Proceedings: gamma-Aminobutyric acid metabolism and the anticonvulsant action of ethanolamine-o-sulphate and di-n-propylacetate.
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Aminobutyrates↗
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Plasma protein binding of valproic acid in healthy subjects and in patients with renal disease.
1 Based on the Scatchard plot of the binding data of valproic acid (VPA) it is concluded that the drug is bound by two groups of binding sites with the association constants K1=40.0 X 10(-3) and K2=0.39 X 10(3), and the number of binding sites n1=1.5 and n2=6.8. 2 The binding is dependent on dialysis time, on temperature, on the drug concentration, and on the protein concentration in plasma. 3 At therapeutic plasma concentrations unbound VPA is 8.4 +/- 2.5%, but is increased to 20.3 +/- 4.7% in patients with significant impairment of renal function (P less than 0.001). 4 In patients with renal disease a good correlation is found between unbound VPA and serum creatinine, creatinine clearance, blood nitrogen and uric acid, respectively. A poor correlation is seen between unbound VPA and total protein or albumin concentration in plasma.
Binding Sites↗
Feeding value of a high oil variety of sunflowers as silage to lactating dairy cows.
Whole-plant sunflowers (oilseed) were chopped and stored as silage and compared to corn silage as the sole forage to 20 lactating Holsteins in a switch-back design of three 5-wk periods. Cows fed sunflower silage produced less milk (22.4 vs. 20.5 kg/day) but similar amounts of 4% fat-corrected milk. Cows fed sunflower silage had greater fat, less protein, and less total solids in milk. Cows consumed 4.0 kg/day less dry matter from sunflower silage than from corn silage. Oleic and linolenic increased, and myristic and palmitic fatty acids decreased in milk fat from cows fed sunflower silage. Cholesterol in serum (mg/dl) was 321 and 160 for cows fed sunflower silage and corn silage. Cows fed sunflower silage had higher molar percentage of acetate, isobutyrate, isovalerate, and a wider acetate propionate ratio with concomitant lower molar percentage of propionate, butyrate, valerate, and less total acids in rumen fluid than cows fed corn silage. Rumen fluid pH was 6.98 and 6.83 for cows fed sunflower silage and corn silage. Acceptable quality silage can be made from whole oilseed sunflowers. For maximum milk production, sunflower silage should not be fed as the only forage to dairy cows.
Animal Feed↗
Long-term treatment of juvenile Huntington's chorea with dipropylacetic acid.
Since the proposed mode of action of dipropylacetic acid, an anticonvulsant, is to increase central nervous system gamma-aminobutyric acid levels, we used this agent to treat identical twins with juvenile Huntington's chorea. Their clinical status did not improve immediately after they received dipropylacetic acid. Furthermore, long-term administration (over a year) of high doses of the agent (up to 2,400 mg per day; 92 mg per kilogram per day) did not seem to alter the slow progression of their disease. Prior to treatment with dipropylacetic acid, the twins had normal cerebrospinal fluid gamma-aminobutyric acid levels. In addition, cerebrospinal fluid 5-hydroxyindoleacetic acid and homovanillic acid were determined before and after 18 hours of high-dose probenecid. The former showed a normal threefold to fourfold increase after probenecid administration, but homovanillic acid had a distinctly subnormal turnover after probenecid, with only a threefold rather than the normal tenfold increase.
Child↗
[Problems in serum-level determination during valproic acid therapy].
An investigation was carried out to determine whether or not a reliable and reproducible steady state serum level of the anticonvulsant drug valproic acid could be found, such that single values of a serum level determination could be used in therapeutic control. 1. A reliable and comparable serum concentration of valproic acid could not be found in 11 patients during a long-term investigation over a period of 8 weeks. Likewise this could not be found in the 24-h serum concentration profile in 8 of the above mentioned patients, who were receiving both mono and combined therapy. 2. The half-life values for valproic acid in these 8 patients lay between 8--12.5 h. 3. The maximum concentration of valproic acid lies in unforeseeable time spans after drug administration. 4. The morning fasting values are comparable only to a limited extent. In future daily profiles it must be decided whether, and if so to what extent, valproic acid serum concentration determinations can be of value to the individual treatment of epileptics.
Adolescent↗
Sequentially combined estradiol valerate plus levonorgestrel therapy decreases 18:1 trans-fatty acid content of plasma lipids in healthy postmenopausal women.
Trans-fatty acids (TFA) have been classified as atherogenic dietary constituents but the effect of hormone replacement therapy (HRT) on their concentrations is not known. We used a washout protocol to study the effect of long-term estrogen and combined estrogen-progestin HRT on plasma elaidate (18:1t), which is the trans isomer of oleate and the major TFA in the diet. The study group comprised 15 women receiving estradiol valerate HRT and 15 women receiving combined HRT with estradiol valerate and levonorgestrel. The concentrations of elaidate in plasma phospholipids, cholesteryl esters and triglycerides were determined by gas chromatography. At baseline, the total plasma elaidate concentration was lower in the combined HRT group than in the estradiol valerate HRT group (p < 0.01). In the combined HRT group, the concentration of elaidate increased significantly after withdrawal of HRT (p < 0.001) and decreased again to the baseline level after restart of therapy (p < 0.001). These changes were due to decreases in the concentrations of phospholipids and triglycerides; in phospholipids there was also a proportional decrease of elaidate. There were no changes in elaidate in women receiving estradiol valerate alone. Our results suggest that long-term combined HRT treatment decreases plasma TFA, which is not achieved by estrogen alone.
Estradiol↗
Development and validation of a reversed-phase liquid chromatography method for the quantitative determination of carboxylic acids in industrial reaction mixtures.
Usually analysis of low molecular-mass carboxylic acids was performed by anion-exchange or ion-exclusion chromatographic methods. Reversed-phase liquid chromatography (RPLC) was evaluated in this work as an alternative method for the analysis of low molecular-mass aliphatic mono- and di-carboxylic acids (formic, acetic, propionic, butyric, valeric, caproic, succinic, glutaric and adipic) in aqueous media. The separation of the nine organic acids was optimised in 21 min on a high-density C18 column with an elution gradient made up of HClO4 aqueous solution 10(-3) mol L(-1) and acetonitrile. For the quantitation, external standard and standard addition methods were compared. Both methods gave similar results, so the most convenient method, external standard, was chosen for acids quantitation. Then the method had been validated and applied to the semi-quantitative analysis of formic and acetic acids and to the quantitative analysis of the others compounds in industrial reaction mixtures with concentrations ranging from 20 to 570 ppm.
Carboxylic Acids↗
Membrane lipid biosynthesis in Acholeplasma laidlawii B: de novo biosynthesis of saturated fatty acids by growing cells.
The de novo biosynthesis of fatty acids of 12 to 18 carbons from precursors of 5 carbons or fewer has been demonstrated in Acholeplasma laidlawii B. Radiolabeling experiments indicated that the normal primers for the synthesis of the even- and odd-chain fatty acids are acetate and propionate or valerate, respectively. Saturated straight-chain monomethyl-branched fatty acids of up to five carbons were readily utilized as primers, wheras more highly branched species and those possessing halogen substituents or unsaturation were not utilized. At primer concentrations of 1 to 3 mM, up to 80% of the total cellular lipid fatty acids were derived from exogenous primer. The mean chain length of the exogenous primer-derived fatty acids rose with increasing primer incorporation for methyl-branched short-chain fatty acids but was invariant for propionate. The products of de novo biosynthesis varied only slightly with temperature or cholesterol supplementation, suggesting that de novo biosynthesis is not directly influenced by membrane fluidity. Cerulenin inhibited de novo biosynthesis in a fashion that suggests the presence of two beta-ketoacyl thioester synthetases, which differ in substrate chain length specificity and in susceptibility to inhibition by the antibiotic.
Acetates↗
[On the enteral absorption of valproic acid (author's transl)].
The absorption of valproic acid (dipropylacetic acid, DPA)--administered by capsules (free valproic acid) and dragees (valproate sodium)--has been studied. Regarding their bioavailability, both forms of administration examined are equivalent, which means that they are representing therapeutical alternatives.
Biological Availability↗
Valproic acid in epilepsy: clinical and pharmacological effects.
The antiepileptic drug valproic acid was studied in an open clinical trial as adjunct medication for 23 patients with uncontrolled seizures of a generalized or partial type. Two-thirds of the patients experienced reduction in seizure frequency ranging from 25 to 100%. Extensive testing revealed no evidence of serious systemic toxicity due to the drug. Minor side effects (e.g., nausea, vomiting, or sedation) were usually transient. Sodium valproate syrup and valproic acid in capsules gave equivalent mean low (23.3 microgram/ml) and maximum (42.5 microgram/ml) serum concentrations. The drug had a relatively short half-life of 8.7 hours, necessitating administration in divided daily doses. During initiation of valproate therapy there was evidence of a decline in total serum phenytoin concentration (16.5 to 10.2 microgram/ml; p less than 0.001) while the percentage of free phenytoin increased (10.9 to 20%). The quantity of unbound phenytoin was relatively stable throughout. This observation was interpreted as a drug interaction: valproic acid competed with phenytoin for access to plasma protein binding sites.
Adult↗
Effects of Lactobacilli and lactose on Salmonella typhimurium colonisation and microbial fermentation in the crop of the young turkey.
1. Three experiments were performed to examine the effects of Lactobacilli and lactose on microbial fermentation and Salmonella enterica serovar Typhimurium colonisation in the crop of the young turkey. 2. The following carboxylic acids were detected in the crop ingesta: formic, acetic, butyric, lactic, valeric, caproic, oxalic, phenyl acetic, succinic and fumaric; propionic, isobutyric and isovaleric acids were not detectable. 3. At the beginning of the night, there were considerable quantities of ingesta in the crop of young turkeys. During the scotophase, there were progressive reductions in the contents and pH. Moreover, there were linear increases in the concentration of lactic, valeric and caproic acids (by approximately 7-fold over 8 h). Much smaller changes in crop pH were observed in the study where dietary treatments of Lactobacilli were not included. 4. Chronic addition of lactose or Lactobacilli to the diet exerted modest effects on the carboxylic acid concentration in the crop contents but did not consistently influence colonisation of the crop by Salmonella enterica serovar Typhimurium. 5. Young turkeys confine eating to the hours of illumination (photophase) with a peak in consumption prior to the subjective dusk.
Aging↗
Effects of dipropylacetic acid on late components of the photically evoked potential and afterdischarge in rat.
The effects of dipropylacetic acid (DPA) on primary, secondary and afterdischarge waves of the photically evoked potential were examined. It was observed that DPA selectively attenuated late wave components and afterdischarge. A thalamic locus of action for these effects is postulated.
Animals↗
A rapid and sensitive gas-liquid chromatographic procedure for the micro determination of sodium valproate (sodium di-N-propylacetate) in plasma or serum.
A gas-liquid chromatographic procedure for the micro determination of sodium valproate is described. Valproic acid is extracted from acidified plasma or serum into n-heptane containing an internal standard (octanoic acid) and after phase separation an aliquot is analysed by gas-liquid chromatography. The procedure is rapid, reliable, sensitive and specific. It requires 25--50 microliter sample for a single estimation, has a detection threshold of less than 10 mumol/l, and is suitable for routine clinical use.
Chromatography, Gas↗
[Proposal for the introduction of a new substance into hospital practice: dipropyl acetate sodium in the prevention and treatment of alcoholic delirium].
Reference is made to two years' work with the sodium salt of N-dipropylacetic acid in the prevention and treatment of alcoholic delirium tremens in 1500 subjects. The drug impeded the onset of the syndrome, or reduced its duration and gravity in cases where it was already present. It appeared suitable for the specific correction of the CNS functional changes responsible for delirium tremens.
Animals↗
Some nutritional characteristics of predominant culturable ruminal bacteria.
Bryant, M. P. (U.S. Department of Agriculture, Beltsville, Md.) and I. M. Robinson. Some nutritional characteristics of predominant culturable ruminal bacteria. J. Bacteriol. 84:605-614. 1962.-The effect of enzymatic hydrolysate of casein, NH(4) (+), a mixture of volatile fatty acids (acetic, n-valeric, isovaleric, 2-methylbutyric, and isobutyric), hemin, and ruminal fluid on growth of 89 freshly isolated strains of predominant culturable ruminal bacteria was studied, using basal media containing glucose, cellobiose, or maltose as energy source, minerals, cysteine, and S(=) as reducing agents, and H(2)CO(3)-HCO(3) (-) buffer. Of these strains, 13% (four morphological groups) grew poorly or not at all in defined medium plus casein hydrolysate; 6% (one morphological group) required casein hydrolysate; 56% (four morphological groups) grew with either NH(4) (+) or casein hydrolysate as the main source of nitrogen; and NH(4) (+), but not casein hydrolysate, was essential for 25% of the strains (five morphological groups). The volatile fatty acid mixture excluding acetate was essential for 19% of the strains (five morphological groups), and this mixture and acetate were necessary for good growth of 23% of the strains (one morphological group) when casein hydrolysate was excluded from the medium; 30% of the strains (one morphological group) required hemin. Similar studies are reported on 35 old laboratory strains of ruminal bacteria, most of which were previously identified. The results indicate that most strains of ruminal bacteria can be grown in defined media, and suggest the relative importance of NH(4) (+) and volatile fatty acids and the relative lack of importance of organic nitrogen compounds such as amino acids in the nutrition of these bacteria.
Amino Acids↗
The estimation of plasma valproate by gas-liquid chromatography.
A gas chromatographic method for the plasma assay of the anticonvulsant, sodium valproate, is described. Derivatization is not necessary. 200 microliter plasma are required for a single estimation. The method involves a chloroform extraction of valproate and the internal standard, cyclopentane carboxylic acid, from acidified plasma. Gas-liquid chromatography using the stationary phase 10% SP-216-PS gives complete separation of valproate and the internal standard in eight minutes. The limit of detection is 20 mumol valproate/1 plasma (equivalent to 40 pmol on column). This is well below the lower therapeutic plasma level. The between-run precision of the method indicates a variation for each sample within+/-3% of its mean value.
Chromatography, Gas↗
Sodium valproate: a review of its pharmacological properties and therapeutic efficacy in epilepsy.
Sodium valproate has a broad spectrum of anticonvulsant activity, but is structurally unrelated to conventional antiepileptic drugs. Its proposed mode of action is mediated through effects on the function of brain gamma-aminobutyric acid (GABA). However, the elevations in brain and cerebellar GABA, and the concomitant reductions in levels of cyclic guanosine monophosphate, occur in animals at dose levels which are unlikely to be achieved during treatment of epileptic patients.
Administration, Oral↗
Effect of di-n-propylacetate on the 'binding of GABA to synaptosome-enriched fraction of rat cerebral cortex.
The effect of di-n-propylacetate (DPA) on the 'binding' of gamma-aminobutyric acid (GABA) to a synaptosome-enriched fraction of rat cerebral cortex has been examined using differential centrifugation and double-isotope liquid scintillation spectrometry. DPA at 10(-4) M caused a slight decrease in GABA binding. This effect could explain in part the in vivo anticonvulsant and behavioral effects of this drug when administered to animals in high systemic doses.
Aminobutyrates↗