Palmitic Ester Research Articles

Cytostatic and antiherpesvirus type 1 and 2 activities of 1-beta-D-arabinofuranosylthymine (ara T) prodrugs.

A series of derivatives of the antibiotic 1-beta-D-arabinofuranosylthymine (ara T) was synthesized by esterification of the hydroxy group in the 5'-position of the arabinose moiety of the nucleoside with straight-chain and branched-chain carboxylic acids: acetyl-ara T, butyryl-ara T, valeroyl-ara T, pivaloyl-ara T and palmitoyl-ara T. These ara T prodrugs were evaluated for their effect on growth of L5178y mouse lymphoma cells and noninfected BHK-21 cells as well as for their antiviral activity in Herpes simplex virus type 1 and 2 infected BHK-21 cells. All compounds exhibited a marked antiherpes virus activity, whereas the cytostatic activity of two of them, the pivaleric ester and the palmitic ester, was extremely weak. The relative antiviral indices of the 5'-pivaloyl-ara T and 5'-palmitoyl-ara T were found to be much better than the index of ara T itself.

Turnover of palmitate, arachidonate and glycerol in phospholipids of rat rod outer segments

Rat retinas were intravitreally labeled with [ 3H]palmitic acid, [ 3H]arachidonic acid or [ 3H]glycerol to study the turnover of the component parts of the major phospholipids in rod outer segments at times ranging from 2 hr to 12 days post injection. Rod outer-segment and retinal debris fractions were extracted and the major phospholipids separated by two-dimensional thin-layer chromatography. In darkness, [ 3H]glycerol rapidly labeled phosphatidylinositol in both rod outer-segment and retinal debris fractions. The label in phosphatidylinositol subsequently decreased dramatically, demonstrating a rapid turnover of phosphatidylinositol with a half-life of less than 1 day. Phosphatidylcholine and phosphatidylethanolamine were maximally labeled by glycerol in the retinal debris at the 2-hr time-point and were maximally labeled in rod outer segments between 1 and 5 days post injection, with somewhat longer residence times in the rod outer segments. Phosphatidylserine showed a lag in initial labeling in both rod outer-segment and retinal debris fractions indicating that this phospholipid is not a major precursor of phosphatidylcholine and phosphatidylethanolamine in rat retinas. [ 3H]Palmitate and [ 3H]arachidonate labels were rapidly incorporated into outer-segment phospholipids by 1–2 hr post injection. Eighty per cent of the palmitate label was initially associated with phosphatidycholine at 2 hr. The total amount of palmitate label in rod outer-segment phosphatidylcholine did not change for 12 days post injection. Outer-segment phosphatidylethanolamine steadily increased in palmitate label throughout the 12-day period, suggesting that phosphatidylethanolamine may be utilized for recapture of palmitate released from breakdown of palmitate esters of rhodopsin or vitamin A or from phospholipids. Arachidonate primarily labeled phosphatidylinositol and phosphatidylcholine of both rod outer segments and retinal debris. The arachidonate label did not decrease dramatically during the first day in phosphatidylinositol as did the glycerol label, indicating that arachidonic acid is reutilized by the retina. Turnover of the individual phospholipids, as measured by a decrease in glycerol labeling of the phospholipid backbone, is more rapid than the loss of palmitate label, indicating that there is extensive reutilization of palmitate in both phosphatidylcholine and phosphatidylethanolamine of the rod outer segment. The data indicate that palmitate derived from many sources could be used by the photoreceptor to acylate rhodopsin. No difference in palmitate or arachidonate labeling of major rod outer-segment phospholipids was noted between light- and dark controls at 5 days post injection.

Dopaminergic control of 125I-labeled neurotensin binding site density in corticolimbic structures of the rat brain.

In the rat brain, destruction of dopaminergic cell groups by injections of 6-hydroxydopamine into the ventral mesencephalic tegmentum results in large decreases in the number of neurotensin binding sites in the mesencephalon and the striatum. In contrast, these lesions produce an increase in the number of 125I-labeled neurotensin binding sites in the lateral part of the prefrontal cortex despite a large decrease in cortical dopamine levels. Increases in the number of 125I-labeled neurotensin binding sites in this cortical area as well as in the entorhinal cortex, the nucleus accumbens, and the central part of the striatum were also obtained after chronic blockade of dopamine neurotransmission by a long-acting neuroleptic pipotiazine palmitic ester. We propose that dopamine inputs regulate the density of postsynaptic neurotensin binding sites through cortical and subcortical dopamine receptors. Therefore, some of the clinical effects of neuroleptics in schizophrenic patients could be partly related to changes in neurotensin neurotransmission.

Variation in the ability of neuroleptics to block the inhibitory influence of dopaminergic neurons on the activity of cells in the rat prefrontal cortex

The stimulation of the ventro-medial mesencephalic tegmentum (VMT) induces an inhibition of the spontaneous activity of prefrontal cortical cells and blocks the excitatory responses evoked by the stimulation of the medio-dorsal nucleus of the thalamus (MD). This effect is mediated by the activation of the mesocortical dopaminergic (DA) system. In the present study, the influence of the systemic administration of several neuroleptics on the inhibition of prefrontal cortical cells induced by VMT stimulation has been analyzed in ketamine anaesthetised rats. The acute IP administration of fluphenazine (2 mg/kg), spiroperidol (2 mg/kg) or (±)sulpiride (100mg/kg) reversed the inhibitory responses. Moreover, the number of cortical cells inhibited by VMT stimulation was considerably decreased after these treatments. Surprisingly, neither haloperidol at any dose used (0.1 to 0.5 mg/kg IV or 0.5 to 5 mg/kg IP) nor levomepromazine (25 mg/kg IP) nor the long acting neuroleptic, pipotiazine palmitic ester (32 mg/kg SC) blocked the inhibitory effect of VMT stimulation and in fact they lengthened the duration of the inhibition. Finally, the inhibition of MD evoked spikes in prefrontal cortical cells produced by VMT stimulation was no longer observed after sulpiride but persisted after haloperidol administration. Our findings confirm that the mesocortico-prefrontal DA neurons exert an inhibitory influence on target cells but they reveal differences in the efficacy of neuroleptics in blocking this effect.

Chronic treatment with five different neuroleptics elicits behavioral supersensitivity to opiate infusion into the nucleus accumbens

It has previously been demonstrated that direct opiate infusion into nucleus accumbens elicits psychomotor activation in rats. In the present study, the effects of chronic treatment with five different neuroleptics on this behavioral response were investigated. All neu- roleptics tested (haloperidol, sulpiride, flupentixol decanoate, perphenazine enanthate, fluphenazine decanoate, palmitic ester of pipotiazine) induced a marked behavioral su- persensitivity to intraaccumbens opiate infusion. A similarly enhanced sensitivity was observed in chronic reserpine-treated rats. The maximum sensitivity to opiates appeared 2–3 weeks after the beginning of neuroleptic treatment and was present up to 1 month after the end of treatment. Naloxone blocked the neuroleptic-induced enhanced response to opiates. It is concluded that chronic blockade of dopaminergic transmission results in considerable functional alterations of the endogenous opiate systems. The results are discussed in terms of possible underlying neuronal mechanisms, and important clinical implications are noted.

Use of chloramphenicol palmitate in neonates

The absorption and disposition of orally administered chloramphenicol palmitate (chloramphenicol-P) was studied in seven neonates (four preterm, three term). The highest measured chloramphenicol serum concentrations occurred greater than or equal to 4 hours after the dose, and ranged from 5.5 to 23 micrograms/ml after doses of chloramphenicol-P 50 mg/kg/day orally. The dosage had to be increased in all preterm neonates from 25 mg/kg/day to 50 mg/kg/day to obtain adequate serum levels during therapy. In four neonates the apparent half-life could not be estimated, because there was no decline in serum concentrations. The apparent half-life was 3 and 6 hours, respectively, in two neonates in whom the serum concentration declined during the dosing interval. Urinary excretion of chloramphenicol and the glucoronide ester in three neonates varied from 24% to 55% of the total dose administered. These preliminary data suggest considerable variability in serum chloramphenicol levels when chloramphenicol-P is administered orally in neonates. The delay in achieving the maximum serum concentration, nondeclining serum curve, and low renal recovery is indicative of incomplete, prolonged, and erratic absorption, possibly related to delayed gastric emptying or decreased intraluminal hydrolysis of the palmitate ester.

Affinity partitioning of proteins in aqueous two-phases systems containing polymer-bound fatty acids : I. Effect of polyethylene glycol palmitate on the partition of human serum albumin and α-lactalbumin

The partition of serum albumin between the two aqueous phases of a polyethylene glycol—dextran—water two-phase system is strongly influenced by replacing a small fraction of the polyethylene glycol by its palmitate ester. The partition of albumin is compared with the partition of polymer-bound palmitate using polyethylene glycol[1- 14C]palmitate. The data indicate that a maximum (“saturation”) effect on the partition of albumin corresponds to a binding of fewer than two palmitate groups per albumin molecule The effect on α-lactalbumin corresponds to the maximum binding of 0.5 palmitate group per protein molecule. These data do not fit the most favoured available model for affinity partitioning. The deviation can be attributed to the observation that the palmitate groups probably form micelle-type aggregates in the polyethylene glycol-rich phase at the concentrations used for albumin extraction.

Clinical pharmacokinetics of chloramphenicol and chloramphenicol succinate.

In recent years there has been a renewal of interest in chloramphenicol, predominantly because of the emergence of ampicillin-resistant Haemophilus influenzae, the leading cause of bacterial meningitis in infants and children. Three preparations of chloramphenicol are most commonly used in clinical practice: a crystalline powder for oral administration, a palmitate ester for oral administration as a suspension, and a succinate ester for parenteral administration. Both esters are inactive, requiring hydrolysis to chloramphenicol for anti-bacterial activity. The palmitate ester is hydrolysed in the small intestine to active chloramphenicol prior to absorption. Chloramphenicol succinate acts as a prodrug, being converted to active chloramphenicol while it is circulating in the body. Various assays have been developed to determine the concentration of chloramphenicol in biological fluids. Of these, high-performance liquid chromatographic and radioenzymatic assays are accurate, precise, specific, and have excellent sensitivities for chloramphenicol. They are rapid and have made therapeutic drug monitoring practical for chloramphenicol. The bioavailability of oral crystalline chloramphenicol and chloramphenicol palmitate is approximately 80%. The time for peak plasma concentrations is dependent on particle size and correlates with in vitro dissolution and deaggregation rates. The bioavailability of chloramphenicol after intravenous administration of the succinate ester averages approximately 70%, but the range is quite variable. Incomplete bioavailability is the result of renal excretion of unchanged chloramphenicol succinate prior to it being hydrolysed to active chloramphenicol. Plasma protein binding of chloramphenicol is approximately 60% in healthy adults. The drug is extensively distributed to many tissues and body fluids, including cerebrospinal fluid and breast milk, and it crosses the placenta. Reported mean values for the apparent volume of distribution range from 0.6 to 1.0 L/kg. Most of a chloramphenicol dose is metabolised by the liver to inactive products, the chief metabolite being a glucuronide conjugate; only 5 to 15% of chloramphenicol is excreted unchanged in the urine. The elimination half-life is approximately 4 hours. Inaccurate determinations of the pharmacokinetic parameters may result by incorrectly assuming rapid and complete hydrolysis of chloramphenicol succinate. The pharmacokinetics of chloramphenicol succinate have been described by a 2-compartment model. The reported values for the apparent volume of distribution range from 0.2 to 3.1 L/kg.(ABSTRACT TRUNCATED AT 400 WORDS)

Isomerization of Retinyl Palmitate Using Conventional Lipid Extraction Solvents

The use of a chloroform-ethanol-water solvent system for the direct extraction of retinyl palmitate isomers from fortified food products was previously shown to be unsuitable because significant isomerization of all-trans-retinyl palmitate occurred during the extraction. This study investigated the extent of isomerization of retinyl palmitate in various extraction solvents when subjected to gold fluorescent laboratory light. Purified solutions of all-trans-retinyl palmitate in hexane were diluted with methyl t-butyl ether, hexane, methylene chloride, and stabilized chloroform and subjected to gold fluorescent laboratory light for 2, 4, and 6.5 h. Similar solutions were subjected to light or kept in the dark for 3.5 h. All-trans-, 9-cis-, and 13-cis-retinyl palmitate esters in the solutions were determined by using normal phase high performance liquid chromatography with fluorometric detection. Results demonstrated a noticeable increase in the 9-cis-retinyl palmitate concentration and a corresponding decrease in all-trans-retinyl palmitate concentration with time, in chloroform and methylene chloride compared with hexane. Chlorinated solvents in the absence of light did not promote isomerization of retinyl palmitate. Use of chlorinated solvents for the extraction of vitamin A esters should be avoided because they promote isomerization of retinyl palmitate when subjected to light, including gold fluorescent laboratory light.

Triterpene und Steroide in Kalluskulturen von Solanum dulcamara

From tissue cultures (callus) of the soladulcidine strain of Solanum dulcamara L. the 4,4-dimethylsterols cycloartenol, cycloartanol, 24-dihydrolanosterol, and 24-methylenecycloartanol and the sterols cholesterol, 24-methylenecholesterol, campesterol, stigmasterol, isofucosterol, and sitosterol were identified by GC and GC/MS. In the callus the sterols are present in the free form and as esters, glucosides and palmitic esters of the glucosides. The total contents and the contents of the combined forms were determined photometrically (total: 0.19% on dry weight basis, 59.4% glucosides and acylated glucosides, 4.7% esters, 35.9% free). The main fatty acids of the petrolether soluble lipids of the callus (1.78%) are palmitic-, linoleic-, and linolenic acid.

Some determinants of partitioning behavior of lymphoblasts in aqueous biphasic systems

Partitioning behavior of murine lymphoblasts was examined in biphasic aqueous systems containing dextran and poly(ethylene glycol) with no potential difference across the interface. Persistence of cells in the upper phase of the system could be promoted by addition of the palmitate ester of poly(ethylene glycol). Partitioning effects seen here may derive from affinity of membrane sialic acid residues for dextran-rich lower-phase droplets, and antagonism of these interactions by poly(ethylene glycol) palmitate. Several determinants of partitioning behavior were examined: 1. Membrane glycosylation. Partitioning behavior of P388 and P388/ADR lymphoblasts were compared. The latter has an inherently higher degree of membrane glycosylation, resulting in a lower partition coefficient in poly(ethylene glycol) palmitate-supplemented systems. 2. Degree of esterification. Singly-esterified poly(ethylene glycol) was substantially more effective at promoting cell partition into the upper phase than was doubly-esterified glycol. Use of the latter was associated with cell-cell aggregation. 3. Relative numbers of lower-phase droplets present. Decreasing the numbers of such droplets initially present markedly increased the partition coefficient. 4. Time-dependence. Even in the presence of poly(ethylene glycol) palmitate, the partition coefficient fell with time, indicating an interaction between cells and lower-phase droplets not antagonized by the ester.

Sterol metabolism—XLVII. oxidized cholesterol esters in human tissues

Human aorta, liver, and plasma have been examined for the presence of fatty acylesters of oxidized cholesterol derivatives using high performance liquid chromatography and chemical ionization mass spectrometry. Many such sterol esters have been detected, including eight individual diesters and six individual monoesters of six sterols and six C 14-C 18 fatty acids. Mono- and di-esters of the epimeric 5-cholestene-3β,7-diols, 5-cholestene-3β,25-diol, and a 5-cholestene-3β,26-diol were found at μ/g levels in aorta; palmitate esters of 5-cholestene-3β,25-diol and 3β-hydroxy-5-cholesten-7-one were detected at ng/g levels in liver; and esterified 5-cholestene-3β,7α-diol,5-cholestene-3β,7β-diol, 3β-hydroxy-5-choles ten-7-one, a 5-cholestene-3β.24-diol, 5-cholestene-3β,25-diol, and a 5-cholestene-3β,26-diol were present in plasma at ng/ml levels. The presence of esterified 5-cholestene-3β,7α-diol, 5-cholestene-3β,7β-diol, and 3β-hydroxy-5-cholesten-7-one together may be interpreted as evidence of in vivo lipid peroxidation of cholesterol.

Clinical pharmacology of two chloramphenicol preparations in children: sodium succinate (iv) and palmitate (oral) esters

The clinical pharmacology of chloramphenicol was evaluated in 14 children with serious bacterial infections. The children received chloramphenicol sodium succinate intravenously for five to six days at which time orally administered chloramphenicol palmitate was substituted for an additional five to six days of therapy. The mean peak serum chloramphenicol concentration when given iv (28.2 +/- 5.1 micrograms/ml) occurred within one hour after the termination of the 60-minute iv infusion and when given orally (19.3 +/- 2.6 micrograms/ml) occurred two to three hours after ingestion. Differences in serum levels of chloramphenicol after iv compared to oral administration of the same dose could be demonstrated at various time points studied during the dose-response curves; however, the areas under the chloramphenicol curve were not significantly different after iv (140 +/- 116 micrograms/ml/hour) versus oral (95 +/- 26 micrograms/ml/hour) administration. In seven patients who had concomitant serum and CSF chloramphenicol levels determined, a CSF to serum ratio of 23 to 85% occurred. The CSF levels (5.5 to 13 micrograms/ml) were not directly proportional to serum levels. All patients recovered from their infection and no side effects from chloramphenicol were encountered. Administration of chloramphenicol orally in the palmitate form produces serum concentrations and areas under the disappearance curve similar to those achieved after iv administration of the same dose, indicating that the oral route is an effective method of achieving therapeutic concentrations of chloramphenicol in serum.

Cell fusion, haemolysis and mitochondrial swelling induced by retinol and derivatives

A comparative study has been made of the abilities of retinol and its derivatives to induce cell fusion and haemolysis of hen erythrocytes and to cause swelling of rat liver mitochondria. Retinol, retinaldehyde, α-retinoic acid, iso-13-retinol and to a lesser extent retinyl acetate were active in all three systems. Iso-13-retinoic acid was extremely membranolytic but did not produce stable fused cells. By contrast retinoic acid, its cyclopentyl derivative RO8-7699, and the long chain fatty acid esters of retinol, viz. the oleate, linoleate and palmitate esters, were neither fusogenic nor haemolytic, nor did they affect mitochondria.

Effect of ingesta on systemic availability of chloramphenicol from two oral preparations in cats

On five separate occasions, five adult cats were dosed orally with 100 mg chloramphenicol tablets or chloramphenicol palmitate suspension. Each preparation was given once when the cats were fasted and once when fed ad lib. In addition, fasted cats were given the tablet preparation on one occasion with 10 ml water orally immediately afterwards. Chloramphenicol concentrations were determined at intervals after dosing, and all urine passed in 24 h after dosing was collected for chloramphenicol assay. The initial plasma antibiotic concentrations were lower with chloramphenicol palmitate suspension than with chloramphenicol tablets, and the bioavailability of chloramphenicol from the palmitate ester was especially poor in starved cats. Chloramphenicol palmitate may thus be undesirable for antimicrobial therapy in inappetent cats. Food and fluid did not appear to influence the availability of chloramphenicol from the tablet preparation, although effects on plasma drug concentrations within 1.5 h of dosing would have been missed in this study. A relatively large proportion of an oral dose of chloramphenicol is excreted unchanged in feline urine. Because of the potential toxicity of the drug, chloramphenicol dose rates should be restricted in cats with renal insufficiency or another antibiotic used.

Separation of geometric isomers of retinyl ester, retinal and retinol, pertaining to the visual cycle, by high-performance liquid-chromatography

A method for the analytical and/or preparative separation of the 13- cis, 11- cis, 9- cis and all all- trans isomers of retinyl palmitate ester, retinal and retinol by high-performance liquid chromatography is described. A straight-phase adsorption system consisting of Si 60 silica gel as the stationary phase and mixtures of n-hexane and dioxane as mobile phases were employed, using photometric detection at either 320 or 360 nm, depending on the nature of the compounds being studied. With simple adaptation of the phase system, all geometric isomers within each group could be separated. The precision of the method was 0.5% at the 10-μg (about 40-nmole) level and 4% at the 10-ng (about 40-pmole) level ( n = 3). The detection limit was about 0.5 ng (about 2 pmole). The suitability of the phase system is demonstrated by chromatograms of test mixtures and of eye extracts. The fractionation of 0.5 mg of an isomeric sample could be achieved on a column of length 250 mm and I.D. 10 mm.

Prostaglandin monolayers II: monomolecular film behavior of dinoprost C-15 alkyl esters.

Monomolecular film compression-relaxation behavior was examined for select dinoprost C-15 alkyl esters. Higher homologs of the series such as palmitate and decanoate esters yielded stable expanded monolayers that exhibited minimal relaxation of surface pressure during noncompression. Their limiting molecular areas were consistent with a Hirschfelder model projection in which the prostaglandin moiety assumes a horizontal orientation at the interface with its alkyl ester chain oriented vertical to the surface plane. Shorter chain homologs such as hexanoate, valerate, butyrate, propionate, and acetate also formed expanded monolayers but exhibited increased instability with decreased alkyl chain length, as reflected in their lower surface pressure development during compression and significant relaxation of pressure during noncompression. Such instability can be tied to their increased solubility in the subphase solution and higher desorption rate from the interface.

Action of the palmitic ester of pipotiazine on dopamine metabolism in the nigro-striatal, meso-limbic and meso-cortiacal systems.

The effects of a single injection of the palmitic ester of pipotiazine on dopamine synthesis were examined in slices of the striatum, the olfactory tubercule + nucleus accumbens and the frontal and anterior cingulate parts of the cerebral cortex in the rat. In the two first structures, dopamine synthesis was determined by measuring the rate of formation of 3H−H2O during the conversion of l-3,5-3H-tyrosine into 3H-Dopa. Newly synthesized 3H-dopamine and 3H-noradrenaline were measured in the cerebral cortex. In some experiments, the specific activity of tyrosine in the tissues was determined in order to calculate the conversion index of tyrosine into dopamine.

Hydrophobic surface properties of erythrocytes studied by affinity partition in aqueous two-phase systems.

Erythrocytes from various species have been partitioned in aqueous two-phase systems consisting of water, dextran, poly-(ethylene glycol), salt and buffer. The terminal hydroxyl groups of the latter polymer were esterified with palmitic, oleic, linoleic and linolenic acids, as well as with deoxycholic acid. In a two-phase system containing unesterified poly(ethylene glycol) the erythrocytes are exclusively in the dextran-rich lower phase. When the poly(ethylene glycol)-rich upper phase depending on the type and concentration of esterified acid. Palmitate ester is most effective in increasing the affinity of the cells for the upper phase, followed by oleate, linolate, linolenate, and deoxycholate esters. The partition behaviour of erythrocytes from various species differs considerably. Two groups can be distinguished: one consisting of erythrocytes from dog, guinea pig and rat, the other from human, sheep and rabbit. This division can be correlated to the content of sphingomyelin and phosphatidyl choline in the erythrocyte membranes.

Long-term effects of teflutixol on the synthesis and endogenous levels of mouse brain catecholamines.

Abstract—The long term effects on accumulation of 14C‐labelled dopamine and noradrenaline after [14C]tyrosine administration and on the endogenous levels of catecholamines in mouse brain were studied after treatment with a new potent thioxanthene neuroleptic, teflutixol. The drug was given as a single dose (5 mg/kg i.p.), as repeated daily doses (1·25 mg/kg p.o.), or as a single dose of the palmitic ester in Viscoleo® (20 mg/kg s.c). After a single dose, teflutixol increased catecholamine synthesis (100%). Noradrenaline synthesis rapidly returned to normal, whereas decreased dopamine synthesis was seen from the third to sixth day, after which it was normal. When the receptors were continuously exposed to teflutixol, either by daily dosage or by the depot preparation, catecholamine synthesis was increased for the first few days but then returned to normal, indicating development of tolerance. Endogenous concentrations of catecholamines were only decreased during the first few days, when the increase in synthesis was greatest. The findings are in accordance with results obtained by Møller Nielsen & Christensen (1975), who found that receptor blockade was followed by receptor supersensitivity after treatment with a neuroleptic compound. The receptor blockade may activate a feedback mechanism that induces increased nervous firing with increased amine synthesis as a consequence. The resulting supersensitivity, if sufficiently great, may lead to reduced nervous firing, followed by slowing of dopamine synthesis.