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PubMed1987

The direct barbituric acid assay for nicotine metabolites in urine: a simple colorimetric test for the routine assessment of smoking status and cigarette smoke intake.

The qualitative direct barbituric acid (DBA) method of detecting urine nicotine metabolites was modified to make it quantitative. The performance of the quantitative DBA method was compared with the qualitative method and an established cotinine radio-immunoassay (RIA), using a panel of urines from 128 reported smokers and 383 reported non-smokers. The quantitative DBA method results were highly correlated with the cotinine RIA results, r = 0.85. The coefficients of variation for the two methods were 6% and 10%, respectively. Assuming that the reported smoking history was correct the qualitative DBA method gave a smoking detection rate of 91% and a false positive rate of 3%. At cut-off levels chosen to yield the same false positive rate the quantitative DBA method detected 93% of smokers, close to that of 98% detected with the cotinine RIA. The quantitative DBA method can be used to analyse over 170 samples per day compared to about 70 per day by RIA. It is therefore a fast and inexpensive alternative to cotinine assays for the assessment of smoking status and cigarette smoke intake.

Barbiturates↗
PubMed1986

5-(2-Cyclohexylideneethyl)-5-ethyl barbituric acid (CHEB): correlation of hypnotic and convulsant properties with alterations of synaptosomal 45Ca2+ influx.

Male ICR mice (20-35 g) were given either 5-(2-cyclohexylideneethyl)-5-ethyl barbituric acid (CHEB) alone (10-15 mg/kg i.p.) or CHEB (25-75 mg/kg i.p.) after a 1 h pretreatment with phenobarbital (75 mg/kg i.p.). CHEB alone (10 mg/kg) produced excitatory behavior but not convulsive seizures. Higher doses (11-15 mg/kg) produced convulsive seizures resulting in death. Pretreatment with phenobarbital prevented seizure activity. Following phenobarbital pretreatment, CHEB in doses of 50 and 75, but not 25 mg/kg, resulted in hypnosis of 53 +/- 16 and 64 +/- 9 min duration, respectively. In vitro, CHEB (10-200 microM) significantly inhibited 'fast-phase' (3 s) K+-stimulated 45Ca2+ uptake into cerebrocortical synaptosomes. CHEB (10 and 100 microM) also significantly increased basal 45Ca2+ uptake. The addition of CHEB (50 and 100 microM) or pentobarbital (100 microM) to striatal synaptosomes inhibited 'fast-phase' K+-stimulated 45Ca2+ uptake and endogenous dopamine release. CHEB (10-200 microM), but not pentobarbital (100 microM), produced a time- and dose-dependent increase in the resting release of endogenous dopamine from striatal synaptosomes. The results of this study show that CHEB possesses hypnotic activity if its lethal convulsant actions are blocked. The hypnotic actions of CHEB appear to correlate with inhibition of voltage-dependent calcium channels in brain synaptosomes.

Animals↗
PubMed1996

5-(m-Benzyloxybenzyl)barbituric acid acyclonucleoside, a uridine phosphorylase inhibitor, and 2',3',5'-tri-O-acetyluridine, a prodrug of uridine, as modulators of plasma uridine concentration. Implications for chemotherapy.

5-(m-Benzyloxybenzyl)barbituric acid acyclonucleoside (BBBA), the most potent inhibitor known of uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for uridine catabolism, and 2',3',5'-tri-O-acetyluridine (TAU), a prodrug of uridine, were used to investigate the possibility of improving the bioavailability of oral uridine in mice. Oral BBBA administered at 30, 60, 120, and 240 mg/kg increased the concentration of plasma uridine (2.6 +/- 0.7 microM) by 3.2-, 4.6-, 5.4-, and 7.2-fold, respectively. After administration of 120 and 240 mg/kg BBBA, plasma uridine concentration remained 3- and 6-fold, respectively, higher than the plasma concentration at zero time (C0) for over 8 hr. On the other hand, BBBA did not change the concentration of plasma uracil. TAU was far more superior than uridine in improving the bioavailability of plasma uridine. The relative bioavailability of plasma uridine released from oral TAU (53%) was 7-fold higher than that (7.7%) obtained by oral uridine. Oral TAU at 460, 1000, and 2000 mg/kg achieved area under the curve (AUC) values of plasma uridine of 82, 288, and 754 mumol.hr/L, respectively. Coadministration of BBBA with uridine or TAU further improved the bioavailability of plasma uridine resulting from the administration of either alone and reduced the Cmax and AUC of plasma uracil. Coadministration of BBBA at 30, 60, and 120 mg/kg improved the relative bioavailability of uridine released from 2000 mg/kg TAU (53%) by 1.7-, 2.7-, and 3.9-fold, respectively, while coadministration of the same doses of BBBA with an equimolar dose of uridine (1320 mg/kg) increased the relative bioavailability of oral uridine (7.7%) by 4.1-, 5.3-, and 7.8-fold, respectively. Moreover, the AUC and Cmax of plasma uridine after BBBA (120 mg/kg) coadministration with TAU were 3.5- and 11.5-fold, respectively, higher than those obtained from coadministration of BBBA with an equimolar dose of uridine. The exceptional effectiveness of the BBBA plus TAU combination in elevating and sustaining high plasma uridine concentration can be useful in the management of medical disorders that are remedied by administration of uridine as well as to rescue or protect from host-toxicities of various chemotherapeutic pyrimidine analogues.

Animals↗
PubMed1988

Historical aspects and applications of barbituric acid derivatives. A review.

This review considers the pharmacological and other applications of barbituric and 2-thiobarbituric acid derivatives. A chronological description about the discovery, structural studies and first clinical assays are given. Therapeutic expectations as anticonvulsant, antimicrobial, spasmolytic, antiinflammatory, antitumoral and some other effects of 5,5-disubstituted barbituric acids and alkylidene- or arylidenebarbituric acids are overviewed. A considerable amount of these types of compounds have been proposed as industrial dyes and pigments, photosensitizers and thermosensitive materials.

Animals↗
PubMed1982

Identification of the major degradation product of 1-propyl-3,5-diethyl-6-chlorouracil in rabbits and mechanism of the formation of bicyclic barbituric acid metabolites.

The major degradation product of 1-propyl-3,5-diethyl-6-chlorouracil in rabbits is identified as 6,8-diethyl-2-methyl-tetrahydrooxazolo[3,2-c]pyrimidine-5,7(4H,6H)-dione. The mechanism of the formation of this bicyclic barbituric acid derivative is discussed. The biotransformation takes place via substitution of the chlorine by beta- and not by alpha-hydroxy group of the intermediate hydroxypropane.

Animals↗
PubMed1981

Thermodynamic dependence of interfacial transfer kinetics of nonionized barbituric acid derivatives in two-phase transfer cell.

A theory was developed to describe interfacial transport kinetics of a series of drug homologs in a two-phase transfer cell. When tested, the theory held true for 5,5-disubstituted barbituric acid derivatives in a preequilibrated octan-1-ol = (pH 5) aqueous buffer system maintained at 37 degrees and stirred symmetrically at 50 and 100 rpm. Theoretical prediction of transfer kinetics was not possible in such a cell if the phases were stirred asymmetrically. For symmetric stirring, successful prediction of the transfer kinetics of any homolog in the series was possible from a knowledge of the partition coefficient and transfer kinetics of the parent compound, the partition coefficient of the homolog, and some easily determined system variables. The viscosity and density of the two phases and the phase-volume ratio were needed to define a system constant dependent on the solute diffusion coefficient, interfacial area, donor phase volume, and the boundary layer thickness for diffusion in the donor phase volume, and the boundary layer thickness for diffusion in the donor phase. A method is described to enable estimation of this constant from a knowledge of the transfer kinetics of the parent compound. The rank order of compounds in terms of their observed first-order transfer rate constants is shown to be dependent on the characteristics of the solvent system and stirring conditions employed, as well as on the physical chemistry of the solutes. The results are discussed in light of previously documented investigations.

Barbiturates↗
PubMed1991

Crystallization of yeast orotidine 5'-monophosphate decarboxylase complexed with 1-(5'-phospho-beta-D-ribofuranosyl) barbituric acid.

Using an incomplete factorial experimental design, we have identified conditions for crystallization of yeast orotidine 5'-monophosphate decarboxylase (ODCase) in an unliganded state and complexed separately to two inhibitors: 6-azauridine 5'-monophosphate (aza-UMP) and 1-(5'-phospho-beta-D-ribofuranosyl) barbituric acid (BMP). Crystals of X-ray diffraction quality have been obtained of yeast ODCase complexed with BMP, a putative transition state analog inhibitor (Ki = 8.8 x 10(-12) M). ODCase:BMP complex crystals with a hexagonal rod habit were grown from a solution initially containing 12 mg/ml ODCase (205 microM dimer) plus 450 microM BMP by microdialysis at 4 degrees C against a mother liquor which consisted of 0.1 M Na-PIPES-acetate (pH 6.4), 37.5 microM BMP, 5 mM mercaptoethanol, 1% polyethylene glycol 400, and 2.3 M ammonium sulfate. Crystals were analyzed using precession photography and were assigned to trigonal space group R32 with unit cell dimensions a = b = 115 A, c = 385 A. The crystal density is 1.245 g/cm3 indicating the presence of two ODCase: BMP complex dimers (118 kDa each) per asymmetric unit with a packing density of 2.08 A3/Da and 41% solvent content. The morphological habit of crystals of the ODCase:BMP complex changed when the initial ammonium sulfate concentration was increased in 0.05 M steps from 2.3 to 2.45 M. All of these crystals diffracted to at least 3.0 A resolution over a period of several weeks at room temperature and are isomorphous.

Ammonium Sulfate↗
PubMed1988

Photochemical degradation of barbituric acid derivatives. Part 8: Photolysis of sodium salts of barbiturates in solid state.

After the UV irradiation of suspensions of barbiturate sodium salts in paraffin oil the IR spectra revealed two IR absorption bands at ca. 2170 and 2250 cm-1. The effects of different conditions of the photochemical process and the addition of nucleophilic reagents after irradiation on the intensity of these bands were studied. The origin of 2170 cm-1 band was interpreted in terms of the isocyanate intermediate which is formed after the pyrimidine ring opening.

Barbiturates↗
PubMed2000

Modulation of 5-fluorouracil host toxicity by 5-(benzyloxybenzyl)barbituric acid acyclonucleoside, a uridine phosphorylase inhibitor, and 2',3',5'-tri-O-acetyluridine, a prodrug of uridine.

Administration of 200 mg/kg of 5-fluorouracil (FUra) to mice bearing human colon carcinoma DLD-1 xenografts resulted in 100% mortality. Oral administration of 2000 mg/kg of 2',3',5'-tri-O-acetyluridine (TAU), a prodrug of uridine, in combination with 120 mg/kg of 5-(benzyloxybenzyl)barbituric acid acyclonucleoside (BBBA), the most potent known inhibitor of uridine phosphorylase (UrdPase, EC 2.4.2. 3), 2 hr after the administration of the same dose of FUra completely protected the mice (100% survival) from the toxicity of FUra. This combination also reduced tumor weight by 67% compared with 46% achieved by the maximum tolerated dose (50 mg/kg) of FUra alone. Similarly, administration of BBBA plus TAU 1 hr before or 4 hr after the administration of FUra reduced the tumor weight by 53 and 37%, respectively. However, these schedules were less effective in protecting the host from the toxicity of FUra than when the treatment was carried out at 2 hr after FUra administration. TAU alone did not protect from FUra host toxicity. The efficiency of the BBBA plus TAU combination in rescuing from FUra host toxicities is attributed to the exceptional effectiveness of this combination in raising and maintaining higher plasma uridine concentrations than those achieved by TAU alone or by equimolar doses of uridine (Ashour et al., Biochem Pharmacol 51: 1601-1612, 1996). The present results suggest that the BBBA plus TAU combination can provide a better substitute for the massive doses of uridine required to achieve the high levels of uridine necessary to rescue or protect from FUra host toxicities without the toxic side-effects associated with such doses of uridine. The combination of TAU plus BBBA may also allow the escalation of FUra doses for better chemotherapeutic efficacy. Alternatively, the combination may be used as a rescue regimen in the occasional cases where cancer patients receive a lethal overdose of FUra.

Acetates↗