A Lipid Emulsion
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LIPID EMULSIONS A lipid emulsion is provided comprising water, an emulsifier, and a glyceride oil component. The weight ratio of the emulsifier to glyceride oil is approximately 0.04 to about 0.01. It has been found that intravenous lipid emulsions having a weight ratio of emulsifier to glyceride oil of approximately 0.04 to about 0.01 are more rapidly metabolically utilized. Lipid emulsion is used as a model compound of a plasma lipoprotein particle and it is applied to the drug delivery system. For example, chylomicron is a complex in which soluble apolipoproteins are bound to lipid emulsion. We found for the first time that emulsion could bind apolipoproteins (apoA-I, apoCs, and apoE) about 10-fold more than liposome. In consequence, the systemic catabolism of the particulates and their interaction with the cultured cell change remarkably. In addition, we understand the mechanism by which apolipoproteins recognize the topology of lipid surface, and we now are studying its application to the delivery. Furthermore, we seek for the mechanism by which cholesterol, cholesteryl ester and sphingomyelin serve as risk factors of myocardial infarction and arteriosclerosis, the diseases known to be related to the quality of plasma lipoproteins.
Schematic representation of lipid emulsions and liposomes.
1
Preparation of Lipid emulsions. A lipid mixture was prepared with 97% (w}w) triolein (95%pure; Sigma), 2±5% egg phosphatidylcholine (95% pure; Prolabo, Paris, France) and 0±5% free cholesterol (99% pure; Sigma) at a ®nal concentration of 16% (w}w) in chloroform} methanol (2 :1, v}v). Aliquots of the lipid mixture solution (1 ml each) were evaporated to dryness under nitrogen in 7 ml glass tubes. The buffer (with or without ®bre) was added to a ®nal volume of 4 ml. The aqueous mixture thus contained 4% (w}w) lipids and 0±2% ®bre, i.e. in the physiological range [5,6,23,24]. The tubes were stoppered, attached horizontally and shaken at 200 strokes}min for 2 h at 37 °C. These operating conditions resulted from preliminary experiments designed to discover conditions that would generate lipid emulsions with droplet sizes in the range found in human and rat stomach during fat digestion.
Emulsification measurements Determination of the amount of emulsi®ed lipids The upper limit for emulsion droplet size was set at 100 lm, given the instability and negligible interfacial area of lipid droplets above this value [6]. To allow accurate measurements, [carboxyl- "%C]triolein (98% pure; 69 mCi}mmol; CEA, Gif-sur-Yvette, France) was added in trace amounts to the lipid mixture. Radioactivity was measured by liquid scintillation counting using a Packard 1600TR instrument (Packard, Meriden, CT, U.S.A.) from 100 ll aliquots of two fractions collected at the end of the emulsi®cation process. One fraction was the ¯oating oily layer composed of unemulsi®ed lipids (oily material plus lipid droplets &100 lm) which collect above the aqueous solution surface when tubes are left to stand for a given time (0±5±10 min at 1 g) calculated from the Stoke's sedimentation equation for droplets &100 lm under the present conditions, as previously reported. According to Stoke's sedimentation law, the relation between sedimentation time and particle diameter is expressed in the following equation: where D is the particle diameter (m), g! is the viscosity coefficient of the solvent (N[s}m#), q is the density of the sample (kg}m$), q! is the density of the solvent (kg}m$), g is acceleration due to gravity (m[s−#), t is the sedimentation time (s) and H is 2
the distance of sedimentation (m). The second fraction was the resulting infranatant containing emulsifed lipid droplets.
Measurement of droplet size The distribution of the emulsion droplet sizes in the infranatant solution was determined by using a particle-size analyser (Capa 700; Horiba, Kyoto, Japan) as previously described [6,8,9,10,11]. The validity of the method has previously been evaluated and calibrations made using microparticles in the size range 0±2±100 lm (polystyrene size standard kit ; Polyscience Inc., Warrington, PA, U.S.A.). Measurements were carried out using gradientmode analysis at a constant centrifuge acceleration rate (960 rev.}min) to allow an accurate measurement of large dropFibres and fat emulsions 271 lets (100 lm) as well as small droplets (0±1 lm). The particle-sizer software calculated the droplet-size distribution which is expressed as a fraction of the total droplet volume. Results are given as a frequency-distribution graph characterized by its median diameter (lm) and a speci®c interfacial area (m#}g). The droplet surface area (m#) was calculated from the amount (g) of emulsi®ed lipids in the infranatant solution.
Effects of fibres on lipid emulsification To determine the effects of soluble ®bres on the extent of fat emulsi®cation, we measured the amount of emulsi®ed lipid and the size of the emulsi®ed lipid droplets produced and calculated the surface area generated. Lipid emulsi®cation occurred to a moderate extent (24±6%) under the conditions selected in the absence of ®bre (control). Adding ®bres did not markedly change this. For instance, 0±3% solutions of the ®bres caused the following extents of emulsi®cation : gum arabic, 23±8%; HVG, 29±7%; MVG, 25±6%; LVG, 24±2%; NND pectin, 27±8%; BNF pectin, 26±1%. The data 3
obtained from droplet-size measurements of emulsi- ®ed lipids are given in Table 2. In control buffer, the median diameter exhibited by the emulsion was 7±19 lm. Gum Arabic (0±3±2±0%), LVG and MVG at low concentrations did not signi®cantly alter the droplet size. In contrast, LVG at 2±0%, MVG at 0±6% and HVG at 0±3% signi®cantly increased the median size of the droplets (45±6, 41±7 and 25±4 lm respectively). Also, BNF pectin and NND pectin signi®cantly increased the droplet median diameter to a comparable extent at concentrations of 0±6% and 0±8% respectively. A comparison of the effects of the ®bres tested at a given concentration (0±3%; Table 2) provides the following information: the highest median diameters were elicited by HVG (25±41³4±09 lm) and to a lesser degree MVG (14±36³4±78 lm) and NND pectin (15±42³4±34 lm) whereas the other ®bres [LVG (8±71³0±29 lm)
Emulsion Test For Lipids Lipids do not dissolve in water, but do dissolve in ethanol. This characteristic is used in the emulsion test. ⇒ Grind up sample ⇒ Shake some test sample with about 4cm3 of ethanol. ⇒Decant the liquid into a test tube of water leaving any un-dissolved substances between. If there are lipids dissolved in the ethanol, they will precipitate in the water, forming a cloudy white emulsion.
Lipid Emulsions: Formation, Stability, and Metabolism Lipid emulsions composed of triacylglycerol (TG) and phosphatidylcholine (PC) have been commonly used for parenteral nutrition for almost 30 years. Recently, lipid emulsions were used as drug carriers in drug-delivery systems.1 For example, the delivery of prostaglandin E1 in injectable lipid emulsions has been well established and is commercially available.2, 3 Lipid emulsions are classified as macroemulsions and thermodynamically unstable, which may bring about aggregation, flocculation, coalescence, and eventual
4
phase separation over time. It is generally believed that freezing or freezedrying lipid emulsion formulations is an effective form of storage after production. However, there have been problems with coalescence of emulsion droplets during the freeze-thawing (F-T) procedures. When emulsions freeze, the lipid droplets become progressively concentrated and come into contact with one another in unfrozen aqueous channels between the ice crystals. The condensation of the lipid droplets in the narrow channels could lead to aggregation as well as coalescence in the F-T process.4, 5 Emulsion types, O/W or W/O, and their stability have been predicted by the Bancroft rule: The phase in which the emulsifier has higher solubility tends to be the continuous outer phase. Numerous exceptions to this rule have been noted. For example, PC has much larger solubility in TG than aqueous medium; however, these mixtures are emulsified to give O/W lipid emulsions. PC also stabilizes water droplets in methyloleate.6 Lipid emulsions containing droplets that are 100 nm in diameter and singlesurface monolayers of zero net charge, i.e., with similar hydrodynamic and electrical properties, were prepared. First, the stability of the lipid droplets against the coalescence in the highly concentrated state [in the floating cream (ultracentrifugation) and in the unfrozen aqueous channels between the ice crystals (F-T processes)] was evaluated with changing surface and core lipid components. The results were discussed on the basis of the coalescence transition state theory recently developed by Kabalnov and collegues.7, 8 The theory predicts that an emulsifier with bulky alkyl chains and a small polar head group (surface lipid with negative spontaneous curvature) stabilizes W/O emulsions well, whereas an emulsifier with small alkyl chains and a bulky polar head group (surface lipid with positive spontaneous curvature) effectively stabilizes O/W emulsions.7, 8 In animals, lipid emulsions are rapidly hydrolyzed by lipoprotein lipase (LPL) and the remnants are readily taken up by the liver after intravenous injection. Because the release of drugs in blood is considered to depend on both the lipolysis of TG and the clearance of the particles from plasma, it is important to control these metabolic processes in order to improve lipid emulsions as injectable drug carriers. Emulsion droplets in this sudy have a size and lipid composition similar to chylomicrons and have also been used as models for plasma lipoproteins. The metabolism of protein-free lipid emulsions in rats is comparable to that of chylomicrons.9, 10 On entering the plasma, lipid emulsions rapidly acquire apolipoproteins, such as apoA-I, C-II, and E, from circulating lipoproteins. It is thought that apoC-II is an activator of LPL, and apoE is necessary for recognition by lipoprotein receptors. On the other hand, an inhibitory effect on hepatic uptake through apoE-specific receptors by apoCs (C-I, C-II, and C-III) has been reported.11-1611, 12, 13, 5
14, 15, 16 The metabolism of lipid emulsions can be affected by the selective binding of these apolipoproteins to lipid particles. Within a blood compartment, TG-rich lipoproteins are converted into remnants through the hydrolysis of TG by LPL.17 These remnants are subsequently taken up by the liver, although hepatic removal appears to be accomplished by several overlapping mechanisms.18 Lipolysis of TG in chylomicrons produces Cholenriched remnant particles.19 It is presumed that the amount of Chol in the lipoprotein surface is an important factor influencing the metabolism of lipoproteins. In addition, differences in sphingomyelin (SM) content among plasma lipoproteins may affect both lipolysis by LPL at endothelial sites and recognition by lipoprotein receptors.20-2420, 21, 22, 23, 24 However, little has been elucidated on the physiological role of SM in lipoprotein metabolism. We assume that the lipid composition of lipoproteins or lipid emulsions plays a crucial role in the metabolism of the particles. In other words, it must be possible to regulate both clearance from plasma and triolein lipolysis of artificial lipid emulsions by modulating the lipid composition of an emulsion surface. In this article we evaluate the effects of Chol and SM in the emulsion surface on the lipolysis and clearance from plasma in rats. The selectivity of apolipoprotein binding was estimated and its relevance to plasma clearance is discussed. These results are useful both for the deeper understanding of lipoprotein metabolism and for the development of improved lipid-emulsion drug carriers.
6
APPLICATIONS OF LIPID EMULSIONS
Use of lipid emulsion in the resuscitation of a patient with prolonged cardiovascular collapse after overdose of bupropion and lamotrigine. Animal studies show efficacy of intravenous lipid emulsion in the treatment of severe cardiotoxicity associated with local anesthetics, clomipramine, and verapamil, possibly by trapping such lipophilic drugs in an expanded plasma lipid compartment ("lipid sink"). Recent case reports describe lipid infusion for the successful treatment of refractory cardiac arrest caused by parenteral administration of local anesthetics, but clinical evidence has been lacking for lipid's antidotal efficacy on toxicity caused by ingested medications. A 17year-old girl developed seizure activity and cardiovascular collapse after intentional ingestion of up to 7.95 g of bupropion and 4 g of lamotrigine. Standard cardiopulmonary resuscitation for 70 minutes was unsuccessful in restoring sustained circulation. A 100-mL intravenous bolus of 20% lipid emulsion was then administered, and after 1 minute an effective sustained pulse was observed. The patient subsequently manifested significant acute lung injury but had rapid improvement in cardiovascular status and recovered, with near-normal neurologic function. Serum bupropion levels before and after lipid infusion paralleled triglyceride levels. This patient developed cardiovascular collapse because of intentional, oral overdose of bupropion and lamotrigine that was initially refractory to standard resuscitation measures. An infusion of lipid emulsion was followed rapidly by restoration of effective circulation. Toxicologic studies are consistent with the lipid sink theory of antidotal efficacy.
Lipid Emulsions in Parenteral Nutrition Lipid emulsions containing a physical mixture of medium and long chain triglycerides (MCT/LCT) are a well-proven concept in parenteral nutrition of critically ill patients. Having a demonstrably higher utilization rate, MCT/LCT emulsions do not impair liver function, produce less immune and no reticuloendothelial system function compromise, and do not interfere with 7
pulmonary hemodynamics or gas exchange. A reduced content of n-6 polyunsaturated fatty acids can also be obtained by using newer preparations based on structured triglycerides or olive oil. Further studies are necessary in order to investigate these new lipid emulsions versus the physical mixture of MCT/LCT. A promising substrate in the development of lipid emulsions can be seen in fish oils. With regard to current literature, fish oils have a beneficial influence on the pathophysiological response to endotoxins and exert important modulations on eicosanoid and cytokine biology. Furthermore their intravenous use may improve organ perfusion in different critical situations.
8
REFRENCE:
WEBSITES: 1. www.pharmainfo.net 2. http://content.karger.com/ 3. http://www.ncbi.nlm.nih.gov 4. http://www.freepatentsonline.com/ 5. http://www.pubmedcentral.nih.gov/ 6. http://www.informaworld.com/
9
Schematic representation of lipid emulsions and liposomes.
1
Preparation of Lipid emulsions. A lipid mixture was prepared with 97% (w}w) triolein (95%pure; Sigma), 2±5% egg phosphatidylcholine (95% pure; Prolabo, Paris, France) and 0±5% free cholesterol (99% pure; Sigma) at a ®nal concentration of 16% (w}w) in chloroform} methanol (2 :1, v}v). Aliquots of the lipid mixture solution (1 ml each) were evaporated to dryness under nitrogen in 7 ml glass tubes. The buffer (with or without ®bre) was added to a ®nal volume of 4 ml. The aqueous mixture thus contained 4% (w}w) lipids and 0±2% ®bre, i.e. in the physiological range [5,6,23,24]. The tubes were stoppered, attached horizontally and shaken at 200 strokes}min for 2 h at 37 °C. These operating conditions resulted from preliminary experiments designed to discover conditions that would generate lipid emulsions with droplet sizes in the range found in human and rat stomach during fat digestion.
Emulsification measurements Determination of the amount of emulsi®ed lipids The upper limit for emulsion droplet size was set at 100 lm, given the instability and negligible interfacial area of lipid droplets above this value [6]. To allow accurate measurements, [carboxyl- "%C]triolein (98% pure; 69 mCi}mmol; CEA, Gif-sur-Yvette, France) was added in trace amounts to the lipid mixture. Radioactivity was measured by liquid scintillation counting using a Packard 1600TR instrument (Packard, Meriden, CT, U.S.A.) from 100 ll aliquots of two fractions collected at the end of the emulsi®cation process. One fraction was the ¯oating oily layer composed of unemulsi®ed lipids (oily material plus lipid droplets &100 lm) which collect above the aqueous solution surface when tubes are left to stand for a given time (0±5±10 min at 1 g) calculated from the Stoke's sedimentation equation for droplets &100 lm under the present conditions, as previously reported. According to Stoke's sedimentation law, the relation between sedimentation time and particle diameter is expressed in the following equation: where D is the particle diameter (m), g! is the viscosity coefficient of the solvent (N[s}m#), q is the density of the sample (kg}m$), q! is the density of the solvent (kg}m$), g is acceleration due to gravity (m[s−#), t is the sedimentation time (s) and H is 2
the distance of sedimentation (m). The second fraction was the resulting infranatant containing emulsifed lipid droplets.
Measurement of droplet size The distribution of the emulsion droplet sizes in the infranatant solution was determined by using a particle-size analyser (Capa 700; Horiba, Kyoto, Japan) as previously described [6,8,9,10,11]. The validity of the method has previously been evaluated and calibrations made using microparticles in the size range 0±2±100 lm (polystyrene size standard kit ; Polyscience Inc., Warrington, PA, U.S.A.). Measurements were carried out using gradientmode analysis at a constant centrifuge acceleration rate (960 rev.}min) to allow an accurate measurement of large dropFibres and fat emulsions 271 lets (100 lm) as well as small droplets (0±1 lm). The particle-sizer software calculated the droplet-size distribution which is expressed as a fraction of the total droplet volume. Results are given as a frequency-distribution graph characterized by its median diameter (lm) and a speci®c interfacial area (m#}g). The droplet surface area (m#) was calculated from the amount (g) of emulsi®ed lipids in the infranatant solution.
Effects of fibres on lipid emulsification To determine the effects of soluble ®bres on the extent of fat emulsi®cation, we measured the amount of emulsi®ed lipid and the size of the emulsi®ed lipid droplets produced and calculated the surface area generated. Lipid emulsi®cation occurred to a moderate extent (24±6%) under the conditions selected in the absence of ®bre (control). Adding ®bres did not markedly change this. For instance, 0±3% solutions of the ®bres caused the following extents of emulsi®cation : gum arabic, 23±8%; HVG, 29±7%; MVG, 25±6%; LVG, 24±2%; NND pectin, 27±8%; BNF pectin, 26±1%. The data 3
obtained from droplet-size measurements of emulsi- ®ed lipids are given in Table 2. In control buffer, the median diameter exhibited by the emulsion was 7±19 lm. Gum Arabic (0±3±2±0%), LVG and MVG at low concentrations did not signi®cantly alter the droplet size. In contrast, LVG at 2±0%, MVG at 0±6% and HVG at 0±3% signi®cantly increased the median size of the droplets (45±6, 41±7 and 25±4 lm respectively). Also, BNF pectin and NND pectin signi®cantly increased the droplet median diameter to a comparable extent at concentrations of 0±6% and 0±8% respectively. A comparison of the effects of the ®bres tested at a given concentration (0±3%; Table 2) provides the following information: the highest median diameters were elicited by HVG (25±41³4±09 lm) and to a lesser degree MVG (14±36³4±78 lm) and NND pectin (15±42³4±34 lm) whereas the other ®bres [LVG (8±71³0±29 lm)
Emulsion Test For Lipids Lipids do not dissolve in water, but do dissolve in ethanol. This characteristic is used in the emulsion test. ⇒ Grind up sample ⇒ Shake some test sample with about 4cm3 of ethanol. ⇒Decant the liquid into a test tube of water leaving any un-dissolved substances between. If there are lipids dissolved in the ethanol, they will precipitate in the water, forming a cloudy white emulsion.
Lipid Emulsions: Formation, Stability, and Metabolism Lipid emulsions composed of triacylglycerol (TG) and phosphatidylcholine (PC) have been commonly used for parenteral nutrition for almost 30 years. Recently, lipid emulsions were used as drug carriers in drug-delivery systems.1 For example, the delivery of prostaglandin E1 in injectable lipid emulsions has been well established and is commercially available.2, 3 Lipid emulsions are classified as macroemulsions and thermodynamically unstable, which may bring about aggregation, flocculation, coalescence, and eventual
4
phase separation over time. It is generally believed that freezing or freezedrying lipid emulsion formulations is an effective form of storage after production. However, there have been problems with coalescence of emulsion droplets during the freeze-thawing (F-T) procedures. When emulsions freeze, the lipid droplets become progressively concentrated and come into contact with one another in unfrozen aqueous channels between the ice crystals. The condensation of the lipid droplets in the narrow channels could lead to aggregation as well as coalescence in the F-T process.4, 5 Emulsion types, O/W or W/O, and their stability have been predicted by the Bancroft rule: The phase in which the emulsifier has higher solubility tends to be the continuous outer phase. Numerous exceptions to this rule have been noted. For example, PC has much larger solubility in TG than aqueous medium; however, these mixtures are emulsified to give O/W lipid emulsions. PC also stabilizes water droplets in methyloleate.6 Lipid emulsions containing droplets that are 100 nm in diameter and singlesurface monolayers of zero net charge, i.e., with similar hydrodynamic and electrical properties, were prepared. First, the stability of the lipid droplets against the coalescence in the highly concentrated state [in the floating cream (ultracentrifugation) and in the unfrozen aqueous channels between the ice crystals (F-T processes)] was evaluated with changing surface and core lipid components. The results were discussed on the basis of the coalescence transition state theory recently developed by Kabalnov and collegues.7, 8 The theory predicts that an emulsifier with bulky alkyl chains and a small polar head group (surface lipid with negative spontaneous curvature) stabilizes W/O emulsions well, whereas an emulsifier with small alkyl chains and a bulky polar head group (surface lipid with positive spontaneous curvature) effectively stabilizes O/W emulsions.7, 8 In animals, lipid emulsions are rapidly hydrolyzed by lipoprotein lipase (LPL) and the remnants are readily taken up by the liver after intravenous injection. Because the release of drugs in blood is considered to depend on both the lipolysis of TG and the clearance of the particles from plasma, it is important to control these metabolic processes in order to improve lipid emulsions as injectable drug carriers. Emulsion droplets in this sudy have a size and lipid composition similar to chylomicrons and have also been used as models for plasma lipoproteins. The metabolism of protein-free lipid emulsions in rats is comparable to that of chylomicrons.9, 10 On entering the plasma, lipid emulsions rapidly acquire apolipoproteins, such as apoA-I, C-II, and E, from circulating lipoproteins. It is thought that apoC-II is an activator of LPL, and apoE is necessary for recognition by lipoprotein receptors. On the other hand, an inhibitory effect on hepatic uptake through apoE-specific receptors by apoCs (C-I, C-II, and C-III) has been reported.11-1611, 12, 13, 5
14, 15, 16 The metabolism of lipid emulsions can be affected by the selective binding of these apolipoproteins to lipid particles. Within a blood compartment, TG-rich lipoproteins are converted into remnants through the hydrolysis of TG by LPL.17 These remnants are subsequently taken up by the liver, although hepatic removal appears to be accomplished by several overlapping mechanisms.18 Lipolysis of TG in chylomicrons produces Cholenriched remnant particles.19 It is presumed that the amount of Chol in the lipoprotein surface is an important factor influencing the metabolism of lipoproteins. In addition, differences in sphingomyelin (SM) content among plasma lipoproteins may affect both lipolysis by LPL at endothelial sites and recognition by lipoprotein receptors.20-2420, 21, 22, 23, 24 However, little has been elucidated on the physiological role of SM in lipoprotein metabolism. We assume that the lipid composition of lipoproteins or lipid emulsions plays a crucial role in the metabolism of the particles. In other words, it must be possible to regulate both clearance from plasma and triolein lipolysis of artificial lipid emulsions by modulating the lipid composition of an emulsion surface. In this article we evaluate the effects of Chol and SM in the emulsion surface on the lipolysis and clearance from plasma in rats. The selectivity of apolipoprotein binding was estimated and its relevance to plasma clearance is discussed. These results are useful both for the deeper understanding of lipoprotein metabolism and for the development of improved lipid-emulsion drug carriers.
6
APPLICATIONS OF LIPID EMULSIONS
Use of lipid emulsion in the resuscitation of a patient with prolonged cardiovascular collapse after overdose of bupropion and lamotrigine. Animal studies show efficacy of intravenous lipid emulsion in the treatment of severe cardiotoxicity associated with local anesthetics, clomipramine, and verapamil, possibly by trapping such lipophilic drugs in an expanded plasma lipid compartment ("lipid sink"). Recent case reports describe lipid infusion for the successful treatment of refractory cardiac arrest caused by parenteral administration of local anesthetics, but clinical evidence has been lacking for lipid's antidotal efficacy on toxicity caused by ingested medications. A 17year-old girl developed seizure activity and cardiovascular collapse after intentional ingestion of up to 7.95 g of bupropion and 4 g of lamotrigine. Standard cardiopulmonary resuscitation for 70 minutes was unsuccessful in restoring sustained circulation. A 100-mL intravenous bolus of 20% lipid emulsion was then administered, and after 1 minute an effective sustained pulse was observed. The patient subsequently manifested significant acute lung injury but had rapid improvement in cardiovascular status and recovered, with near-normal neurologic function. Serum bupropion levels before and after lipid infusion paralleled triglyceride levels. This patient developed cardiovascular collapse because of intentional, oral overdose of bupropion and lamotrigine that was initially refractory to standard resuscitation measures. An infusion of lipid emulsion was followed rapidly by restoration of effective circulation. Toxicologic studies are consistent with the lipid sink theory of antidotal efficacy.
Lipid Emulsions in Parenteral Nutrition Lipid emulsions containing a physical mixture of medium and long chain triglycerides (MCT/LCT) are a well-proven concept in parenteral nutrition of critically ill patients. Having a demonstrably higher utilization rate, MCT/LCT emulsions do not impair liver function, produce less immune and no reticuloendothelial system function compromise, and do not interfere with 7
pulmonary hemodynamics or gas exchange. A reduced content of n-6 polyunsaturated fatty acids can also be obtained by using newer preparations based on structured triglycerides or olive oil. Further studies are necessary in order to investigate these new lipid emulsions versus the physical mixture of MCT/LCT. A promising substrate in the development of lipid emulsions can be seen in fish oils. With regard to current literature, fish oils have a beneficial influence on the pathophysiological response to endotoxins and exert important modulations on eicosanoid and cytokine biology. Furthermore their intravenous use may improve organ perfusion in different critical situations.
8
REFRENCE:
WEBSITES: 1. www.pharmainfo.net 2. http://content.karger.com/ 3. http://www.ncbi.nlm.nih.gov 4. http://www.freepatentsonline.com/ 5. http://www.pubmedcentral.nih.gov/ 6. http://www.informaworld.com/
9
