Borinium adduct ion formation with barbiturates in a quadrupole ion-trap mass spectrometer.

Colorado A, Brodbelt J.

Department of Chemistry and Biochemistry, University of Texas, Austin, USA.

Barbiturates are a class of drugs that are utilized as anesthetics and sleeping agents and are used for the treatment of anxiety, epilepsy and other psychiatric disorders. Because of their pyrimidine structures, barbiturates are highly basic compounds. The evaluation of the formation of adducts involving the borinium ion, B(OCH3)2+, and the barbiturates in a quadrupole ion trap is described. The adducts [M + 73]+ dissociate by elimination of methanol followed by the attachment of a trimethylborate or water molecule. This multi-step pathway is characteristic of a basic, nitrogen-containing structure that has at least one acidic hydrogen. Model compounds were used to probe the nature of this unusual reaction pathway, which involves nucleophilic attack by a methoxyl oxygen of neutral trimethyl borate at the boron atom of the adduct.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8799285&dopt=Abstract barbiturate Butalbital Fioricet





Differential inhibitory effects of thiopental, thiamylal and phenobarbital on both voltage-gated calcium channels and NMDA receptors in rat hippocampal slices.

Zhan RZ, Fujiwara N, Yamakura T, Taga K, Fukuda S, Shimoji K.

Department of Anaesthesiology, Niigata University School of Medicine, Japan.

Although it is known that there are some pharmacological differences between the structurally similar barbiturates, the underlying mechanism of action remains unclear. We have compared the effects of thiopental, thiamylal and phenobarbital on both voltage-gated calcium channels (VGCC) and N-methyl-D-aspartate (NMDA) receptors in rat hippocampal slices by determining changes in intracellular calcium ([Ca2+]i). Experiments were performed in adult rat hippocampal slices perfused with Krebs solution (37 degrees C). Concentrations of [Ca2+]i in the pyramidal cell layer of the CA1 region were measured using a calcium indicator dye, fura-2. To activate VGCC and NMDA receptors, slices were exposed to K+ 60 mmol litre-1 (< or = 60 s) and NMDA 100 mumol litre-1 (30 s), respectively. Thiopental, thiamylal and phenobarbital were present 5 min before, during and 1 min after high K+ or NMDA application. Both thiamylal and thiopental (50-600 mumol litre-1) attenuated the increases in [Ca2+]i produced by high K+ or NMDA in a concentration-dependent manner, while phenobarbital 50-1000 mumol litre-1 only slightly attenuated the [Ca2+]i increase produced by high K+ at concentrations of more than 200 mumol litre-1 and was ineffective on the [Ca2+]i response produced by NMDA. Although the increases in [Ca2+]i caused by membrane depolarization with high K+ were reduced equally with thiamylal and thiopental, thiamylal was more effective in attenuating the increase in [Ca2+]i produced by NMDA receptor activation than thiopental. We conclude that the depressant effects of barbiturates on both VGCC and NMDA receptors varied between agents. Differential inhibition of both VGCC and NMDA receptors may determine the pharmacological properties of barbiturates and their ability to protect neurones against ischaemia.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10211022&dopt=Abstract barbiturate Butalbital Fioricet





Effects of barbiturates on facilitative glucose transporters are pharmacologically specific and isoform selective.

Haspel HC, Stephenson KN, Davies-Hill T, El-Barbary A, Lobo JF, Croxen RL, Mougrabi W, Koehler-Stec EM, Fenstermacher JD, Simpson IA.

Anesthesia Research, Department of Anesthesiology, 1FP-4D, Henry Ford Health System, One Ford Place, Detroit, MI 48202-3450, USA.

Barbiturates inhibit GLUT-1-mediated glucose transport across the blood-brain barrier, in cultured mammalian cells, and in human erythrocytes. Barbiturates also interact directly with GLUT-1. The hypotheses that this inhibition of glucose transport is (i) selective, preferring barbiturates over halogenated hydrocarbon inhalation anesthetics, and (ii) specific, favoring some GLUT-# isoforms over others were tested. Several oxy- and thio-barbiturates inhibited [3H]-2-deoxyglucose uptake by GLUT-1 expressing murine fibroblasts with IC50s of 0.2-2.9 mm. Inhibition of GLUT-1 by barbiturates correlates with their overall lipid solubility and pharmacology, and requires hydrophobic side chains on the core barbiturate structure. In contrast, several halogenated hydrocarbons and ethanol (all </=10 mm) do not significantly inhibit glucose transport. The interaction of these three classes of anesthetics with purified GLUT-1 was evaluated by quenching of intrinsic protein fluorescence and displayed similar specificities and characteristics. The ability of barbiturates to inhibit other facilitative glucose transporters was determined in cell types expressing predominantly one isoform. Pentobarbital inhibits [3H]-2-deoxyglucose and [14C]-3-O-methyl-glucose uptake in cells expressing GLUT-1, GLUT-2, and GLUT-3 with IC50s of approximately 1 mm. In contrast, GLUT-4 expressed in insulin-stimulated rat adipocytes was much less sensitive than the other isoforms to inhibition by pentobarbital (IC50 of >10 mm). Thus, barbiturates selectively inhibit glucose transport by some, but not all, facilitative glucose transporter isoforms.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10227851&dopt=Abstract barbiturate Butalbital Fioricet





Barbiturate coma for severe, refractory vasospasm following subarachnoid haemorrhage.

Finfer SR, Ferch R, Morgan MK.

Intensive Therapy Unit, Royal North Shore Hospital, St Leonards, NSW, Australia. sfinfer med.usyd.edu.au

OBJECTIVE: To document the outcome of patients treated with barbiturate coma for severe symptomatic angioplasty-resistant vasospasm. To compare mortality with that predicted by admission APACHE II score, and neurological outcome with that of historical controls treated with barbiturate coma for vasospasm, and with historical controls with delayed ischaemic deficits from vasospasm treated with nimodipine. DESIGN: Cohort study. SETTING: Neurosurgical Intensive Care Unit of tertiary referral university teaching hospital. PATIENTS: Eleven (6.7%) of 164 consecutive patients with aneurysmal SAH managed according to our protocol who were treated with thiopentone-induced burst suppression coma for severe symptomatic, angioplasty-resistant vasospasm. INTERVENTIONS: Chart, database and literature review. MEASUREMENTS AND RESULTS: All 11 patients survived to hospital discharge (mortality 0%) compared with first-day APACHE II predicted mortality of 30.6% (p=0.15). Outcome at 6 months was: good recovery 8/11 (72.7%), moderate disability 2/11 (18.2%), vegetative survival 1/11 (9.1%). Ten of 11 (90.9%) had a good neurological outcome compared with 50.6% of historical controls with delayed ischaemic deficit from vasospasm (odds ratio 9.78, 95% confidence interval 1.24-77.0, p=0.02), and 0% of previously reported patients treated with barbiturate coma for vasospasm (p < 0.01). CONCLUSION: Our results are better than previously published outcomes and suggest formal evaluation of barbiturate coma in the treatment of severe resistant symptomatic vasospasm following SAH is warranted.

Publication Types: