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PubMed1976

Gas chromatographic analysis of dialkylbarbituric acids.

A variety of procedures for the derivatization of barbituric acids for gas-liquid chromatography (GLC) are described and a convenient procedure for n-alkylation of barbiturates is reported. The gas chromatographic behavior of derivatives(methyl, ethyl, propyl, butyl, pentyl and hexyl) is discussed on the basis of the retention index. For the identification and quatitation of 23 barbiturates in biological fluids, use of the propyl derivatives allows a clear gas chromatogram to be obtained by using only one stationary phase. Alkylation with n-alkylating reagents gives only the N,N'-derivative, as confirmed by nuclear magnetic resonance (NMR) and infrared spectroscopy and gas chromatography-mass spectrometry (GC-MS). The fragmentation pattern by electron-impact mass spectrometry is discussed. Alkylation with branched alkylating reagents gives up to three peaks, the major peak being the N,N'-derivative; the other peaks identified by NMR and GC, correspond to the isomeric N,O-derivatives.

Alkylation↗
PubMedDate not supplied

Phase II trial of merbarone in patients with malignant brain tumors.

The standard treatment for patients with primary malignant glioma includes surgical resection, radiotherapy, and nitrosourea. Despite this multimodality approach, adults with newly diagnosed glioblastoma multiforme (GBM) and high-grade astrocytoma have a median survival duration of 50 weeks and 150 weeks respectively. Chemotherapy has had a limited impact on the survival of these patients. Merbarone (5-phenylcarboxamide-2-thiobarbituric acid) is a nonsedating derivative of barbituric acid that crosses the blood brain barrier. Antitumor activity of merbarone has been described against L1210, B16 melanoma cell line and the M5076 sarcoma cells in phase I studies. Merbarone inhibits DNA synthesis and tumor growth by inducing single strand breaks in DNA. It also inhibits RNA and protein synthesis. We evaluated merbarone in a phase II trial in patients (pts) with recurrent or refractory GBM (7 pts) and high grade anaplastic astrocytoma (7 pts). Fourteen patients (nine males, five females) were treated with merbarone at a dose of 1000 mg per m2 per day by continuous intravenous infusion for 5 days every 3 weeks. Every patient received at least two cycles of treatment. No complete or partial responses were observed, although one patient had stable disease lasting 20 weeks. Our conclusion is that merbarone is ineffective against GBM and high-grade anaplastic astrocytoma at the dose and schedule in which it was administered in this trial.

Adult↗
PubMed1978

Metabolic effects of some electrofluorimetric dyes.

The effect of five electrofluorimetric dyes on mitochondrial metabolism was examined to determine their suitability for mitochondrial studies and other biological uses. The dyes merocyanine 540, 8-anilino-1-naphthalene sulfonic acid and bis(1,3-dibutyl barbituric acid-(5))-pentamethane oxonol were found to be inhibitors of the respiratory chain. However, the first two exerted their effect only at high concentrations. 3.3'-Dihexyl-2,2'-oxacarbocyanine was found to act as an uncoupler. 3,3'-Dipropyl-thiocarbocyanine inhibited beta-hydroxybutyrate respiration while dissociating succinate supported respiration from the phosphorylation of ADP. Merocyanine 540 and 8-anilino-1-naphthalene sulfonic acid may be the best suited for studies of membrane potentials in mitochondria since their effect on metabolism is negligible

Animals↗
PubMed1980

Barbiturate receptor sites are coupled to benzodiazepine receptors.

Barbiturates enhance the binding of [3H]diazepam to benzodiazepine receptor sites in rat brain. This effect occurs at pharmacologically relevant concentrations of barbiturates, and the relative activity of a series of compounds correlates highly with anesthetic activity of the barbiturates and with their ability to enhance postsynaptic inhibitory responses to the neurotransmitter gamma-aminobutyric acid. Barbiturate enhancement of benzodiazepine binding is stereospecific, with the more active anesthetic isomers of N1-methylbarbiturates being also more active than their stereoisomers in enhancing benzodiazepine binding. The active barbiturates produce a reversible enhancement in the affinity of specific benzodiazepine binding with no effect on the number of binding sites. The barbiturate enhancement, but not the baseline benzodiazepine binding, is competitively inhibited by the convulsant picrotoxinin (at 1-10 microM), a drug that has been shown to label barbiturate-sensitive brain membrane sites related to the gamma-aminobutyric acid receptor-ionophore complex. The barbiturate effect is also dependent upon the presence of certain anions, and only those anions, that penetrate the chloride channels regulated by gamma-aminobutyric acid receptors. These results suggest that picrotoxin-sensitive barbiturate binding sites are coupled to benzodiazepine receptors in the gamma-aminobutyric acid receptor-ionophore complex, and that these binding sites have the properties of pharmacologically relevant receptors that mediate at least part of the action of various nervous system depressant and excitatory drugs.

Animals↗
PubMed1979

Anticonvulsant and anesthetic barbiturates: different postsynaptic actions in cultured mammalian neurons.

Mammalian spinal cord neurons were grown in dissociated cell culture and used to study the effects of the anticonvulsant barbiturates phenobarbital and mephobarbital, and the anesthetic barbiturates pentobarbital, secobarbital, and 1,3-dimethyl-butylethyl barbituric acid on amino acid responses and neuronal membrane properties. All barbiturates augmented responses to GABA and diminished glutamate (GLU) responses, but the anesthetic barbiturates were more potent. The anesthetic barbiturates directly depressed excitability by increasing membrane conductance, an effect reversed by the GABA antagonists picrotoxin and penicillin. Anticonvulsant barbiturates, however, had only minimal GABA-mimetic inhibitory action at high doses. Modulation of synaptic events mediated by GABA and GLU might contribute to barbiturate anticonvulsant activity; and direct GABA-mimetic inhibition, combined with similar modulation of synaptic transmission, might underlie barbiturate anesthesia.

Animals↗
PubMed1994

Phase II study of merbarone (NSC 336628) in patients with advanced gastric carcinoma.

Merbarone, 5-(N-phenylcarboxamido)-2-thiobarbituric acid (NSC 336628), is a derivative of barbituric acid and represents a unique class of antineoplastic agents. We treated 16 patients with advanced gastric carcinoma in a phase II study of merbarone. All patients were previously untreated with chemotherapy or biological therapy. The starting dose of merbarone was 1000mg/m2 infused over 24 hr for 5 consecutive days every 21 days. A median of two courses (range, 1-7) was given. None of the patients achieved a complete or partial response; however, 3 patients achieved a transient minor response. Toxicity was mild to moderate in most patients, but 1 patient died of treatment-related neutropenia and sepsis. Our data suggest that merbarone at this dose and schedule is inactive against gastric carcinoma. The evidence of minor response suggests that analog research may be worthwhile to pursue.

Antineoplastic Agents↗
PubMed1976

[Therapeutic possibilities in idiopathic headaches. Analysis of about 1000 cases].

This work is an attempt to find an answer to the question: once arrived at the diagnostic identification of a certain type of idiopathic headache, which treatment should be followed? On the basis of recent researches and experience acquired during ten years' activity of our Headache Unit, a diagnostic identification can be made for migraine (in all its types and evolution stages), cluster headache, tension headache and pure psycogenic headache. Among the most widely used drugs, positive pharmacological results were obtained with: cyproheptadine, pizotifen, cinnarizine, lysergic acid derivatives, histamine, reserpine, clonidine and a barbituric acid derivative. The therapeutic cycles were standardized, for each drug, in the way of administration, dosage and total duration of the treatment. A comparison between the data obtained and the pre-therapeutic situation was made. When repeated, the most efficacious therapeutic cycle was evaluated. According to Pearson's dispersion index, each group of patients improved respresents 16.68% of the expected total results (frequency of attacks reduced to 50%, 25% and 0%): for cyproheptadine, pizotifen, methysergide, histamine, clonidine and allil-propyl-malonylurea, the "p" is less than 0.001; for cinnarizine, less than 0.02. This "a posteriori" analysis does not take into account the placebo control, the "anticipation effect", and the "carry over effect". It cannot therefore be a comparison of efficacy among the various drugs. An evaluation based on "among patients" and "inside patient" method by means of the cross over system, can instead give some useful suggestion about which treatment is to be recommended to patients suffering from recurrent headaches. With regard to migraine sufferers: cinnarizine, cyproheptadine, clonidine, histamine, pizotifen und reserpine. For cluster headaches: cinnarizine, cyproheptadine, clonidine, histamine and reserpine. For tension headaches: cyproheptadine. For pure psychogenic headache: allyl-propyl-malonylurea. For migraine attacks or parossystic crises in the course of ondulating or continuous headaches, positive therapeutic results, statistically significant, were obtained with an association of indomethacin, caffeine and prochlorperazine.

Cinnarizine↗
PubMed1976

Circular dichroism and carbon-13 nuclear magnetic resonance spectra of (S)-5-alkyl-5-(2'-pentyl)-2-thiobarbituric acids.

The circular dichroism (CD) and carbon-13 nuclear magnetic resonance (13C NMR) spectra of (S)-5-(2'-pentyl)-2-thiobarbituric acid and several (S)-5-alkyl-5-(2'-pentyl)-2-thiobarbituric acids were obtained. The results were compared to CD and 13C NMR spectral data obtained from (S)-5-(2'-pentyl)bartituric acid and (S)-5-alkyl-5-(2'-pentyl)barbituric acids.

Carbon Isotopes↗
PubMed2002

Liquid chromatography-mass spectrometry (LC-MS) investigation of the thiobarbituric acid reactive substances (TBARS) reaction.

The thiobarbituric acid reactive substances (TBARS) assay is a commonly used method for the detection of lipid peroxidation. Malondialdehyde is formed as a result of lipid peroxidation and reacts with thiobarbituric acid to form a pink pigment that has an absorption maximum at 532 nm. Other compounds also react with thiobarbituric acid to form colored species that can interfere with this assay, but little is known about these interfering species. This is the first investigation using LC-MS and MS-MS to study the structures of the pink adduct as well as a common unstable yellow interference compound, which absorbs at 455 nm. Also, the presence of barbituric acid impurities in the thiobarbituric acid reagent was found to produce 1:1:1 thiobarbituric acid/malondialdehyde/barbituric acid and 2:1 barbituric acid/malondialdehyde adducts that absorbed at 513 and 490 nm, respectively, indicating that thiobarbituric acid should be purified before use.

Barbiturates↗
PubMedDate not supplied

Uracil catabolism by Escherichia coli K12S.

Experiments designed to elucidate the mechanism of uracil degradation by E. coli K12S showed that in contrast to uracil, dihydrouracil--the postulated intermediate of a reductive mechanism--did not stimulate the growth of bacteria as additional source of nitrogen, nor it was catabolized to ureido carbon dioxide. However, the chromatographic analysis of dihydrouracil metabolic products, revealed the presence of an enzyme converting dihydrouracil to beta-ureidopropionic acid. Results of growth and biochemical studies indicated that barbituric acid--the postulated intermediate of an oxidative pathway--is not involved in uracil degradation.

Escherichia coli↗
PubMed1985

Strychnine-like action of the convulsant barbiturate, CHEB.

The effect of 5-(2-cyclohexylideneethyl)-5-ethyl barbituric acid (CHEB) on the isolated spinal cord of the immature rat was examined using extracellular recording. At concentrations less than 20 microM CHEB increased the monosynaptic reflex (MSR) but depressed the reflex at greater concentrations (30-100 microM). At concentrations which enhanced the monosynaptic reflex, CHEB reduced the responses of motoneurones to glycine and to a lesser extent to those of L-glutamate. In the presence of strychnine (5 microM), which enhanced both mono- and polysynaptic reflexes, CHEB produced only slight enhancement of the monosynaptic reflex. At concentrations of 30-100 microM the responses to gamma-aminobutyric acid (GABA), glycine, L-glutamate and eledoisin-related peptide (ERP a substance P and analogue) were all reduced. At these concentrations CHEB directly depolarised the motoneurone membrane. Increases in [Mg2+]0, which reduced spontaneous activity, blocked the enhancement, by CHEB, of the monosynaptic reflex. The actions of CHEB in small doses may be due therefore to its ability to block the action of glycine and thus block tonic inhibition.

Amino Acids↗
PubMed1979

[The tissue distribution of racemic S-(+)- and R-(R)-(-)-MPPB (1-methyl-5-phenyl-5-propylbarbituric acid) in the rat].

Distribution of racemic 1-methyl-5-phenyl-5-propyl-barbituric acid (= racem. MPPB), of the S-(+)- and R-(-)-enantiomer (= (+)- and (-)-MPPB) between serum and several tissues was investigated after i.v. administration of the substances to rats. Anesthesia produced by the racem. MPPB--(+)-MPPB causes convulsions whereas (-)-MPPB is anesthetically active--cannot be explained by a stereoselective difference of the MPPB-concentration measured in serum and brain when giving the enantiomers. Reversely as expected in the brain MPPB-concentration is significantly higher after administration of (+)-MPPB than after that of (-)-MPPB during the appearance of the CNS symptoms.--Significant stereoselectively different MPPB-concentrations, which are time dependent, could also be detected in liver, spleen and fatty tissue; however, in contrast to the brain in these tissues MPPB-concentration is higher after administration of (-)-MPPB than after that of (+)-MPPB. Concentration differences which are measured in liver, spleen and fatty tissue already 1--10 min after i.v. administration of the enantiomers cannot be explained by a stereoselectivity of the metabolism and/or renal elimination. However, a stereoselective metabolism and/or renal elimination of the enantiomers can be responsible for concentration differences which are observed during the late period of 60--180 min after administration: in serum, brain, liver and fatty tissue MPPB-concentration is lower if (4)-MPPB is administered. For that reason it can be supposed that (+)-MPPB is faster eliminated than (-)-MPPB.

Animals↗
PubMed1985

[3H]adenosine uptake and release from synaptosomes. Alterations by barbiturates.

The effects of barbiturates on adenosine movements across the synaptic plasma membrane have been investigated using rodent whole brain synaptosomes. The hypothesis tested was that some of the depressant actions of these drugs may be mediated through interference with an endogenous adenosine system. Adenosine uptake was studied using synaptosomes prepared from Swiss-Webster mice. After preincubation at 37 degrees, [3H]adenosine was added to the synaptosomes in the presence or absence of pentobarbital, methohexital, phenobarbital, or 5-(2-cyclohexylideneethyl)-5-ethyl barbituric acid (CHEB) at various concentrations and times. All four compounds significantly inhibited [3H]adenosine uptake at concentrations of 100-300 microM. Pentobarbital did not affect the distribution of synaptosomal adenosine metabolites. Release of [3H]adenosine was studied using the P2 pellet from male CD-1 mice. Addition of 50 mM KCl caused an enhancement of 3H-efflux mainly due to increased release of adenosine and inosine. This effect was abolished in the presence of 250 microM ethylene glycol bis(beta-aminoethyl-ether)-N,N2-tetraacetic acid (EGTA). Pentobarbital, 0.3 mM, caused a significant increase in the net potassium-induced release of [3H]adenosine. These results suggest that some of the depressant effects of barbiturates may be due to inhibition of adenosine reuptake and enhancement of release resulting in elevated synaptic adenosine levels.

Adenosine↗
PubMed2003

The aminobarbituric acid-hydantoin rearrangement.

A general synthesis protocol for the generation of tri- and tetrasubstituted 5-carbamoylhydantoins is described. Starting from barbituric acids and following bromination and reaction with primary amines, 5-aminobarbituric acids 3a-s and 8 were prepared. Compounds 3 and 8 were subjected to different conditions of a base-catalyzed rearrangement reaction to yield the 1,5,5-trisubstituted hydantoins 4a-s and the 1,3,5,5-tetrasubstituted hydantoin 5c, respectively. Alkylation of 4a-s afforded 1,3,5,5-tetrasubstituted hydantoins 5a-h. Mechanisms that explain the transformation of corresponding aminobarbituric acids to hydantoins 4a-s and 5c were discussed in terms of the formation of ring-opened intermediates. Aminobarbituric acids 3a-s unsubstituted at position 3 underwent a ring contraction via intermediate isocyanates which were trapped by the amino function. A different mechanism involving a carbamate intermediate was concluded for conversion of the 1,3,5,5-tetrasubstituted aminobarbituric acid 8.

Alkylation↗
PubMed1995

Anesthetic barbiturates enhance Gs alpha-dependent cyclic AMP production in S49 mouse lymphoma cells.

Cyclic AMP (cAMP) regulates many important physiological processes. Barbiturates influence cAMP regulation, possibly through effects on G proteins. This study used intact S49 mouse lymphoma cells to characterize the role of G proteins in the effect of barbiturates on cAMP regulation. cAMP accumulation was determined in intact S49 WT (wild-type) and S49 cyc- cells (the Gs alpha-deficient mutant) by measuring the conversion of [3H]-ATP to [3H]cAMP in cells preloaded with [3H]adenine. Pentobarbital enhanced cAMP accumulation in WT cells in the absence (basal) or presence of isoproterenol but had no effect on the EC50 for isoproterenol. This effect was dose dependent with a 50-60% enhancement at 2 mM pentobarbital. Pentobarbital did not affect forskolin-stimulated cAMP accumulation in WT cells. In cyc- cells, basal and forskolin-stimulated cAMP accumulation were stimulated only at the highest concentration of pentobarbital used (2 mM). Pentobarbital did not affect the inhibition of cAMP accumulation by somatostatin in WT cells, and pertussis toxin treatment of WT cells did not affect the action of pentobarbital on cAMP accumulation. Pentobarbital did not affect isoproterenol-stimulated adenylyl cyclase activity in whole-cell homogenates or membranes prepared from WT cells. The S-(-)-isomer of pentobarbital enhanced isoproterenol-stimulated cAMP accumulation more than the R-(-)-isomer. Phenobarbital and barbituric acid did not enhance isoproterenol-stimulated cAMP accumulation, whereas the anesthetic barbiturates hexobarbital, pentobarbital, and thiopental all enhanced activity. These results suggest that pentobarbital enhances cAMP accumulation in intact WT cells by a mechanism that is dependent on Gs alpha but independent of Gi.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthetics↗
PubMedDate not supplied

Lipids and lipid oxidation with emphasis on cholesterol oxides in some Indian sweets available in London.

Ghee (clarified butter oil), a major ingredient in Indian sweets, is an important source of saturated fatty acids, cholesterol and cholesterol oxidation products (COP) that are considered risk factors for atherosclerosis. The high frequency of atherosclerotic complications reported among the Indian immigrants in England prompted determination of lipids and lipid oxidation status of a ghee sample and 15 Indian sweets available in London supermarkets. The fatty acid profile of the samples shows saturated fats (about 73%), mainly composed of myristic, palmitic and stearic acids, except in two samples. There were large variations in thio-barbituric acid reacting substance values (19-260 microg/100 g) and total COP (1.4-51.2 microg/g lipids) among the sweet samples. Regular consumption of some of these sweets can be a source of considerable amounts of saturated fatty acids, cholesterol and COP in the diet and may contribute to atherosclerosis.

Atherosclerosis↗
PubMed1988

Relationship between lipophilicity and tubular reabsorption for a series of 5-alkyl-5-ethylbarbituric acids in the isolated perfused rat kidney preparation.

The renal clearances of a homologous series of six 5-substituted barbituric acids, of varying lipophilicity, were examined using a recirculating isolated perfused rat kidney preparation. Renal clearance was found to decrease with increasing lipophilicity. The renal clearance of the individual compounds was shown to be dependent on urine flow, with the dependence increasing with increasing lipophilicity. A simple physiologically based model of tubular reabsorption, evoking nonequilibrium permeability considerations, is used to explain this influence of urine flow on renal clearance. The relationship between clearance and tubular permeability was examined with the purpose of integrating lipophilicity into the model.

Animals↗