Predicting the efficacy of opioid sequestration by intravenous lipid emulsion using biologically relevant in vitro models of drug distribution (original) (raw)
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Comparison of lipid sinks in sequestering common intoxicating drugs
Journal of Separation Science, 2012
Intravenous lipid emulsion is a recommended treatment for local anesthetic intoxication. The lipid sink theory hypothesizes that the mechanism behind the lipid treatment is the entrapment of toxic drugs in plasma, preventing them from reaching target receptors. Lipid sink treatment has also been used as a last refuge treatment for severe tricyclic antidepressant intoxication with seemingly beneficial results. We selected three drugs, i.e. amiodarone, ketamine, and amitriptyline, that can cause severe intoxication and compared their interactions with two commercial fat emulsions (Intralipid R and ClinOleic R ) and one synthetic liposome (80:20 mol% phosphatidylcholine/phosphatidylglycerol) dispersion. The interaction studies were carried out by capillary electrokinetic chromatography and the retention factors and distributions constants of the drugs were calculated. The results demonstrate that there is stronger interaction between the drugs and the synthetic liposome dispersion than with the commercial emulsions.
Interaction of opiate molecules with lipid monolayers and liposomes
Journal of Pharmaceutical Sciences, 1992
0 The interaction of opiate molecules (buprenorphine, codeine, dextromethorphan, diprenorphine, etorphine, meperidine, methadone, morphine, and naloxone) with lipids (phosphatidylcholine, phosphatidylinositol, phosphatidylserine, and cholesterol) by using liposomes and monomolecular layers as membrane models is described. The ability of opiates to induce leakage of carboxyfluorescein from liposomes is highly dependent on the hydrophobicity of the opiate molecules. Buprenorphine and etorphine increased the membrane permeability in all the experiments. On the contrary, naloxone, morphine, and codeine only caused a slight release of the entrapped dye in the presence of acidic phospholipids. Moreover, the leakage of carboxyfluorexein is directly related to the concentration of drug in the incubation media. Studies of the kinetics of the surface penetration of these molecules into monolayers of phospholipids were performed. Again, in this system, buprenorphine and etorphine exhibited stronger interactions than the most hydrophilic opiates. Nevertheless, in these experiments, differences among the opiate molecules are not so high as in the liposomes. The time course of the penetration of all of these molecules in the monolayers fits the Lineweaver-Burk equation. This fact suggests a lack of specific interactions and the predominance of hydrophobic factors. Moreover, the high percentage of release of entrapped dye caused by some opiate molecules suggests a possible toxic side-effect for these agents. Log Drug Concentration, M Figure 2-Effect of concentrations (M) of (0) naloxone, (+) dextromethorphan, and (V) methadone on the release of CF from liposomes. Lipid composition was PC: PI:Ch (0.25:0.25:0.5).
Intravenous lipid emulsion in clinical toxicology
Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine, 2010
Intravenous lipid emulsion is an established, effective treatment for local anesthetic-induced cardiovascular collapse. The predominant theory for its mechanism of action is that by creating an expanded, intravascular lipid phase, equilibria are established that drive the offending drug from target tissues into the newly formed 'lipid sink'. Based on this hypothesis, lipid emulsion has been considered a candidate for generic reversal of toxicity caused by overdose of any lipophilic drug. Recent case reports of successful resuscitation suggest the efficacy of lipid emulsion infusion for treating non-local anesthetic overdoses across a wide spectrum of drugs: beta blockers, calcium channel blockers, parasiticides, herbicides and several varieties of psychotropic agents. Lipid emulsion therapy is gaining acceptance in emergency rooms and other critical care settings as a possible treatment for lipophilic drug toxicity. While protocols exist for administration of lipid emulsion in the setting of local anesthetic toxicity, no optimal regimen has been established for treatment of acute non-local anesthetic poisonings. Future studies will shape the evolving recommendations for lipid emulsion in the setting of non-local anesthetic drug overdose.
Review of the pharmacological data on intravenous lipid emulsions
Scripta Scientifica Pharmaceutica, 2022
INTRODUCTION: Initially, the clinical application of lipid emulsions (LEs) was parenteral nutrition. Since 2006, LEs have been widely used as an antidote for various intoxications with lipophilic drugs. Despite the widespread use of LEs, there is insufficient information regarding their pharmacokinetics and mechanism of antidote action. That is why detailed knowledge of their pharmacokinetic parameters and complex mechanism of action is particularly important. AIM: The aim of the study is to make a detailed literature analysis of the pharmacokinetics and of all putative mechanisms of antidote action of LEs. MATERIALS AND METHODS: Over 100 literature sources were studied in various databases, including PubMed, ScienceDirect, Research Gate, Google Scholar, and others. These include clinical cases (over 40), laboratory animal experiments (over 20), and medical guidelines and protocols (over 30). RESULTS: Lipid emulsions have good absorption and 100% bioavailability after intravenous administration. They do not bind to plasma proteins. Lipid emulsions undergo hepatic metabolism similar to chylomicrons. Their plasma half-life is ±10 minutes. The osmolarity of LEs is 270-345 mosm/l. Lipid emulsions cross the blood-brain barrier but do not cross the placental barrier. They are mainly removed from skeletal muscles (47%), splanchnic organs (25%), myocardium (14%) and subcutaneous tissue (13%). LD 50 in rats is 67.72 mL/kg and in dogs 135 mL/kg. The maximum single harmless dose for a person (70 kg) is 4000-7000 mL/24 h. The most widely advocated mechanism of non-antidote action of LEs is the lipid uptake phenomenon. CONCLUSION: Evidence collected from numerous clinical cases and laboratory experiments shows high efficiency and great therapeutic safety. Lipid emulsions are distinguished by their ability to dissolve and absorb lipophilic xenobiotics. In the blood, LEs prevent their binding to target receptors or, through the concentration gradient, extract them from critical organs, such as the brain and heart. Lipid emulsions have a cardioprotective effect as energy donors for the myocardium. They also exhibit vasoconstriction, which is important for overcoming toxic shock. Therefore, LEs represent an important therapeutic tool in the fight against intoxications with lipophilic drugs, such as anesthetics, psychopharmacology, and cardiovascular drugs.
Intralipid emulsion treatment as an antidote in lipophilic drug intoxications
The American Journal of Emergency Medicine, 2014
Intravenous lipid emulsion (ILE) is a lifesaving treatment of lipophilic drug intoxications. Not only does ILE have demonstrable efficacy as an antidote to local anesthetic toxicity, it is also effective in lipophilic drug intoxications. Our case series involved 10 patients with ingestion of different types of lipophilic drugs. Intravenous lipid emulsion treatment improved Glasgow Coma Scale or blood pressure and pulse rate or both according to the drug type. Complications were observed in 2 patients (minimal change pancreatitis and probable ILE treatmentrelated fat infiltration in lungs). In our case series, ILE was used for different lipophilic drug intoxications to improve cardiovascular and neurologic symptoms. According to the results, it was found that ILE treatment is a lifesaving agent in lipophilic drug intoxications and it can be used in unconscious patients who have cardiac and/or neurologic symptoms but no history of a specific drug ingestion.
Absorption of morphine from a slow-release emulsion used to induce morphine dependence in rats
Journal of Pharmacological and Toxicological Methods, 1998
This study was performed to measure absorption of morphine from the injection site following treatment of rats with slow-release emulsions formulated with morphine hydrochloride and morphine base. Samples of emulsion were collected from the injection site of halothane anesthetized animals at 24 and 48 h following emulsion treatment and concentrations of morphine remaining in the emulsion were analyzed using high-performance liquid chromatography (HPLC). In another group of morphine-treated rats, at times equivalent to collecting samples of emulsion, the intensity of naloxone-precipitated withdrawal behaviors was monitored. Both morphine base-and hydrochloride-containing emulsions induced a high degree of physical dependence in animals treated over 48 h. Release of morphine from emulsions containing morphine base was slower than that from the hydrochloride formulations. In the 24-h morphine base-treated animals, approximately 45% was absorbed from the injection site as opposed to 99% in the 24-h morphine hydrochloride-treated animals. These results suggest that morphine base containing emulsions provide a more sustained exposure to the opioid.
Binding of Long-lasting Local Anesthetics to Lipid Emulsions
Anesthesiology, 2009
Background Rapid infusion of lipid emulsion has been proposed to treat local anesthetic toxicity. The authors wanted to test the buffering properties of two commercially available emulsions made of long- and of long- and medium-chain triglycerides. Methods Using the shake-flask method, the authors measured the solubility and binding of racemic bupivacaine, levobupivacaine, and ropivacaine to diluted Intralipid (Fresenius Kabi, Paris, France) and Medialipide (B-Braun, Boulogne, France). Results The apparent distribution coefficient expressed as the ratio of mole fraction was 823 +/- 198 and 320 +/- 65 for racemic bupivacaine and levobupivacaine, and ropivacaine, respectively, at 500 mg in the Medialipide/buffer emulsion; and 1,870 +/- 92 and 1,240 +/- 14 for racemic bupivacaine and levobupivacaine, and ropivacaine, respectively, in the Intralipid/buffer emulsion. Decreasing the pH from 7.40 to 7.00 of the Medialipide/buffer emulsion led to a decrease in ratio of molar concentration f...
Dosage of Lipid Emulsions as an Antidoteto Lipid-Soluble Substances
Folia Medica
Introduction: Lipid emulsions are increasingly used as an antidote to lipophilic drug intoxications. The dose recommended by the American Society of Regional Anesthesia is used primarily for the treatment of local anesthetic systemic toxicity. There is insufficient information about what the dose of lipid emulsions (LE) should be in other intoxications depending on their severity. Aim: To determine the LE dose in a shock or haemodynamic instability in patients with acute exogenous intoxications treated with LE. Materials and methods: Forty-nine patients with acute lipophilic drug intoxications were treated with LE in the Clinic of Toxicology at the Naval Hospital in Varna. Statistical analysis was performed using the statistical functions of Excel 2016 and the Statistica 7.0 software package. Results: The percentage of patients receiving a low dose of LE of 0.3 ml/kg (93.87%) was significantly higher than the percentage of patients treated with a medium (2.04%) and a high dose (4.08...
Basic & Clinical Pharmacology & Toxicology, 2016
In recent years, there has been increasing interest in the role of intravenous lipid formulations as potential antidotes in patients with severe cardiotoxicity caused by drug toxicity. The aim of this study was to conduct a comprehensive bibliometric analysis of all human and animal studies featuring lipid emulsion as an antidote for the treatment of acute poisoning. The Scopus database search was performed on 5 February 2016 to analyse the research output related to intravenous lipid emulsion as an antidote for the treatment of acute poisoning. Research indicators used for analysis included total number of articles, date (year) of publication, total citations, value of the h-index, document types, countries of publication, journal names, collaboration patterns and institutions. A total of 594 articles were retrieved from Scopus database for the period of 1955-2015. The percentage share of global intravenous lipid emulsion research output showed that research output was 85.86% in 2006-2015 with yearly average growth in this field of 51 articles per year. The USA,
The impact of intravenous lipid emulsion on lipophilicity in poisoned patients: A systematic review
2017
Objective: Although the action mechanism of intravenous lipid emulsion has not been fully elucidated yet, its use in liposoluble drugs intoxications. In this study, we examined the lipophilic features of causative agents and the success of the treatment ILE therapy in intoxication cases. Methods: We reviewed 765 cases published in PubMed between 1966 and June, 2015. After applying exclusion criteria, totally 141 cases ingested single substance and received ILE therapy with 20% ILE solution were included in present study. Amount of lipid solutions given and the results were recorded. Success rate was statistically assessed according to log p values of the substances taken and the amount of lipid emulsion used. Results: 141 patients were involved in this study; log p values were calculated for all drugs regardless of the success of ILE therapy. ILE therapy under the amount of 100 ml failed to achieve successful outcome. ALOGPS and ChemAxon log P values were higher in cases, which rece...