32]. there was no signifi cant diff erence between the NS group Although the lipid sink theory could explain the antihy- and the ILE group in the amount of the amylase and lipase. potensive eff ect of ILE in lipophilic drug toxicity, it is sug- Th e number of blood platelets and white blood cell in rats gested that there are other important mechanisms. Free receiving NS compared with ILE after clozapine intoxica- fatty acids increase the calcium infl ux into myocytes and tion signifi cantly reduced (P < 0.001). Other cell count cri- smooth muscles [33]. It not only improves impaired car- teria were almost similar in both groups. diac function but also raises blood pressure [34, 35]. Al- though we did not evaluate the cardiac function of intox- icated rats, it is possible that some of the antidotal eff ects Table 1 Th e result of comparing the biochemical tests in both of ILE on resolving clozapine-induced hypotension are groups receiving normal saline or intralipid after clozapine poi- related to its cardiac eff ects, as well. soning. (Signifi cant diff erence *: P < 0.05) Th e toxic level of clozapine causes neurotoxicity symp- toms, such as ataxia and seizure. In addition to blocking dopamine receptors, clozapine antagonizes a number of other receptor sites, including the norepinephrine, hista- mine, acetylcholine and serotonin system and partially re- verses the inhibitory eff ect of GABA on 35S-t-butyl bicycle phosphorothionate (35S-TBPS) binding [36]. According to previous studies, clozapine aff ects excitatory amino acid release in nucleus accumbens [37], alters glutamate-de- pendent excitatory postsynaptic potentials in hippocam- pal slices [38] and glutamate- mediated evoked fi eld po- tentials in rat striatum [39]. Clozapine-induced ataxia may relate to its serotonergic eff ect [40]. However, clozapine administration induced ataxia and some levels of the sei- zure (time 0), at time 1 these signs have rectifi ed more 4. Discussion rapidly in the ILE group than in the NS group. Th e most important hypothesis that explains the mechanism of the As the result revealed fat emulsion could reduce toxic antidotal eff ect of ILE against CNS intoxication of xenobi- signs of clozapine same as other lipophilic medicines. otics is the lipid sink theory [31]. It suggests that lipophilic After clozapine administration, animals were assessed for medicines or xenobiotics, when administered at toxic lev- survival and 2 deaths were recorded in the NS group dur- els, were redistributed from their site of action to a new in- ing the 24 hours evaluation. Although the mortality rate of ner compartment made by ILE in the vessels. Also, there ILE treated group was lower than NS, there was no signifi - is another antidotal mechanism for ILE in neurotoxicity cant diff erence between the two groups, and it may be due caused by clozapine, ILE and high chain free fatty acid are to small sample size. Th erefore, further study is needed to capable of increasing intracellular calcium concentrations evaluate the eff ects of ILE on clozapine mortality. in neurons, and also in ventricular muscles cells. Th us, it Using plasma expanders is an eff ective way for the treat- is suggested that ILE not only reduces clozapine concen- ment of clozapine-induced hypotension. In our investiga- tration in target organs based on the lipid sink theory but tion, clozapine-induced hypotension has responded to a also restores the clozapine-induced neurotoxicity through volume expander solution like normal saline. Normal sa- increasing the intraneuronal calcium concentration. line could raise reduced BP of rats after administration, al- Most patients who take clozapine, especially in the fi rst though its eff ect was not long-lasting and BP reduced again month of use, symptoms of infl ammation of the pancreas at the fi rst hour (Fig.3). A persistent rise in BP after ILE ad- and increasing enzymes like amylase and lipase are visible ministration suggests that it may also act through mech- [41]. In this study after pathological tests, pancreatitis was anisms other than volume expansion. It seems that ILE observed in both groups receiving normal saline and ILE could redistribute clozapine, which is a high lipid soluble after clozapine intoxication, but the parenchymal infl am- medicine from peripheral or central receptors into the new mation of pancreas tissue was signifi cantly higher in the neutral compartment and resolves the signs of toxicity. NS group compare with the ILE group. But other patholog- Previous animal tests support the eff ect of ILE in reveling ical factors explored in the study did not show a signifi cant lipophilic drugs induced hypotension. In a study ILE has diff erence between the two groups. On the other hand, shown signifi cant positive eff ects for primary or secondary there were no signifi cant diff erences in the amount of am- hemodynamic endpoints in metoprolol, verapamil, tram- ylase and lipase in both groups. adol and haloperidol intoxication [2, 7, 28-30]. Th ere is a One of the important body organ that clozapine was suggested mechanism for ILE in revealing drugs-induced stored and causes toxicity is the lungs [42]. In this study, hypotension, the lipid sink theory. Th rough lipid sink the- ILE also neither reduce nor raised clozapine intoxication ory, lipophilic drugs redistribute from the site of toxicity lung injuries. Perhaps no decrease in lung injury is due to into a new lipid compartment following ILE infusion. Lipid the fat emulsion potential to cause pulmonary injury [43]. Journal of Pharmacopuncture 2019;22[3]:147-153 http://www.journal.ac Th erefore, we can conclude that these results represent References the little eff ect of ILE in resolving tissue damages caused by clozapine toxicity. 1. Aksel G, Guneysel O, Tasyurek T, Kozan E, Cevik SE. 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Journal of clinical psy- chopharmacology. 2008;28(6): 706-7. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Pharmacopuncture Pubmed Central

Effect of Intravenous Lipid Emulsion on Clozapine Acute Toxicity in Rats

Yousefsani, Bahareh Sadat; Mohajeri, Seyed Ahmad; Moshiri, Mohammad; Jafarian, Amir Hossein; Hosseinzadeh, Hossein
Journal of Pharmacopuncture , Volume 22 (3) – Sep 30, 2019
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© 2019 Korean Pharmacopuncture Institute
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2093-6966
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2234-6856
DOI
10.3831/KPI.2019.22.019
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Abstract

administration causes pancreatitis and lung injury but Objectives: Many studies have been reported the effi - fat emulsion did not show an optimal eff ect on tissue cacy of intravenous lipid emulsion (ILE) as an antidote damages caused by clozapine toxicity. on acute lipophilic drug toxicity. Clozapine, highly li- pophilic dibenzodiazepine neuroleptics, is an impor- Conclusion: In conclusion, ILE can remove toxic signs tant medication in the schizophrenia therapy regimen. of clozapine same as other lipophilic medicines, how- Acute intoxication with antipsychotics is one of the ever, clinical uses of ILE for this intention requires main reasons for the referral of poisoned patients to more appraisement to determine the precise implica- the hospital. We expected that ILE could be used for the tion and safety. therapy of acute clozapine intoxicated patients. 1. Introduction Methods: We used two groups of consisting of six male rats. Both groups received a toxic dose of clozapine (40 AILE has been used to supply calories in the form of mg/kg) intravenously, via the tail vein. After 15 minutes, free fatty acids in patients who require parenteral nu- they were treated with intravenous infusion of 18.6 mg/ trition. Th ere are many reports on the effi cacy of intra- kg normal saline (NS group), or 18.6 mg/kg ILE 20% (ILE venous lipid emulsion (ILE) as an antidotal candidate group). We evaluated blood pressure (BP) and heart rate in intoxication with medications [1-3]. Investigations by power lab apparatus through the tail artery, ataxia by and case reports about this novel benefi t of ILE result a rat rotary circle, seizure scores and death in multiple in adding it into Guidelines for the Management of times after starting clozapine administration. For bio- Severe Local Anesthetic Toxicity [4-6]. ILE has been shown to have positive impacts toxicity resulted in li- pophilic drugs overdose through some case reports Received: Feb 02, 2019 Reviewed: Apr 15, 2019 Accepted: May 31, 2019 This is an Open-Access article distributed under the terms of the Creative Commons Corresponding Author Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad Univer- which permits unrestricted noncommercial use, distribution, and reproduction in any sity of Medical Sciences, Mashhad, Iran. medium, provided the original work is properly cited. Tel: +98-513-881-9042 Fax: +98-513-882-3251 E-mail: hosseinzadehh@mums.ac.ir This paper meets the requirements of KS X ISO 9706, ISO 9706-1994 and ANSI/NISO Z39.48-1992 (Permanence of Paper). ⓒ 2019 Korean Pharmacopuncture Institute http://www.journal.ac Journal of Pharmacopuncture 2019;22[3]:147-153 http://www.journal.ac and animal studies [7, 8]. Acute antipsychotic drug poison- 2.3.3. Evaluation of cardiovascular toxicity, ing is one of the most important reasons for referring to blood pressure, and heart rate measurement the hospital [9, 10]. Clozapine, highly lipophilic dibenzo- diazepine neuroleptics, is one of the most eff ective for the Blood pressure (BP) and heart rate were evaluated by therapy of schizophrenia and is increasingly being used to power lab apparatus (Data Acquisition Systems, US) treat aff ective disorders, some neurological disorders, and through the tail artery, in the conscious animals. For this aggression [11, 12]. Clozapine toxicity has been common- purpose, rats were restricted in the clear restraint tube. ly seen in psychotic patients [13, 14], especially in patients Th eir tails were warming up to 28-29°C. After allowing 15 who received diff erent drugs simultaneously [13, 15]. min for each animal to acclimatize in the tube, an 11-mm Clozapine toxicity like other antipsychotic toxicity causes cuff was placed around the tail. Th e pulses were recorded side eff ects in several organ systems that need emergency at a rate of 3 mm Hg/s. Th e systolic pressure was incorpo- evaluation and treatment, like serious cardiovascular side rated as the pressure at the point when the fi rst tail pulse eff ects include hypotension and myocarditis; the serious was discovered. By calculating the number of pulses reg- neurological side eff ects include seizures and ataxia; seri- istering over a 2-s period, the heart rate was calculated ous hematological side eff ect of agranulocytosis and tissue (beats/min). [25]. injuries [16-22] Th e primary objective of this study is to determine if ILE would have benefi cial eff ects in the setting of clozapine 2.4. Evaluation of neurotoxicity, ataxia, and toxicity. seizure 2. Materials and Methods: 2.4.1. Rotarod performance 2.1. Animals Rotarod test (Borj Sanat, Iran), as ataxic criteria, meas- ured the ability of the animal to maintain itself on the re- Adult male Wistar rats (Bu-Ali Research Institute, Mash- volving rod. Four days before the onset of tests, the rats had, I.R. Iran), weighing 250-300 g, were used for all ex- were trained (three 2-min trials/day). Only animals able periments. Th ese animals were housed in a pathogen-free for remaining 120 seconds on the rod without any fall, facility on a 12 hour light/dark schedule and with ad lib were selected for experiments [26]. access to food and water. All animal procedures were ap- proved by the ethics committee of MUMS (Mashhad Uni- 2.4.2. Seizure scores versity of Medical Sciences). Seizure scores were classifi ed according to a modifi ed 2.2. Preparation of clozapine intravenous scale [27]. solution 2.5. Biochemical and Histopathological Studies 5 mg of the clozapine powder (Exir Pharmaceutical Co., Iran) dissolved in HCl for preparing the clozapine intra- For biochemical and pathological evaluations the sam- venous (IV) solution. Th en, normal saline was used for ples of tissue and blood were taken from all animals after reaching working concentration. Th e neutralization was 24h or at the death point. All tests were blindly carried out done with NaCl solution [23]. Th e sterile pyrpgen free nor- with a single pathologist. mal saline (NS) and ILE (Fresenius Kabi AB, Spain) were also IV administered. 2.6. Statistical Analysis: Statistical analysis of all variables was performed using 2.3. Procedures Statistical Package for Social Sciences software version 2.3.1 Animal Groups 11.5 (SPSS Inc., Chicago, Illinois, USA). Two-way repeated measures analysis of variance (ANOVA) was used to evalu- We used two groups of consisting six male rats. Both ate the diff erences in BP of diff erent groups. Kruskal–Wal- groups received a toxic dose of clozapine, 40 mg/kg intra- lis ANOVA or Mann–Whitney test was used, if necessary. venously, through tail vein through 60 seconds (time 0). Th e alpha level was set at 0.05. After 15 minutes (time 1) the fi rst group received 18.6mg/ kg normal saline intravenously (NS group), and the sec- 3. Results ond group received 18.6 mg/kg ILE 20% intravenously (ILE group) [24]. 3.1. Survival 2.3.2. Animal Toxicity Tests After Clozapine administration, animals were assessed for their survival and 2 deaths were recorded in the NS All toxicological evaluations and survival observations group before 24 hours. were performed at 0, 15, 30, 45, 60, 180, 360, 720 and 1440 According to Fisher Exact test, there were no signifi cant minutes after starting clozapine administration. diff erences with regard to the number of deaths between the 2 groups receiving either NS or ILE. (P = 0.4545) Journal of Pharmacopuncture 2019;22[3]:147-153 http://www.journal.ac ed group become hypotensive again, while the BP of ILE 3.2. Seizur treated group remained near normal up to the end of measurement (P < 0.001). According to seizure assessment, seizure scores during a 24-hour observation were recorded. Seizures initiated as soon as Clozapine injection was completed in all groups. ILE signifi cantly decreased (P < 0.05) seizure scores in comparison with NS (Fig. 1). Figure 3 Eff ect of lipid emulsion on blood pressure after acute clozapine poisoning in diff erent groups of animals. Signifi cant diff erence *= (P < 0.05), **= (p < 0.01); ***= (p < 0.001), (N = 6) 3.5. Histopathological Studies Figure 1 Eff ect of infusion of 18.6 ml/kg intravenous lipid emul- sion (ILE) on seizure scores induced by acute clozapine (40 mg/ Th e histopathological evaluation of the lung of the rats kg) poisoning in comparing with normal saline (NS).* P < 0.5, ** showed similar educative secretions and alveolar wall In- P<0.01 data were reported by Mean ± SE, analyzed by ANOVA, fl ammation in both groups (Fig. 4). However, the conjuga- post test = Tuky, (N = 6) tion of vessels and fat necrosis of pancreatic tissue slides were reported equal in both groups, the scoring of pan- creatic parenchyma infl ammation in ILE group was lower 3.3. Ataxia than NS treated group (1 ± 0.089 and 1.67 ± 0.51; P < 0.05) (Fig. 5). ILE signifi cantly rectifi ed ataxia more rapid than NS, and ILE treated rats were able to stay and walk on the rat ro- tarod at the 3rd hour (P < 0.01), however, the NS-treated group was ataxic more than 24 hours (Fig. 2). Figure 4 Pancreas slides of rats treated by Clozapine and in- travenous lipid emulsion (ILE) or normal saline (NS). Magnifi - cation = ×400. (A) Moderate infl ammation: Clozapine+NS (B) Sever infl ammation: Clozapine+NS. (C) Mild infl ammation: Clozpine+ILE , (N=6) Figure 2 Eff ect of infusion of 18.6 ml/kg intravenous lipid emul- sion (ILE) on acute clozapine (40 mg/kg) induced an ataxia in comparing with normal salin (NS).**= (p < 0.01); ***= (p < 0 .001) data were reported by Mean ± SE, analyzed by ANOVA, post test Figure 5 Lung slides of rats treated by Clozapine and intravenous = Tuky, (N = 6) lipid emulsion (ILE) or normal saline (NS). (A) Magnifi cation = ×400, Infl ammation of the lining of the lung alveoli in both groups 3.4. Blood pressure (Clozapine+NS and Clozapine+ILE). (B) Magnifi cation = ×100 Pul- monary alveolar wall with hemorrhage, infl ammation and vessels As shown in fi gure 3, administration of 18.5 ml/kg of NS Conjugated in both groups (clozapine+NS and Clozapine+ILE). or ILE to clozapine poisoned hypotensive rats raised their (C) Magnifi cation = ×100 Exudative secretions and edematous wall blood pressure to near normal baseline, but NS-treat- of the alveoli in both groups (Clozapine+NS and Clozapine+ILE). Journal of Pharmacopuncture 2019;22[3]:147-153 http://www.journal.ac sink theory justifi es the failure of ILE to improve intoxica- 3.6. Biochemical tests tion of less lipid-soluble drugs such as nifedipine [31]. Clo- zapine volume of distribution is lower than that of other As demonstrated in table 1, following clozapine intoxi- antipsychotic drugs, but, is nonetheless considerable (2.0 cation, lipase and amylase increased in both groups, and – 5.1 L/kg) [32]. there was no signifi cant diff erence between the NS group Although the lipid sink theory could explain the antihy- and the ILE group in the amount of the amylase and lipase. potensive eff ect of ILE in lipophilic drug toxicity, it is sug- Th e number of blood platelets and white blood cell in rats gested that there are other important mechanisms. Free receiving NS compared with ILE after clozapine intoxica- fatty acids increase the calcium infl ux into myocytes and tion signifi cantly reduced (P < 0.001). Other cell count cri- smooth muscles [33]. It not only improves impaired car- teria were almost similar in both groups. diac function but also raises blood pressure [34, 35]. Al- though we did not evaluate the cardiac function of intox- icated rats, it is possible that some of the antidotal eff ects Table 1 Th e result of comparing the biochemical tests in both of ILE on resolving clozapine-induced hypotension are groups receiving normal saline or intralipid after clozapine poi- related to its cardiac eff ects, as well. soning. (Signifi cant diff erence *: P < 0.05) Th e toxic level of clozapine causes neurotoxicity symp- toms, such as ataxia and seizure. In addition to blocking dopamine receptors, clozapine antagonizes a number of other receptor sites, including the norepinephrine, hista- mine, acetylcholine and serotonin system and partially re- verses the inhibitory eff ect of GABA on 35S-t-butyl bicycle phosphorothionate (35S-TBPS) binding [36]. According to previous studies, clozapine aff ects excitatory amino acid release in nucleus accumbens [37], alters glutamate-de- pendent excitatory postsynaptic potentials in hippocam- pal slices [38] and glutamate- mediated evoked fi eld po- tentials in rat striatum [39]. Clozapine-induced ataxia may relate to its serotonergic eff ect [40]. However, clozapine administration induced ataxia and some levels of the sei- zure (time 0), at time 1 these signs have rectifi ed more 4. Discussion rapidly in the ILE group than in the NS group. Th e most important hypothesis that explains the mechanism of the As the result revealed fat emulsion could reduce toxic antidotal eff ect of ILE against CNS intoxication of xenobi- signs of clozapine same as other lipophilic medicines. otics is the lipid sink theory [31]. It suggests that lipophilic After clozapine administration, animals were assessed for medicines or xenobiotics, when administered at toxic lev- survival and 2 deaths were recorded in the NS group dur- els, were redistributed from their site of action to a new in- ing the 24 hours evaluation. Although the mortality rate of ner compartment made by ILE in the vessels. Also, there ILE treated group was lower than NS, there was no signifi - is another antidotal mechanism for ILE in neurotoxicity cant diff erence between the two groups, and it may be due caused by clozapine, ILE and high chain free fatty acid are to small sample size. Th erefore, further study is needed to capable of increasing intracellular calcium concentrations evaluate the eff ects of ILE on clozapine mortality. in neurons, and also in ventricular muscles cells. Th us, it Using plasma expanders is an eff ective way for the treat- is suggested that ILE not only reduces clozapine concen- ment of clozapine-induced hypotension. In our investiga- tration in target organs based on the lipid sink theory but tion, clozapine-induced hypotension has responded to a also restores the clozapine-induced neurotoxicity through volume expander solution like normal saline. Normal sa- increasing the intraneuronal calcium concentration. line could raise reduced BP of rats after administration, al- Most patients who take clozapine, especially in the fi rst though its eff ect was not long-lasting and BP reduced again month of use, symptoms of infl ammation of the pancreas at the fi rst hour (Fig.3). A persistent rise in BP after ILE ad- and increasing enzymes like amylase and lipase are visible ministration suggests that it may also act through mech- [41]. In this study after pathological tests, pancreatitis was anisms other than volume expansion. It seems that ILE observed in both groups receiving normal saline and ILE could redistribute clozapine, which is a high lipid soluble after clozapine intoxication, but the parenchymal infl am- medicine from peripheral or central receptors into the new mation of pancreas tissue was signifi cantly higher in the neutral compartment and resolves the signs of toxicity. NS group compare with the ILE group. But other patholog- Previous animal tests support the eff ect of ILE in reveling ical factors explored in the study did not show a signifi cant lipophilic drugs induced hypotension. In a study ILE has diff erence between the two groups. On the other hand, shown signifi cant positive eff ects for primary or secondary there were no signifi cant diff erences in the amount of am- hemodynamic endpoints in metoprolol, verapamil, tram- ylase and lipase in both groups. adol and haloperidol intoxication [2, 7, 28-30]. Th ere is a One of the important body organ that clozapine was suggested mechanism for ILE in revealing drugs-induced stored and causes toxicity is the lungs [42]. In this study, hypotension, the lipid sink theory. Th rough lipid sink the- ILE also neither reduce nor raised clozapine intoxication ory, lipophilic drugs redistribute from the site of toxicity lung injuries. Perhaps no decrease in lung injury is due to into a new lipid compartment following ILE infusion. Lipid the fat emulsion potential to cause pulmonary injury [43]. Journal of Pharmacopuncture 2019;22[3]:147-153 http://www.journal.ac Th erefore, we can conclude that these results represent References the little eff ect of ILE in resolving tissue damages caused by clozapine toxicity. 1. Aksel G, Guneysel O, Tasyurek T, Kozan E, Cevik SE. 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