Barbiturate model

The potential for normal brain tissue injury is one of the limiting factors in the use of XRT for brain tumors. Pentobarbital is a cerebral radioprotectant in rodent and primate models after single doses, but is associated with significant risks. Of alternative barbiturates, thiopental given to tats receiving 70-Gy (7000-rad) whole-brain irradiation in a single fraction enhances the 30-day survival similarly to pentobarbital, whereas ethohexital and phenobarbital show no radioprotective activity (250). 

Benzodiazepines and similar agents occupy a position of intermediate abuse potential, compared with most other sedative-hypnotics (Griffiths and Weerts 1997). Animal models of abuse habihty indicate that the reinforcing effects of benzodiazepines are less pronounced than are those of the barbiturates, opioids, and stimulants. Differences in abuse potential within the class have not been consistently demonstrated however, most chnicians agree that benzodiazepines with a rapid onset and short duration of action pose the greatest risk in susceptible individuals. 

Despite the work of Overton and Meyer, it was to be many years before structure-activity relationships were explored further. In 1939 Ferguson [10] postulated that the toxic dose of a chemical is a constant fraction of its aqueous solubility hence toxicity should increase as aqueous solubility decreases. Because aqueous solubility and oil-water partition coefficient are inversely related, it follows that toxicity should increase with partition coefficient. Although this has been found to be true up to a point, it does not continue ad infinitum. Toxicity (and indeed, any biological response) generally increases initially with partition coefficient, but then tends to fall again. This can be explained simply as a reluctance of very hydrophobic chemicals to leave a lipid phase and enter the next aqueous biophase [11]. An example of this is shown by a QSAR that models toxicity of barbiturates to the mouse [12] ... 

Nestorov lA, Aarons LJ, Rowland M. Physiologically based pharmacokinetic modeling of a homologous series of barbiturates in the rat a sensitivity analysis. / Pharmacokinet Biopharm 1997 25 413-47. 

Blakey GE, Nestorov lA, Arundel PA, Aarons LJ, Rowland M. Quantitative structure-pharmacokinetics relationships I. Development of a whole-body physiologically based model to characterize changes in pharmacokinetics across a homologous series of barbiturates in the rat. J Pharmacokinet Biopharm 1997 Jun 25(3) 277-312. Erratum in J Pharmacokinet Biopharm 1998 Feb 26(l) 131. 

If excessive noradrenergic transmission is a causal factor in anxiety, then it would be predicted that a lesion of central noradrenergic neurons would have an anti-anxiety effect in behavioural models of this condition. Unfortunately, the behavioural effects of such lesions are notoriously inconsistent and there are many reports of negative findings (e.g. Salmon, Tsaltas and Gray 1989). One study has even shown that a lesion of central noradrenergic neurons, induced by the selective neurotoxin, DSP-4, abolishes the anti-anxiety effects of tricyclic antidepressants and MAO inhibitors, but not those of the benzodiazepine, alprazolam, or the barbiturate, phenobarbitone (Fontana,... 

PCP, like barbiturates, also has anticonvulsant effects in various animal models (Chen et al. 1959 Geller et al. 1981 Hayes and Balster 1985). Certain convulsants, such as strychnine, are not antagonized, and PCP has some specificity for tonic rather than clonic convulsions. 

During the early twentieth century the barbiturates were used in children and adolescents for their sedative and hypnotic effects however, their safety profile and propensity to cause physical dependence led scientists in search of safer anxiolytics. The development of animal models of behavioral disorders facilitated the formulation of drugs with more specific central nervous system (CNS) effects. In 1959, chlordiazepoxide (Librium) was the first benzodiazepine (BZ) to receive a patent. It entered the market in 1960, followed by diazepam (Valium) in 1963. Today, over 35 BZs have been formulated and over 10 are available in the United States (Ballenger, 1995 Hobbs et ah, 1996). 

Drugs such as 2-thiobarbituric acid are oxidized in the presence of iodide mediators. In aqueous media, an electroio-dination process occurs and the resulting voltammetric signal allows quantitative determination [190]. A similar methodology with a limit of detection at ca. 40 gM level has been developed for barbiturates [191]. Also, catechin as a model system for polyphenols was studied in the presence of an iodide redox mediator [192]. 

Barbiturates may precipitate episodes of acute intermittent porphyria (AIP) and their use is contraindicated in patients who are predisposed to this condition. Some animal models indicate that ketamine, etomidate, and the benzodiazepines may be porphyrinogenic and propofol is considered to be the intravenous anaesthetic of choice in AlP-prone patients. 

Benzodiazepines, barbiturates, and most older sedative-hypnotic drugs exert calming effects with concomitant reduction of anxiety at relatively low doses. In most cases, however, the anxiolytic actions of sedative-hypnotics are accompanied by some depressant effects on psychomotor and cognitive functions. In experimental animal models, benzodiazepines and older sedative-hypnotic drugs are able to disinhibit punishment-suppressed behavior. This disinhibition has been equated with antianxiety effects of sedative-hypnotics, and it is not a characteristic of all drugs that have sedative effects, eg, the... 

The C-13 magnetic resonance spectra of the naturally occurring uracils79-81 have been interpreted in terms of the diketo structures of the compounds. Similarly the triketo structure 36 has been found81 to predominate for 1 - (/3-D-ribofuranosyl) barbituric acid by a comparison of C-13 spectra of several model nucleosides. Also in the case of 6-hydroxycytidine the equilibrium lies 81 strongly toward the diketo form 37b in comparison with the lactim-lactam form 37a. Very recent N-14... 

FIG U RE 65.2 Schematic model of the GABAa receptor. The receptor spans the cell membrane. GABA binds to the outside of the receptor, causing an influx of Cl ions through the channel. Benzodiazepines and barbiturates interact with different recognition sites on the receptor and increase the effectiveness of GABA. 

J. Yanai, An animal model for the effect of barbiturate on the development of the central nervous system, in J. Yanai (Ed.), Neurobehavioral Teratology, Elsevier, Amsterdam, 1984, pp. 111-132. 

Searching for other 6-membered "diazido malonyl N-heterocycles" we have selected the pyridazine derivative 25 and diazido barbituric acids 32 as model systems, since they are available easily and in large quantities. Compound 25 is obtained in the usual way by chlorination of 23 with sulfuryl chloride and exchange of the halogen atoms with sodium azide. 

Numerous applications of pharmacokinetic-dynamic models incorporating a biophase (or effect) compartment for a variety of drugs that belong to miscellaneous pharmacological classes, e.g., anesthetic agents [419], opioid analgesics [420-422], barbiturates [423,424], benzodiazepines [425], antiarrhyth-mics [426], have been published. The reader can refer to a handbook [427] or recent reviews [405] for a complete list of the applications of the biophase distribution model. 

Hydrogen-bonding metrics and patterns are characteristic properties of molecules. It is by no means certain that a )NH 0=C bond will have exactly the same metrical properties when it occurs in a peptide, a barbiturate, and a nucleoside. In fact, as will be shown later, there are small, but significant, differences in these metrical properties. There are also differences in the pattern characteristics. The patterns that are observed in the crystal structures of these various types of small biological molecules provide a portfolio of observed hydrogen bond structures. These can be used as models for interpretations of structure and for hypotheses concerning intermolecular interactions in those situations where direct observation of the position of the hydrogen atom is experimentally impossible. 

Boyadzhiev L, Sapundhiev T, and Bezenshek E. Modeling of carrier-mediated extraction. Sep Sci Technol 1977 12 541-551. Bouboukas G, Colinart P, Renon H, and Trouve G. Transfer of barbiturates through emulsified liquid membranes. In Li NN, Calo JM, eds. Recent Developments in Separation Science, Volume IX, Chapter 25.11. Boca Raton, FL CRC Press, 1986 209-226. 

Barbiturates are all derived from barbituric acid, first obtained from uric acid and synthesized in Germany by Dr. Adolf van Baeyer in 1864. Conrad and Guthzeit synthesized the first barbiturate, 5,5-diethylbarbituric acid (barbital) in 1882. In 1903, Emile Fischer and Baron Josef von Meiing introduced barbital into clinical medicine under the trade name Veronal . Phenobarbital, which has remained the model T of barbiturates, first appeared on the market in 1912 as Luminal . Unfortunately, intoxication with barbiturates is qualitatively similar to intoxication with alcohol and produced similar problems of abuse. 

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