Ethyl Oleate Delays Depot Release?
- Thread starter DocJ
- Start date
StoneColdNTO
Administrator
Never heard that one before, and honestly it doesn't make much sense.
I've had my script filled with pharmacutical (Cytex, Canada) Test cypionate in EO, mind you it's only 100mg/ml, but it has all the same properties, active and half lives as any other test cypionate.
I've had my script filled with pharmacutical (Cytex, Canada) Test cypionate in EO, mind you it's only 100mg/ml, but it has all the same properties, active and half lives as any other test cypionate.
Uridium245
Fluffy Bunny Hater
The good news:
Marion Merrell Dow, Winnersh, Berks, England.
The level of solubilization of the drug testosterone propionate into 2% w/w oil-in-water (o/w) microemulsions, stabilized by the nonionic surfactant polyoxyethylene 10-oleyl ether (Brij 96) and containing a range of oils, has been determined. Although testosterone propionate was readily soluble in the ethyl esters ethyl oleate, ethyl caprylate, and ethyl butyrate, and the triglycerides soybean oil, Miglyol 812, and tributryin, and the alkene 1-heptene, only microemulsions containing the ethyl esters and the triglyceride oils exhibited a significant increase in solubilization over the corresponding micellar solution (i.e., surfactant solution in the absence of oil). Furthermore, the increase in drug solubility observed in the microemulsion systems was not related to the solubility of the drug in the bulk oil. That is, while the smaller molecular volume oils, such as ethyl butyrate, exhibited a greater capacity for the drug, microemulsions containing these oils were only marginally better at solubilizing the drug than the corresponding micellar solution. In contrast, microemulsions containing the larger molecular volume oil, Miglyol 812, gave levels of drug solubilization almost three times those containing ethyl butyrate, yet the bulk capacity for drug in this oil was less than half that of ethyl butyrate. Light scattering and phase inversion temperature studies suggested that the structure of the microemulsion was sensitive to the oil being used, in that, at the low oil concentrations used in this study, the smaller molecular volume oils generally penetrated the interfacial surfactant monolayer in much the same way as a cosurfactant, causing an alteration, presumably a dilution, of the relatively concentrated polyoxyethylene region close to the hydrophobic core, thereby destroying one of the main loci of drug solubilization and counteracting any advantages encountered due to the high solubility of the drug in the bulk oil.
Pfizer Central Research, Sandwich, UK.
The pharmacokinetics of doramectin, a novel avermectin, were evaluated following parenteral administration in a range of oil-based formulations in an attempt to optimise the formulation. Therapeutic and persistent efficacies against Cooperia oncophora were also evaluated. This approach led to the identification of formulations based upon sesame oil and ethyl oleate which gave more prolonged doramectin plasma concentrations with no loss in therapeutic efficacy and improved persistent efficacy following subcutaneous administration to cattle at a dosage of 200 micrograms kg-1. The importance of using both pharmacokinetic and efficacy end points to distinguish between formulations is discussed. All formulations were well tolerated as evidenced by the absence of any reaction to injection either in the form of behavioural responses, injection site swelling or postmortem lesions. Sesame oil with ethyl oleate was the best parenteral vehicle tested for doramectin, allowing the expression of a high level of therapeutic and persistent efficacy and offering the benefit of excellent injection site toleration.
The bad news:
Department of Internal Medicine, Saint Louis University Health Sciences Center, Missouri 63110, USA.
Fatty acid ethyl ester (FAEE), a myocardial metabolite of ethanol, causes mitochondrial dysfunction in vitro in rabbits. We investigated the effect of these esters on rat heart mitochondria in vitro and in vivo. In vitro studies were conducted to investigate the binding of ethyl oleate (FAEE) to mitochondria and their capacity to hydrolyze these FAEE. In vivo effects of ethyl esters were studied by the direct transfer of [3H]oleate into the myocardium. Mitochondria were prepared from the myocardium of injected rats, and the amount of [3H]oleate bound to them was determined. In another in vivo study, 50 microliters of 50 microM cold oleic acid ethyl ester was injected into the rat myocardium and the histopathological changes induced by oleic acid ethyl ester were examined by light microscopy. Our results show that fatty acid ethyl ester can bind to myocardial mitochondria in vitro as well as in vivo and the mitochondria can hydrolyze FAEE to fatty acid, which is a known uncoupler of oxidative phosphorylation. Of the total ethyl [3H] oleate injected, 8 microM [3H]oleate and 1 microM ethyl [3H]oleate was bound to the mitochondria. Significant myocardial cell damage was first observed on day 4 and markedly increased on day 30 after ethyl ester injection, with cells showing gross deformation and enlargement. However, no significant histopathological changes were observed in the myocardial tissue on day 2 after injection. Our results suggest that the FAEE may damage the myocardial cells as well as the mitochondria and may provide a metabolic link between ethanol abuse and myocardial dysfunction.
Department of Pathology, Massachusetts General Hospital, Boston.
BACKGROUND/AIMS: Fatty acid ethyl esters (FAEEs) are nonoxidative products of ethanol metabolism. They have been implicated as mediators of ethanol-induced organ damage because FAEE and FAEE synthase have been found specifically in the organs damaged by ethanol abuse. This study showed toxicity specifically related to FAEE or their metabolites for intact human hepatoblastoma-derived cells (HepG2). METHODS: The lipid core of human low-density lipoprotein (LDL) was extracted and the LDL particle reconstituted with either ethyl oleate or ethyl arachidonate. Cultured HepG2 cells were incubated with LDL containing FAEE. Cell proliferation was measured by [methyl-3H]thymidine incorporation. Protein synthesis was determined using L-[35S]methionine. RESULTS: Incubation of cells with 600 mumol/L ethyl oleate or 800 mumol/L ethyl arachidonate decreased [methyl-3H]thymidine incorporation into HepG2 cells by 31% and 37%, respectively. LDL reconstituted with 400 mumol/L ethyl oleate decreased protein synthesis in intact HepG2 cells by 41%. Electron microscopy revealed significant changes in cell morphology, particularly involving the cell nucleus. FAEE delivered in reconstituted LDL were rapidly hydrolyzed and the fatty acids re-esterified into phospholipids, triglycerides, and cholesterol esters, with preference for triglycerides. CONCLUSIONS: These findings provide evidence that FAEE are toxic for intact human hepatoblastoma cells and that they or their metabolites may be an important causative agent in ethanol-induced liver damage.
Marion Merrell Dow, Winnersh, Berks, England.
The level of solubilization of the drug testosterone propionate into 2% w/w oil-in-water (o/w) microemulsions, stabilized by the nonionic surfactant polyoxyethylene 10-oleyl ether (Brij 96) and containing a range of oils, has been determined. Although testosterone propionate was readily soluble in the ethyl esters ethyl oleate, ethyl caprylate, and ethyl butyrate, and the triglycerides soybean oil, Miglyol 812, and tributryin, and the alkene 1-heptene, only microemulsions containing the ethyl esters and the triglyceride oils exhibited a significant increase in solubilization over the corresponding micellar solution (i.e., surfactant solution in the absence of oil). Furthermore, the increase in drug solubility observed in the microemulsion systems was not related to the solubility of the drug in the bulk oil. That is, while the smaller molecular volume oils, such as ethyl butyrate, exhibited a greater capacity for the drug, microemulsions containing these oils were only marginally better at solubilizing the drug than the corresponding micellar solution. In contrast, microemulsions containing the larger molecular volume oil, Miglyol 812, gave levels of drug solubilization almost three times those containing ethyl butyrate, yet the bulk capacity for drug in this oil was less than half that of ethyl butyrate. Light scattering and phase inversion temperature studies suggested that the structure of the microemulsion was sensitive to the oil being used, in that, at the low oil concentrations used in this study, the smaller molecular volume oils generally penetrated the interfacial surfactant monolayer in much the same way as a cosurfactant, causing an alteration, presumably a dilution, of the relatively concentrated polyoxyethylene region close to the hydrophobic core, thereby destroying one of the main loci of drug solubilization and counteracting any advantages encountered due to the high solubility of the drug in the bulk oil.
Pfizer Central Research, Sandwich, UK.
The pharmacokinetics of doramectin, a novel avermectin, were evaluated following parenteral administration in a range of oil-based formulations in an attempt to optimise the formulation. Therapeutic and persistent efficacies against Cooperia oncophora were also evaluated. This approach led to the identification of formulations based upon sesame oil and ethyl oleate which gave more prolonged doramectin plasma concentrations with no loss in therapeutic efficacy and improved persistent efficacy following subcutaneous administration to cattle at a dosage of 200 micrograms kg-1. The importance of using both pharmacokinetic and efficacy end points to distinguish between formulations is discussed. All formulations were well tolerated as evidenced by the absence of any reaction to injection either in the form of behavioural responses, injection site swelling or postmortem lesions. Sesame oil with ethyl oleate was the best parenteral vehicle tested for doramectin, allowing the expression of a high level of therapeutic and persistent efficacy and offering the benefit of excellent injection site toleration.
The bad news:
Department of Internal Medicine, Saint Louis University Health Sciences Center, Missouri 63110, USA.
Fatty acid ethyl ester (FAEE), a myocardial metabolite of ethanol, causes mitochondrial dysfunction in vitro in rabbits. We investigated the effect of these esters on rat heart mitochondria in vitro and in vivo. In vitro studies were conducted to investigate the binding of ethyl oleate (FAEE) to mitochondria and their capacity to hydrolyze these FAEE. In vivo effects of ethyl esters were studied by the direct transfer of [3H]oleate into the myocardium. Mitochondria were prepared from the myocardium of injected rats, and the amount of [3H]oleate bound to them was determined. In another in vivo study, 50 microliters of 50 microM cold oleic acid ethyl ester was injected into the rat myocardium and the histopathological changes induced by oleic acid ethyl ester were examined by light microscopy. Our results show that fatty acid ethyl ester can bind to myocardial mitochondria in vitro as well as in vivo and the mitochondria can hydrolyze FAEE to fatty acid, which is a known uncoupler of oxidative phosphorylation. Of the total ethyl [3H] oleate injected, 8 microM [3H]oleate and 1 microM ethyl [3H]oleate was bound to the mitochondria. Significant myocardial cell damage was first observed on day 4 and markedly increased on day 30 after ethyl ester injection, with cells showing gross deformation and enlargement. However, no significant histopathological changes were observed in the myocardial tissue on day 2 after injection. Our results suggest that the FAEE may damage the myocardial cells as well as the mitochondria and may provide a metabolic link between ethanol abuse and myocardial dysfunction.
Department of Pathology, Massachusetts General Hospital, Boston.
BACKGROUND/AIMS: Fatty acid ethyl esters (FAEEs) are nonoxidative products of ethanol metabolism. They have been implicated as mediators of ethanol-induced organ damage because FAEE and FAEE synthase have been found specifically in the organs damaged by ethanol abuse. This study showed toxicity specifically related to FAEE or their metabolites for intact human hepatoblastoma-derived cells (HepG2). METHODS: The lipid core of human low-density lipoprotein (LDL) was extracted and the LDL particle reconstituted with either ethyl oleate or ethyl arachidonate. Cultured HepG2 cells were incubated with LDL containing FAEE. Cell proliferation was measured by [methyl-3H]thymidine incorporation. Protein synthesis was determined using L-[35S]methionine. RESULTS: Incubation of cells with 600 mumol/L ethyl oleate or 800 mumol/L ethyl arachidonate decreased [methyl-3H]thymidine incorporation into HepG2 cells by 31% and 37%, respectively. LDL reconstituted with 400 mumol/L ethyl oleate decreased protein synthesis in intact HepG2 cells by 41%. Electron microscopy revealed significant changes in cell morphology, particularly involving the cell nucleus. FAEE delivered in reconstituted LDL were rapidly hydrolyzed and the fatty acids re-esterified into phospholipids, triglycerides, and cholesterol esters, with preference for triglycerides. CONCLUSIONS: These findings provide evidence that FAEE are toxic for intact human hepatoblastoma cells and that they or their metabolites may be an important causative agent in ethanol-induced liver damage.
simpllyhuge
New member
well wouldnt slower be better for more stable levels?
ethanol-induced liver damage.
How serious is this? Should we just be sticking to normal substances like oil and staying with lower concentrations? Or would the key wording here be that this was induced by ethanol abuse, and by this I mean in excess and they were taking it orally so it was digested?
How serious is this? Should we just be sticking to normal substances like oil and staying with lower concentrations? Or would the key wording here be that this was induced by ethanol abuse, and by this I mean in excess and they were taking it orally so it was digested?
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Uridium245
Fluffy Bunny Hater
Yeah I wasn't too happy when I was researching this either. The second article is why I've been making my stuff with sesame and 1/3rd EO. Right now I'm injecting 21ml per week so 7ml of that is EO. In the test 2500iu was injected directly into heart tissue. 7ml of EO equals 5800iu which will be distributed throughout the entire body over one week. There may be cumulative effects over time with these lower doses that we are not aware of. However, since most of us don't drink, eat right and do some cardio I'm no overly concerned by the amounts we typically inject. But it is best to be informed.DocJ said:
Uridium245
Fluffy Bunny Hater
Yep that was the plan. Test prop was not something that I tolerated well. So I mixed the oils with 1/3 EO and made all my props and aces at 110mg using 2% BA and 15% BB. I barely even notice the injections now. I've been considering trying for 200mg/ml using the same ratios in straight EO. Have you tried any high concentrations using less co-solvents?
Amateur, It would appear that the ethanol abuse is what produces FAEE's in the body and they and their metabolites appear to assist in the damage caused by ethanol.
Amateur, It would appear that the ethanol abuse is what produces FAEE's in the body and they and their metabolites appear to assist in the damage caused by ethanol.
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Uridium245
Fluffy Bunny Hater
Yeah that is strange you'd think with NPP having the slightly longer ester and deca being soluble in oil alone that 10% would work just as well. I think I may try some small test batches @ 200 and see how I tolerate it. Thanks for the formulas Doc.
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