Treatment of essential tremor with the barbiturate T2000 (1,3-dimethoxymethyl-5,5-diphenyl-barbituric acid).

The effect of the barbiturate T2000 (1,3-dimethoxymethyl-5,5-diphenyl-barbituric acid; DMMDPB) on essential tremor, given in twice daily doses of 400 and 300 mg, was assessed in two brief, randomized, placebo-controlled, parallel-group, double-blinded, single-center trials in 12 and 22 patients, respectively. These trials represent the first clinical use of T2000 for a specific indication. The primary endpoint was the change in the mean scores of the treated and control groups based on the Fahn-Tolosa-Marin tremor scale. In the first study of 12 patients treated with 400 mg or placebo twice daily for 14 days, the mean change from baseline at day 14 was 19.3 (P < 0.0001) in the treated group and 9.0 (P = 0.0121) in the control group. Using a two-factor mixed ANOVA model to evaluate within group and between group changes, the effect of T2000 was significantly different from that of the placebo group (P = 0.03). In the second study of 22 patients treated with 300 mg of T2000 or placebo twice daily for 20 days, statistically significant changes were seen in treated patients compared to baseline, but the ANOVA model did not demonstrate a significant treatment effect of T2000 compared to placebo. When the treated groups from each study are compared, the 800-mg daily group is significantly different from the 600-mg daily group (P = 0.02). Some treated patients in each study, but no placebo patients, experienced marked improvement. These results support further evaluation of T2000 in the treatment of essential tremor.     

Measurements of CO2 reactivity and barbiturate reactivity in patients with severe head injury

Summary In nine patients with severe head injury subjected to continuous hyperventilation and barbiturate coma treatment with pentobarbitone, the regional cerebral blood flow was measured as initial slope index (ISI) with a 32 channel Cerebrograph, and cerebral metabolic rate of oxygen (CMRO₂) was calculated as the product of mean global CBF and the arterio-venous oxygen content difference.CBF was measured at strategic intervals either to follow the treatment (hyperventilation and/or pentobarbitone), or to determine whether these principles of treatment should be intensified or reduced. During the flow measurements the CO₂ reactivity and the reactivity to a bolus injection of thiopentone 5 mg/kg were calculated globally and regionally. The global CO₂ reactivity was calculated as relative (%change CBF/PaCO₂ mmHg) and absolute (CBF/ PaCO₂ mmHg), and the reactivity to barbiturate was calculated globally as CMRO₂, and regionally as %change rCBF.The absolute and relative global CO₂ reactivities correlated positively with the mean. CBF values before hyperventilation, and the global barbiturate reactivity was dependent on the CMRO₂ value obtained before hyperventilation. However, at low levels of CMRO₂ ranging between 1.0 and 1.1 ml O₂ the barbiturate reactivity was abolished. The regional studies of CBF, CMRO₂, CO₂ reactivity and barbiturate reactivity gave important information, when decisions concerning therapeutic regimes with special reference to hyperventilation and sedation with pentobarbitone were necessary.     

Thermodynamics and kinetics of t-butylbicyclophosphorothionate binding differentiate convulsant and depressant barbiturate stereoisomers acting via GABAA ionophores

The temperature dependence of [³⁵S]-t- butylbicyclophosphorothionate (TBPS) binding to the convulsant sites of the GABA_A receptor complex was studied in membrane preparations of rat forebrain. Although specific [³⁵S]TBPS binding was maximal around 20° C, the rate constants of dissociation decreased monotonously between 37°C and 2° C. The displacing potencies of the convulsant S(+) enantiomer of 1-methyl-5-phenyl-5-propyl-barbituric acid (MPPB) (IC₅₀ = 1250 ± 30 M) and the depressant R(–) MPPB (IC_5O = 310 ± 5 M) did not show significant changes between 19° C and 37° C. Therefore barbiturate binding seems to be driven by entropic, rather than enthalpic changes. An excess of MPPB enantiomers elicited accelerated and polyphasic dissociations of [³⁵S]TBPS as compared to the monophasic dissociation by TBPS. Arrhenius analysis was applied to the measurable initial rate constants of dissociation. Arrhenius plots were linear between 2° C and 37° C. Activation parameters were similar when [³⁵S] TBPS dissociation was triggered by the convulsants TBPS and S(+) MPPB. It can be attributed to similar conformations of the closed ionophore complex. In contrast, the depressant R(–) MPPB strongly decreased the activation energy of TBPS dissociation from the open ionophore ternary complex.In whole-cell patch-clamp experiments R(–) MPPB, but not S(+) MPPB, elicited chloride currents in rat primary cortical cultures with an EC₅₀ value of 560 ± 30 M and a Hill coefficient of 2.9 ± 0.2. These currents were similar to those elicited by GABA and blocked by TBPS. A kinetic scheme is proposed for the dissociation of TBPS and to explain the different effects of MPPB enantiomers. Submillimolar R(–) MPPB is supposed to bind to (about three) barbiturate sites on GABA_A-ionophores and to open them in a cooperative manner to result in a decreased activation energy for accelerated displacement of convulsant binding.     

Brain palmitate incorporation in awake and anesthetized rats

Uniformly labeled [14C]palmitate was injected intravenously in awake and barbiturate-anesthetized rats, and arterial plasma radioactivity due to unesterified [14C]palmitate was determined on plasma samples removed at timed intervals up to the time of death. Overall brain radioactivity was determined by liquid scintillation spectroscopy, and regional brain radioactivity was determined by quantitative autoradiography. The transfer constant, k, for the unidirectional uptake of radiotracer palmitate into the brain at 4 h was calculated from the brain radioactivity and the integrated plasma radioactivity from injection to 4 h. The unidirectional palmitate uptake was calculated as the product of k and the plasma concentration of unesterified palmitate. Barbiturate anesthesia reduced regional palmitate transfer constants and unidirectional palmitate uptakes into different brain regions by 40-60%. Palmitate incorporation into the brains of awake rats at 4 h represents uptake into structural brain components which contain lipids. The results indicate that pentobarbital anesthesia reduces this rate of incorporation by about half.     

Interaction of stereoisomers of barbiturates with [H]α-dihydropicrotoxinin binding sites

Racemic depressant barbiturates inhibit the binding of gamma-aminobutyric acid antagonist [³H]α-dihydropicrotoxinin (DHP) to rat brain membranes with IC₅₀ values ranging from 5 to 50 μM. The (−) isomers of pentobarbital and secobarbital were three to four-fold more potent than their (+) isomers in inhibiting [³H]DHP binding. In contrast, the (+) isomer of hexobarbital was a better inhibitor than (−) hexobarbital. The stereoisomers of 1-methyl-5-phenyl-5-propyl barbituric acid (MPPB), which show opposite pharmacological activity, inhibited [³H]DHP binding in a biphasic manner with a plateau at 4–100 nM MPPB. These results suggest heterogeneity of DHP binding sites. The possibility that depressant and convulsant barbiturates may act at the level of DHP site at the GABA synapse is discussed.     

Cardioprotective effects of desflurane: effect of timing and duration of administration in rat myocardium

Background. We compared the cardioprotective effects of 1 minimumalveolar concentration (MAC) desflurane administered before,during or after ischaemia, or throughout the experiment (before,during and after ischaemia) on myocardial infarct size following30 min occlusion of the left anterior descending coronary arteryand 3 h reperfusion in adult rats. Methods. Fifty male Sprague–Dawley rats were anaesthetizedwith pentobarbital, intubated and mechanically ventilated. Bloodgases, pH and body temperature (37.5–38°C) were controlled.Heart rate and arterial pressure were measured continuously.Animals were randomly assigned to the following groups (n=10in each group): pentobarbital only (‘Pento’); 15min desflurane administration followed by 10 min of washoutbefore 30 min ischaemia and 3 h reperfusion (‘Precond’);30 min desflurane administration during ischaemia period (‘Isch’);desflurane administration during the 15 first min of reperfusion(‘Reperf’) and desflurane administration throughoutthe experiment (before, during and after ischaemia; ‘Long’).Volumes at risk and infarct sizes were assessed by Indian inkand with 2,3,5-triphenyltetrazolium chloride staining, respectively. Results. Physiological parameters and volumes at risk were notsignificantly different between groups. In the Pento group,mean myocardial infarct size was 65 (SD 15)% of the volume atrisk; myocardial infarct size was reduced to a significant andcomparable extent in the desflurane-treated groups (Precond42 (14)%; Isch 34 (11)%; Reperf 41 (15)%; Long 33 (10)%; P<0.0002vs Pento group). Conclusions. In rats, desflurane 1 MAC significantly decreasedmyocardial infarct size whatever the period and duration ofadministration. Br J Anaesth 2004; 92: 552–7     

The effects of indomethacin on intracranial pressure,cerebral blood flow and cerebral metabolism in patients with severe head injury and intracranial hypertension

Summary In five head-injured patients with cerebral contusion and oedema in whom it was not possible to control intracranial pressure (ICP) (ICP>20 mmHg) by artificial hyperventilation (PaCO₂ level 3.5–4.0 kPa) and barbiturate sedation, indomethacin was used as a vasoconstrictor drug. In all patients, indomethacin (a bolus injection of 30 mg, followed by 30 mg/h for seven hours) reduced ICP below 20 mmHg for several hours. Studies of cerebral circulation and metabolism during indomethacin treatment showed a decrease in CBF at 2h. After 7h, ICP remained below 20 mmHg in three patients, and these still had reduced CBF. In the other patients a return of ICP and CBF to pretreatment levels was observed. In all patients indomethacin treatment was followed by a fall in rectal temperature. These results suggest that indomethacin due to its cerebral vasoconstrictor and antipyretic effect should be considered as an alternative for treatment of ICP-hypertension in head-injured patients.Presented at the Fifth Nordic CBF Symposium, Lund, Sweden, 21–22 May 1990.     

Pentobarbital promotes bursts of gamma-aminobutyric acid-activated single channel currents in cultured mouse central neurons

The extracellular patch clamp method was used to study the influence of pentobarbital (PB) on membrane channels induced by gamma-aminobutyric acid (GABA) in cultured mouse spinal neurons. PB (200 microM) increased the probability of finding GABA-sensitive channels in the open state; it also increased the average frequency at which GABA-induced single channel currents occur, without decreasing the number of data sweeps which showed no single channel activity. These results indicate that PB potentiates GABA responses by promoting burst-like openings of the GABA-sensitive channel.