Lipid emulsion for the treatment of acute organophosphate poisoning: an Open-Label randomized trial.

INTRODUCTION: Many organophosphate (OP) pesticides are lipid-soluble; therefore, intravenous lipid emulsion (ILE) has been evaluated as a possible treatment for acute poisoning. A single bolus dose of 100 ml of 20% ILE was found safe in a pilot observational study. This randomized trial aimed to assess the effectiveness and safety of an extended dose of ILE in acute OP poisoning. METHODS: This was an investigator-initiated, parallel-group, open-label, randomized controlled trial conducted at PGIMER, Chandigarh (India), from January 2019 to June 2020, in patients aged above 13 years with acute OP poisoning. The primary efficacy outcome was to study the change in atropine dose requirement (total and over the first 24 h) for cholinergic crisis after giving an initial bolus dose of 100 ml of 20% ILE followed by an infusion of 100 ml of 20% ILE over 6 h in addition to the standard care. The secondary efficacy outcomes were to detect the effects on hemodynamic variables, length of hospital stay, and duration of mechanical ventilation required. The incidence of adverse events was evaluated. RESULTS: A total of 45 patients were assigned to receive either ILE (intervention group, n = 23) or normal saline (control group, n = 22) in addition to standard treatment. Baseline variables in both groups were comparable. The median dose of atropine (in mg) in the first 24 h and at complete resolution in the ILE group were similar to the control group (124.0 versus 141.8, p-value 0.916; and 150.8 versus 175.0, p-value 0.935). Hemodynamic variables (systolic and diastolic blood pressures, mean arterial pressure, and pulse rate) over 24, 48, and 72 h of treatment, length of hospital stay, and duration of mechanical ventilation were also unaffected by ILE. Case fatality was 4 and not statistically different between intervention and control groups (1 versus 3, p-value 0.346). There was no excessive fever, dyspnea, elevation of serum amylase, or pancreatitis from ILE. CONCLUSION: ILE has no apparent benefit in acute OP poisoning. However, an extended dose appears safe for the indication.

Heterogeneity and bias in animal models of lipid emulsion therapy: a systematic review and meta-analysis.

INTRODUCTION: Clinicians utilize lipid emulsion to treat local anesthetic toxicity and non-local anesthetic toxicities, a practice supported by animal experimentation and clinical experience. Prior meta-analysis confirmed a mortality benefit of lipid emulsion in animal models of local anesthetic toxicity but the benefit of lipid emulsion in models of non-local anesthetic toxicity remains unanswered. Further, swine suffer an anaphylactoid reaction from lipid emulsions calling into question their role as a model system to study lipid, so we examined swine and non-swine dependent outcomes in models of intravenous lipid emulsion. METHODS: We conducted a systematic review and meta-analysis examining the use of lipid emulsion therapy in animal models of cardiac toxicity. We quantified mortality using a random-effects odds-ratio method. Secondary outcomes included survival in the following subgroups: local-anesthetic systemic toxicity, non-local anesthetic toxicity, swine-based models, and non-swine models (e.g., rat, rabbit and dog). We assessed for heterogeneity with Cochran's Q and I2. We examined bias with Egger's test & funnel plot analysis. RESULTS: Of 2784 references screened, 58 met criteria for inclusion. Treatment with lipid emulsion reduced chance of death in all models of toxicity with an odds ratio of death of 0.26 (95% CI 0.16-0.44, Z-5.21, p < 0.00001, Cohen's-d = 0.72, n = 60). Secondary outcomes confirmed a reduced chance of death in models of local anesthetic toxicity (OR 0.16 {95% CI 0.1-0.33}) and non-local anesthetic toxicity (OR 0.43 {95% CI 0.22-0.83}). Heterogeneity (Cochran's Q 132 {df = 59, p < 0.01}, I 2 = 0.55) arose primarily from animal-model and disappeared (I 2 < = 0.12) when we analyzed swine and non-swine subgroups independently. Swine only benefited in models of local anesthetic toxicity (OR 0.28 {95% CI 0.11-0.7}, p = 0.0033) whereas non-swine models experienced a homogeneous benefit across all toxins (OR 0.1 {95% CI 0.06-0.16}, p < 0.00001). Egger's test identified risk of bias with outliers on funnel plot analysis. DISCUSSION: Lipid emulsion therapy reduces mortality in animal models of toxicity. Heterogeneity arises from the animal-model used. Swine only benefit in models of local anesthetic toxicity, potentially due to lipid dose, experimental design or swine's anaphylactoid reaction to lipid. Outlier analysis reinforced the need for appropriate dosing of lipid emulsion along with airway management and chest compressions in the setting of cardiac arrest.

Quality by design approach for the preparation of fat-soluble vitamins lipid injectable emulsion.

The fat-soluble vitamins lipid injectable emulsion, a parenteral supplement, commonly used for hospitalized patients to meet daily requirements of fat-soluble vitamins. This study attempts to reduce risk, improve the stability and safety of fat-soluble vitamins lipid injectable emulsion using a Quality by Design (QbD) approach. The quality target product profile and critical quality attributes were defined based on a comprehensive understanding of fat-soluble vitamins lipid injectable emulsions. The emulsions were prepared using a high-pressure homogenization method. Critical quality attributes (CQAs) were identified using risk assessment tools such as fishbone diagram and risk estimation matrix. The assay, mean droplet size, polydispersity index, zeta potential, and the volume-weighted percentage of fat greater than 5 µm (PFAT5) were identified as CQAs. Accordingly, three critical formulation and process parameters for the emulsions were the percentage of emulsifier, homogenization pressure, and homogenization recirculation. The design space was obtained via a design of experiment (DoE), and an optimum formulation was successfully prepared. All physicochemical attributes of the optimal formulation were within the design space (i.e., droplet size: 217.2 ±â€¯0.37 nm; polydispersity index: 0.115 ±â€¯0.012; PFAT5: less than 0.05%; zeta potential: -34.6 ±â€¯1.09 mV; and viscosity: 20.95 mPa at 0.1 s-1). The optimal formulation remained acceptable physicochemical stability at 25 ±â€¯2 °C/60% RH ±â€¯5% RH over a 12-month period. Safety of the optimal emulsion was evaluated as acceptable through the determination of lysophospholipid content and an in vitro hemolysis assay. In conclusion, an optimal lipid injectable emulsion for fat-soluble vitamins was successfully prepared using a QbD approach.

ESPGHAN Committee on Nutrition Position Paper. Intravenous Lipid Emulsions and Risk of Hepatotoxicity in Infants and Children: a Systematic Review and Meta-analysis.

The aim of the present article was to perform a systematic review with meta-analysis of available scientific evidence regarding the role of different intravenous lipid emulsions (ILE) in the pathogenesis of cholestasis and parenteral nutrition-associated liver disease. A systematic review of the literature (up to March 2015) identified 23 randomized controlled trials (RCTs). Of these, 17 were performed in preterm infants or critically ill neonates with a short duration of intervention, 2 in older children with short-term use (following surgery or bone marrow transplantation), 1 in neonates with long-term use, and 3 in infants and children receiving long-term parenteral nutrition (PN). Meta-analysis showed no differences in the rate of cholestasis or bilirubin levels associated with short-term use of different ILEs. Because of high heterogeneity of the long-term studies no meta-analysis could be performed. Available studies found that the use of multicomponent fish oil (FO)-containing ILE compared with pure soya bean oil (SO), ILE-reduced liver enzymes, and bilirubin levels in noncholestatic children on long-term PN and one other RCT found that FO-based ILE-reversed cholestasis in a proportion of patients. The ESPGHAN Committee on Nutrition concludes that there is no evidence of a difference in rates of cholestasis or bilirubin levels between different ILE for short-term use in neonates. The use of multicomponent FO-containing ILE may contribute to a decrease in total bilirubin levels in children with IF on prolonged PN. Well-designed RCTs are, however, lacking and long-term effects have not been determined.

Propofol (Diprivan®) and Intralipid® exacerbate insulin resistance in type-2 diabetic hearts by impairing GLUT4 trafficking.

BACKGROUND: The IV anesthetic, propofol, when administered as fat emulsion-based formulation (Diprivan) promotes insulin resistance, but the direct effects of propofol and its solvent, Intralipid, on cardiac insulin resistance are unknown. METHODS: Hearts of healthy and type-2 diabetic rats (generated by fructose feeding) were aerobically perfused for 60 minutes with 10 µM propofol in the formulation of Diprivan or an equivalent concentration of its solvent Intralipid (25 µM) ± insulin (100 mU•L). Glucose uptake, glycolysis, and glycogen metabolism were measured using [H]glucose. Activation of Akt, GSK3ß, AMPK, ERK1/2, p38MAPK, S6K1, JNK, protein kinase Cθ (PKCθ), and protein kinase CCßII (PKCßII) was determined using immunoblotting. GLUT4 trafficking and phosphorylations of insulin receptor substrate-1 (IRS-1) at Ser307(h312), Ser1100(h1101), and Tyr608(hTyr612) were measured. Mass spectrometry was used to determine acylcarnitines, phospholipids, and sphingolipids. RESULTS: Diprivan and Intralipid reduced insulin-induced glucose uptake and redirected glucose to glycogen stores in diabetic hearts. Reduced glucose uptake was accompanied by lower GLUT4 trafficking to the sarcolemma. Diprivan and Intralipid inactivated GSK3ß but activated AMPK and ERK1/2 in diabetic hearts. Only Diprivan increased phosphorylation of Akt(Ser473/Thr308) and translocated PKCθ and PKCßII to the sarcolemma in healthy hearts, whereas it activated S6K1 and p38MAPK and translocated PKCßII in diabetic hearts. Furthermore, only Diprivan phosphorylated IRS-1 at Ser1100(h1101) in healthy and diabetic hearts. JNK expression, phosphorylation of Ser307(h312) of IRS-1, and PKCθ expression and translocation were increased, whereas GLUT4 expression was reduced in insulin-treated diabetic hearts. Phosphatidylglycerol, phosphatidylethanolamine, and C18-sphingolipids accumulated in Diprivan-perfused and Intralipid-perfused diabetic hearts. CONCLUSIONS: Propofol and Intralipid promote insulin resistance predominantly in type-2 diabetic hearts.

Development of intravenous lipid emulsion of vinorelbine based on drug-phospholipid complex technique.

In order to reduce the severe venous toxicity, we developed an intravenous lipid emulsion of vinorelbine and investigated its preclinical stability, toxicity and antitumor efficacy. Vinorelbine-phospholipid complex was prepared to enhance the lipophilicity of vinorelbine thus facilitating the encapsulation into lipid emulsion. After complexation more than 70% of vinorelbine was encapsulated into the oil phase. Meanwhile, the lipid emulsion showed good stability without drug leakage. Local irritation after injection of the lipid emulsion was investigated in rabbits and compared with Navelbine(®) (the commercial product). The antitumor therapeutic efficacies were evaluated in tumor-bearing mouse models inoculated with A549 human lung cancer cells and BCAP-37 human breast cancer cells and compared as well. Results showed that the lipid emulsion significantly reduced the injection irritation compared with that of Navelbine(®), while maintained the antitumor activity in A549 and BCAP-37 cells xenograft tumor mouse models. Taken together, lipid emulsion loaded with vinorelbine-phospholipid complex is a promising vinorelbine intravenous injection with reduced venous irritation.

Effect of lipid emulsion on the central nervous system and cardiac toxicity of bupivacaine and levobupivacaine in awake rats.

PURPOSE: Despite numerous studies examining the effect of lipid emulsion on bupivacaine-induced cardiac toxicity, few studies have examined its effect on central nervous system (CNS) toxicity of local anesthetics. We investigated the effect of lipid emulsion on the CNS and cardiac toxicity of bupivacaine and levobupivacaine in awake, spontaneously breathing rats. METHODS: Male Sprague-Dawley rats were randomly allocated to control-bupivacaine (CB), control-levobupivacaine (CL), lipid-bupivacaine (LB), and lipid-levobupivacaine (LL) groups (n = 8 in each group). After infusion of saline (CB and CL groups) or 20 % lipid emulsion (LB and LL groups) for 5 min, bupivacaine (CB and LB groups) or levobupivacaine (CL and LL groups) was administered IV at 1 mg/kg/min. Cumulative dose of anesthetics and their plasma concentrations at the onset of convulsions and cardiac arrest were measured. RESULTS: The doses of bupivacaine for inducing convulsions and cardiac arrest in the LB group (8.8 ± 1.7 and 10.2 ± 1.5 mg/kg, respectively) were significantly larger than those in the CB group (5.9 ± 1.1 and 7.1 ± 1.3 mg/kg, respectively, p < 0.001 for both). The doses of levobupivacaine for inducing convulsions and cardiac arrest in the LL group (10.0 ± 2.0 and 13.7 ± 3.6 mg/kg, respectively) were significantly larger than those in the CL group (7.7 ± 1.6 and 9.4 ± 2.4 mg/kg, p = 0.03 and p = 0.02, respectively). Plasma concentrations of bupivacaine at the onset of convulsions and cardiac arrest in the LB group (12.9 ± 2.9 and 41.4 ± 5.2 µg/ml, respectively) were significantly higher than those in the CB group (7.9 ± 1.2 and 21.6 ± 3.3 µg/ml, respectively, p < 0.001 for both). Plasma concentrations of levobupivacaine at the onset of convulsions and cardiac arrest in the LL group (17.5 ± 1.5 and 47.6 ± 6.1 µg/ml, respectively) were significantly higher than in the CL group (10.9 ± 2.2 and 29.2 ± 3.5 µg/ml, respectively, p < 0.001 for both). CONCLUSIONS: Lipid emulsion decreased CNS and cardiac toxicity of both bupivacaine and levobupivacaine.

Delayed-onset seizure and cardiac arrest after amitriptyline overdose, treated with intravenous lipid emulsion therapy.

In recent years, intravenous lipid emulsion (ILE) therapy has emerged as a new rescue antidote for treatment of certain toxicities, including cyclic antidepressants, and as the primary treatment of toxic manifestations after local anesthetic exposure. We present a case of a 13-year-old girl who developed delayed seizures and cardiac arrest after amitriptyline ingestion. As part of the treatment, she was treated with ILE therapy. The patient's laboratories were not interpretable for several hours after the lipid emulsion. The patient developed pancreatitis after the ILE therapy. This case is unique; not only is it one of the first reported cases of lipid emulsion being used in a pediatric patient, but in that the patient developed delayed toxicity and iatrogenic harm from the ILE.

Development of intravenous lipid emulsion of tanshinone IIA and evaluation of its anti-hepatoma activity in vitro.

The purpose of this study was to develop a lipid emulsion of tanshinone IIA (Tan IIA-LE) for intravenous administration and to investigate its feasibility for future clinical practice. The formulation was optimized using central composite design-response surface methodology (CCD-RSM), and the homogenization process was investigated systematically. The Tan IIA-LE was evaluated in terms of stability, safety and in vitro anti-hepatoma activity. The formulation of Tan IIA-LE is composed of 0.05% (w/v) Tan IIA, 20% (w/v) soybean oil-MCT mixture (1:1, w/w), 1.2% (w/v) soybean lecithin, 0.3% (w/v) F68 and 2.2% (w/v) glycerol, a high pressure homogenization at 100 MPa for 3 cycles was selected as the optimal homogenization process. The Tan IIA-LE was light-sensitive but stable for at least 12 months at room temperature in dark. The safety study demonstrated that the Tan IIA-LE did not cause venous irritation or obvious acute toxicity. Furthermore, the Tan IIA-LE displayed significant anti-tumor activity against human hepatoma cell lines in vitro. Overall, the Tan IIA-LE developed in this study was suggested to be a suitable and safe dosage form of Tan IIA for intravenous administration and has potential in liver cancer therapy in future.

Aging per se increases the susceptibility to free fatty acid-induced insulin resistance.

Elevations in systemic free fatty acids (FFA) contribute to insulin resistance. To determine the effects of an acute elevation in FFA on insulin action with aging, we infused saline or intralipid (IL) during a hyperinsulinemic-euglycemic clamp in three groups of rats: young ad libitum-fed (YAL), old ad libitum-fed (OAL), and old on lifelong calorie restriction (OCR). The OCR group was included to distinguish between aging per se and age-related changes in body fat distribution. IL induced marked insulin resistance in both YAL and OCR, but the onset of insulin resistance was approximately two to three times more rapid in OCR as compared with YAL. In response to IL infusion, plasminogen-activating inhibitor-1 (PAI-1) expression was increased in subcutaneous fat from OAL animals. In visceral fat, a marked increase in PAI-1 and interleukin-6 expression was observed in OAL and OCR rats, but not YAL, in response to IL treatment. Thus, aging per se increases the inflammatory response to excess nutrients and vulnerability to FFA-induced insulin resistance with aging.

Safety of high volume lipid emulsion infusion: a first approximation of LD50 in rats.

BACKGROUND: Lipid infusion reverses systemic local anesthetic toxicity. The acceptable upper limit for lipid administration is unknown and has direct bearing on clinical management. We hypothesize that high volumes of lipid could have undesirable effects and sought to identify the dose required to kill 50% of the animals (LD(50)) of large volume lipid administration. METHODS: Intravenous lines and electrocardiogram electrodes were placed in anesthetized, male Sprague-Dawley rats. Twenty percent lipid emulsion (20, 40, 60, or 80 mL/kg) or saline (60 or 80 mL/kg), were administered over 30 mins; lipid dosing was assigned by the Dixon "up-and-down" method. Rats were recovered and observed for 48 hrs then euthanized for histologic analysis of major organs. Three additional rats were administered 60 mL/kg lipid emulsion and euthanized at 1, 4, and 24 hrs to identify progression of organ damage. RESULTS: The maximum likelihood estimate for LD(50) was 67.72 (SE, 10.69) mL/kg. Triglycerides were elevated immediately after infusion but returned to baseline by 48 hrs when laboratory abnormalities included elevated amylase, aspartate aminotransferase, and serum urea nitrogen for all lipid doses. Histologic diagnosis of myocardium, brain, pancreas, and kidneys was normal at all doses. Microscopic abnormalities in lung and liver were observed at 60 and 80 mL/kg; histopathology in the lung and liver was worse at 1 hr than at 4 and 24 hrs. CONCLUSIONS: The LD(50) of rapid, high volume lipid infusion is an order of magnitude greater than doses typically used for lipid rescue in humans and supports the safety of lipid infusion at currently recommended doses for toxin-induced cardiac arrest. Lung and liver histopathology was observed at the highest infused volumes.

Effects of bolus injection of soybean-based fat emulsion and fatty acids on pulmonary gas exchange function.

To determine whether or not a "bolus injection" of soybean-based fat emulsion (SFE), which contains oleic acid (OA), a potent lung-toxic unsaturated C-18 fatty acid, can induce pulmonary dysfunction, we examined the effect of SFE injection on the partial oxygen pressure of arterial blood (Pao2) and pulmonary vascular permeability. In addition, we compared the effect of an injection of SFE with that of OA, soybean oil (a source of SFE), emulsified OA and C-18 fatty acids. Bolus injection of SFE (0.3-4.8 ml/kg) had little effect on Pao2) and pulmonary vascular permeability. Injection of an equivalent amount of OA, on the other hand, significantly decreased Pao2 and increased pulmonary vascular hyper-permeability. This decrease in Pao2 was attenuated by emulsification. Unemulsified soybean oil also induced a decrease in Pao2, although the effect was weaker than that of OA. Other unsaturated C-18 fatty acids (linoleic and linolenic acid) induced a decrease in Pao2 as potent as OA while stearic acid, a C-18 saturated fatty acid, had little effect. Although we did not observe pulmonary toxicity as a result of "bolus injection" of SFE, the chemical form, for example, emulsification and the degree of saturability of the carbon chain, seems to influence the pulmonary toxicities of lipids and fatty acids. Furthermore, the potent pulmonary toxicity of OA seems to depend not only on pulmonary vascular embolization but also pharmacological and/or inflammation-inducing properties.

Lipid injectable emulsions: Pharmacopeial and safety issues.

Lipid injectable emulsions have been routinely used in patients worldwide for over 40 years as a nutritional supplement in patients requiring parenteral nutrition. They can be given as a separate infusion or added into total parenteral nutrition admixtures. Despite such broad use, no pharmacopeial standards exist with respect to the optimal pharmaceutical characteristics of the formulation. Several attempts to establish standard physical and chemical attributes have been attempted by various pharmacopeias around the world, but without success largely due to technical issues regarding the creation of globule size limits. Recently, the United States Pharmacopeia has revised its previous efforts and developed two methods and criteria (under Chapter <729>) to measure the mean droplet size (Method I), and the large-diameter tail > 5 mum (Method II) of the globule size distribution to verify the stability of lipid injectable emulsions. Importantly, it is the latter size limits of Method II that have the greatest implications for infusion safety. The major safety issues involving lipid injectable emulsions include impairments in plasma clearance in susceptible patients, and the infusion of an unstable emulsion containing large quantities of potentially embolic fat globules. Recent animal studies investigating the toxicity from the infusion of unstable lipid injectable emulsions have shown evidence of oxidative stress and tissue damage to the liver when recommended globule size limits determined by Method II of the USP are exceeded. Adoption of Chapter <729> of the USP seems appropriate at this time.

Toxicity of a soybean oil emulsion on human lymphocytes and neutrophils.

BACKGROUND: The incorporation of lipid emulsions in parenteral diets is a requirement for energy and essential fatty acid supply to critically ill patients. In this study, the toxicity of a lipid emulsion rich (60%) in triacylglycerol of omega-6 polyunsaturated fatty acids on leukocytes from healthy volunteers was investigated. METHODS: Eleven volunteers were recruited, and blood samples were collected before infusion of a soybean oil emulsion, immediately afterwards, and 18 hours later. The cells were studied immediately after isolation and again after 24 hours or 48 hours in culture. The following determinations were made: composition and concentration of fatty acids in plasma, lymphocytes and neutrophils, lymphocyte proliferation, levels of cell viability, DNA fragmentation, phosphatidylserine externalization, mitochondrial depolarization, reactive oxygen species production, and neutral lipid accumulation. RESULTS: Soybean oil emulsion decreased lymphocyte proliferation and provoked neutrophil and lymphocyte apoptosis and necrosis. Evidence is presented herein that soybean oil emulsion is less toxic to neutrophils than to lymphocytes. The mechanism of cell death induced by this oil emulsion was characterized by mitochondrial membrane depolarization and neutral lipid accumulation but did not alter reactive oxygen species production. CONCLUSIONS: Soybean oil emulsion given as a single dose of 500 mL promotes lymphocyte and neutrophil death that may enhance the susceptibility of the patients to infections.

The study of cerebral hemodynamics in the hyperacute stage of fat embolism induced by triolein emulsion.

PURPOSE: The purpose of this study was to evaluate the cerebral hemodynamic change in the hyperacute stage of cerebral fat embolism induced by triolein emulsion, by using MR perfusion imaging in cat brains. METHODS: By using the femoral arterial approach, the internal carotid arteries of 14 cats were infused with an emulsion of triolein 0.05 mL. T2-weighted (T2WI), diffusion-weighted (DWI), apparent diffusion coefficient (ADC) map, perfusion-weighted (PWI), and gadolinium-enhanced T1-weighted (Gd-T1WI) images were obtained serially at 30 minutes and 2, 4, and 6 hours after infusion. The MR images were evaluated qualitatively and quantitatively. Qualitative evaluation was performed by assessing the signal intensity of the serial MR images. Quantitative assessment was performed by comparing the signal-intensity ratio (SIR) of the lesions to the contralateral normal side calculated on T2WIs, Gd-T1WIs, DWIs, and ADC maps at each acquisition time and by comparing the relative cerebral blood volume (rCBV), cerebral blood flow (CBF), and mean transit times (MTT) of the lesions to the contralateral normal side calculated on PWI. RESULTS: In the qualitative evaluation of the MR images, the lesions showed hyperintensity on T2WIs, enhancement on the Gd-T1WIs, and isointensity on DWIs and the ADC maps. In the quantitative studies, SIRs on the Gd-T1WIs, DWIs, and ADC maps peaked at 2 hours after infusion. The SIRs on the T2WIs peaked at 4 hours after infusion and decreased thereafter. On PWIs, the rCBV, rCBF, and MTT of the lesion showed no significant difference from the contralateral normal side (P = .09, .30, and .13, respectively) and showed no significant change of time course (P = .17, .31, and .66, respectively). CONCLUSION: The embolized lesions induced by triolein emulsion showed no significant difference in cerebral hemodynamic parameters from those on the contralateral normal side. The result may suggest that consideration of the hemodynamic factor of embolized lesions is not necessary in further studies of the blood-brain barrier with triolein emulsion.

Pharmacological parameters of intravenously administered amphotericin B in rats: comparison of the conventional formulation with amphotericin B associated with a triglyceride-rich emulsion.

The LD50 determined in rats for the potent antifungal amphotericin B (AB) increased from 4.2 to 12.0 when the conventional AB-deoxycholate (DOC) was compared with AB associated with a triglyceride-rich emulsion (AB-emulsion). The reduction in amphotericin B toxicity is not due to a modification in plasma clearance, as both formulations seem to be removed from plasma at the same rate. Major differences in amphotericin B tissue distribution were not seen for kidney and liver but were seen for the lung. After 24 h administration of a single amphotericin B dose (2.0 mg/kg body weight) 23.78 +/- 11.71 mg/kg tissue was recovered from the lung of animals treated with AB-DOC whereas for AB-emulsion only 5.19 +/- 2.50 mg/kg tissue was recovered. The higher lethality of AB-DOC may be related to the higher concentration of amphotericin B in the lung. The therapeutic efficacy of AB-emulsion was similar to that of AB-DOC as attested by survival curves obtained after treatment of mice infected by Candida albicans. This is highly relevant, as the same is not necessarily found for other less toxic proposed vehicles. The equivalent efficacy and the increment in the LD50 will result in an important improvement in the therapeutic activity of amphotericin B. Furthermore, some data related to storage and stability indicate the clinical utility of this type of drug delivery.

Developmental toxicity study in rats and rabbits administered an emulsion containing medium chain triglycerides as an alternative caloric source.

Triglyceride-containing lipid emulsions have been designed as caloric sources that can be administered intravenously to patients that cannot meet their nutritional needs by conventional parenteral therapies. In their study, we evaluate the developmental toxicity of a 20% lipid emulsion that contains a 3:1 ratio of medium chain triglyceride (MCT) to one long chain containing lipid emulsion (LCT). This emulsion was administered by intravenous infusion to rats and rabbits at dosages of 1 and 4.28 g lipid/kg body weight (g lipid/kg) at dose volumes of 5 and 21.4 mL/kg, respectively, once daily during organogenesis to assess the potential developmental toxicity of the test article. The control group received 0.9% saline at a dose volume of 21.4 mL/kg. Animals were observed for clinical signs of toxicity and adverse effects on body weights and feed consumption. On Day 20 (rats) or Day 29 (rabbits), females were necropsied and examined for maternal and embryo/fetal toxicity. Fetuses were removed, weighed, and examined for external, soft tissue, and skeletal abnormalities. Dosages of 4.28 g lipid/kg resulted in lower feed consumption for rats and rabbits, an expected finding based on the high-caloric nature of the test article. Potentially test article-related gross necropsy findings, including enlarged lymph nodes and spleen, small thymus, and enlarged renal pelvis, for rats given 4.28 g lipid/kg were present at a low incidence. There were no adverse effects on fetal parameters for rats even in the presence of some maternal toxicity. However, embryo and fetal toxicity (i.e., resorptions) and skeletal abnormalities were present for rabbits given 4.28 g lipid/kg. Under the conditions of this study, the no-observable-effect level for developmental toxicity was greater than or equal to 4.28 g lipid/kg for rats and greater than or equal to 1 g lipid/kg but less than 4.28 g lipid/kg for rabbits.

Survival to lipopolysaccharide, cytokine release and phagocyte functions in mice treated with different total parenteral nutrition regimens.

Effects on host defenses of Total Parenteral Nutrition (TPN) with long- (LCT) and medium-chain triglycerides (MCT) were studied. Survival to lipopolysaccharide (LPS) challenge, blood clearance of Escherichia coli, in vivo and in vitro production of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were investigated. In BALB/c mice, LCTs produced a 25% reduction in mortality, compared with controls. TPN performed with a LCT plus MCT mixture reduced mortality by 50%. Spasms appeared after 18 h and 12 h respectively in mice treated with LCT-MCT mixture or LCTs alone, respect to controls (8 h). The LCT-MCT mixture produced a 67% blood clearance of E. coli after 1 h, while the treatment with LCTs alone had no significant effects compared to controls (about 40%). The LCT-MCT mixture induced a 50% increase in chemiluminescence respect to controls. A 33% increase was observed in rats treated with LCTs alone. TNF-alpha serum levels after challenge with LPS were not modified by any of the triglycerides or their combinations. IL-6 increased by 43% with LCT-MCT mixture and by 39% with LCTs alone versus controls. After a 3 h in vitro treatment with LCTs, human monocytes were stimulated to release TNF-alpha at levels higher than those stimulated with the LCT-MCT mixture, and respect to controls. In contrast after 3 h the stimulation with LCT-MCT mixture induced a higher IL-6 release than controls and cells stimulated with LCTs alone, or with LPS.