Barbiturate complexation

The results suggest that in a-cyclodextrin-barbiturate complexes the cyclodextrin-cavity includes only R. while in 8-cyclodextrin complexes both R. and part of the pyrimidine moiety are included. 

Figure 4.24 Barbiturate compLexation by both complementary hydrogen-donor and acceptor groups and tt-tt interactions...

H-NMR spectra of some barbiturates complexed with lanthanide ions were also investigated.116-118... 

Phenobarbital 100 mg once daily given to 10 healthy subjects for 14 days caused reductions of 10 to 86% in the AUC of paroxetine in 6 subjects, but the mean AUC values were unaltered. One subject showed a 56% increase in AUC. The sedative effects and impairment of psychomotor performance caused by amobarbital 100 mg were not increased by paroxetine 30 mg. Two cases of hepatitis in young women were considered to be caused by the concurrent use of Atrium (a barbiturate complex) and paroxetine, which are both hepatotoxic. ... 

A 15-day study in 591 patients, to assess the effects of the concurrent use of acamprosate with other drugs eommonly used in the management of alcohol withdrawal, found no evidence of additional adverse effeets with meprobamate, oxazepam, or the barbiturate complex tetrabamate (that includes phenobarbital). Other studies found that acamprosate eaused no clinically relevant ehanges in imipramine pharmacokinetics, and the pharmacokinetics of both diazepam and acamprosate were unchanged by concurrent use. ... 

The infrared spectra of barbiturates and of barbiturate complexes have been examined by several groups of workers (Umberger and Adams, 1952 Price et ai, 1954 Levi and Hubley, 1956 Chatten and Levi, 1957 and Mesley, 1970). JThe barbiturates are derivatives of barbituric acid (malonylurea) and have substitutions... 

Figure 5. Specific hydrogen bonding receptors a) Adenine complex b) barbiturate complex (a Reproduced with permisison from reference 37. Copyright 1990 VCH b Reproduced from reference 45. Copyright 1988, American Chemicd Society).

The analysis of clinical samples is often complicated by the complexity of the sample matrix, which may contribute a significant background absorption at the desired wavelength. The determination of serum barbiturates provides one example of how this problem is overcome. The barbiturates are extracted from a sample of serum with CHCI3, and extracted from the CHCI3 into 0.45 M NaOH (pH 13). The absorbance of the aqueous extract is measured at 260 nm and includes contributions from the barbiturates as well as other components extracted from the serum sample. The pH of the sample is then lowered to approximately 10 by adding NH4CI, and the absorbance remeasured. Since the barbiturates do not absorb at this pH, the absorbance at pH 10 is used to correct the absorbance at pH 13 thus... 

Cyanide compounds are classified as either simple or complex. It is usually necessary to decompose complex cyanides by an acid reflux. The cyanide is then distilled into sodium hydroxide to remove compounds that would interfere in analysis. Extreme care should be taken during the distillation as toxic hydrogen cyanide is generated. The cyanide in the alkaline distillate can then be measured potentiometricaHy with an ion-selective electrode. Alternatively, the cyanide can be determined colorimetricaHy. It is converted to cyanogen chloride by reaction with chloramine-T at pH <8. The CNCl then reacts with a pyridine barbituric acid reagent to form a red-blue dye. 

Beryllium, calcium, boron, and aluminum act in a similar manner. Malonic acid is made from monochloroacetic acid by reaction with potassium cyanide followed by hydrolysis. The acid and the intermediate cyanoacetic acid are used for the synthesis of polymethine dyes, synthetic caffeine, and for the manufacture of diethyl malonate, which is used in the synthesis of barbiturates. Most metals dissolve in aqueous potassium cyanide solutions in the presence of oxygen to form complex cyanides (see Coordination compounds). 

Cyclization of the two pendant alkyl side chains on barbiturates to form a spiran is consistent with sedative-hypnotic activity. The synthesis of this most complex barbiturate starts by alkylation of ethyl acetoacetate with 2-chloropentan-3-one to give 152. Hydrolysis and decarboxylation under acidic conditions gives the diketone, 153. This intermediate is then reduced to the diol (154), and that is converted to the dibromide (155) by means of hydrogen bromide. Double Internal alkylation of ethyl... 

GABAa receptors are pentameric complexes on the postsynaptic membrane with a central pore with selectivity for chloride ions. Benzodiazepines and barbiturates increase the GABA-induced chloride currents, leading to hyperpolarization of the postsynaptic membrane. 

Saunders PA, Ho IK Barbiturates and the GABA receptor complex. Prog Drug Res 34 261-286, 1990... 

The ZwKKER reaction involving Co salts is frequently used for the detection of barbituric acid derivatives [31-35], but some purine, pyridine and piperidine derivatives and heterocyclic sulfonamides also yield colored derivatives. The Zwkker reaction is particularly sensitive when it is possible to form a tetrahedral complex [Co(Barb)2 Xj] (X = donor ligand, e.g. amine) [4]. 

Figure 11.6 Schematic representation of the GABAa receptor complex. Examples of the many structurally diverse compounds that act at different sites on the receptor (see text for details). Picrotoxinin, the active component of picrotoxin, and TBPS act as non-competitive antagonists. The barbiturates, steroids and anaesthetics are positive allosteric modulators, as are the benzodiazepine site ligands shown, with the exception of DMCM (negative allosteric modulator) and flumazenil (benzodiazepine site antagonist)...

OWENS has prepared antibodies to PCP in goats. When administered to mice the PCP levels in blood rose tenfold as an antibody-bound form that was readily excreted in urine. BROWNE tested the selfadministration by rats of 1,000 compounds related (and not related) to PCP, some of which produced PCP-like effects. One compound that was self-administered prevented the entrance of PCP into brain. BALSTER gave a general review of the effects produced by PCP in laboratory animals and showed that some effects were similar to those produced by amphetamine, some to barbiturates, and some to antipsychotics. This response profile makes PCP a unique drug that stands alone in its complex effects and toxicity. 

The GABA-gated chloride ion channel is modulated by several classes of drugs that bind to allosteric sites on the receptor complex the benzodiazepines, barbiturates and related intravenous general anesthetics such as etomidate and propofol, as well as anesthetic steroids and endogenous neurosteroids. It appears that some types of GABAa receptor are directly enhanced by ethanol and volatile general anesthetics (Fig. 16-2) [7,8,20]. 

Hirschfeldt (H8) has suggested that the small differences in migration rate of the different HpHb complexes in agar gel at pH 8.6 with a Ca++-containing barbiturate buffer can be used for ascertaining the Hp type. In our opinion the results obtained by this simplified procedure are less reliable than those obtained by the somewhat more complicated starch gel electrophoretic method. 

An interesting product in the range of azo metal complexes is the nickel complex of azo barbituric acid (34) [6] ... 

A reaction known as diazo group transfer produces diazo barbituric acid from barbituric acid and p-toluene sulfonyl azide. Additional barbituric acid affords azo barbituric acid [7]. Subsequent complexation with a nickel (II) salt yields a greenish yellow pigment. 

In a 1 2 ratio these compounds yield a mixture of (Z/Z), (EIE) and (E/Z) isomers plus a substantial amount of the (E) and (Z) isomers of the monohydrazone monoketone. The complexity of the mixture (due to several equilibria that are established between its components) was illustrated by its complex H NMR spectrum. However, addition of one equivalent of barbiturate to the mixture led to a dramatic simplification of the NMR spectrum with the disappearance of the different products and the emergence of a single new species. This remarkable simplification of the spectrum is a consequence of the templating effect played by the barbiturate that amplifies the formation of only one of the receptors - in this case the ZyZ isomer. Interestingly, the addition of other species to the mixture such as acetate or 1-benzyluracil (with similar pKa values to barbiturate but different hydrogen bonding patterns) did not lead to the amplification of any specific species. 

The resulting product (II) is subsequently coupled to bovine-serum-albumin in a glycerol-w ater mixture in the presence of dicyclohexylcarbodiimide. The mixture is incubated overnight at 4°C, and the protein-hapten complex is dialysed against distilled water thereby causing its purification. Conjugation of the respective barbiturate to the protein carrier, comparison of the barbiturate BGG-conjugate to control BGG-solution and preparation of 14C-pentobarbital sodium are carried out respectively. 

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