Self-injection of barbiturates,benzodiazepines and other sedative-anxiolytics in baboons

Self-injection of 12 sedative-anxiolytics was examined in baboons. Intravenous injections and initiation of a 3-h time-out were dependent upon completion of a fixed-ratio schedule requirement, permitting eight injections per day. Before testing each dose of drug, self-injection performance was established with cocaine. Subsequently, a test dose was substituted for cocaine. At some doses, all five of the benzodiazepines examined (alprazolam, bromazepam, chlordiazepoxide, lorazepam, triazolam) maintained rates (number of injections per day) of drug self-injection above vehicle control in each of the baboons tested. Maximum rates of benzodiazepine self-injection were generally submaximal. Of the benzodiazepines examined, triazolam maintained the highest rates of self-injection. Among the three barbiturates tested, methohexital generally maintained high rates of self-injection in contrast to hexobarbital and phenobarbital, which only maintained low rates. Of the four non-benzodiazepine non-barbiturate sedatives examined, both chloral hydrate and methyprylon occasionally maintained high rates of self-injection. Although there were differences within and across animals, baclofen maintained intermediate rates of self-injection. The novel anxiolytic buspirone maintained only low rates of self-injection that were not different from vehicle. This study further validates the self-injection methodology for assessing sedative-anxiolytic abuse liability and provides new information about drug elimination rate as a determinant of drug self-administration.     

多巴、5-羟色胺酸和戊巴比妥钠对大白鼠脑涨落图的影响

对40只大白鼠进行了包括对照、DL-DOPA、L-5-HTP、戊巴比妥钠4组进行实验,记录EEG。用ET 技术分析获得重要结果。发现对照组动物大脑活动状态表现多样性,特征频率有较多变异,注射药物后明显趋向一致。S11(S22)与脑内DA 活动有关;S4系与5-HT 活动有关。5-HT系统在脑内作用较复杂,并与DA 系统存在相互作用。戊巴比妥钠对中枢有强抑制作用,特征频率为S13,认为可能与脑内GABA 过度活动有关。以上结果说明ET 技术在未来脑研究中,是有发展前途的。     

Barbiturates in severe head injuries?

Possible mechanisms for the therapeutic effects of barbituric acid derivatives in severe head injuries have been discussed for half a century. In the following, a survey of the literature, and a discussion of three controlled clinical studies available until now is presented. A proven effect in terms of a beneficial long-term outcome for all injured patients has not been established.On the other hand there might be a subgroup of patients with an intact CO₂ reactivity of the brain vessels who may profit from barbiturates administered after head trauma.Dedicated to Marianne and Gerhard Winkler     

Estado actual y perspectivas futuras en el manejo de la hipertensión intracraneal posterior a traumatismo craneoencefálico: craniectomía descompresiva,hipotermia terapéutica y barbitúricos

IntroductionIncreased intracranial pressure has been associated with poor neurological outcomes and increased mortality in patients with severe traumatic brain injury. Traditionally, intracranial pressure-lowering therapies are administered using an escalating approach, with more aggressive options reserved for patients showing no response to first-tier interventions, or with refractory intracranial hypertension.DevelopmentThe therapeutic value and the appropriate timing for the use of rescue treatments for intracranial hypertension have been a subject of constant debate in literature. In this review, we discuss the main management options for refractory intracranial hypertension after severe traumatic brain injury in adults. We intend to conduct an in-depth revision of the most representative randomised controlled trials on the different rescue treatments, including decompressive craniectomy, therapeutic hypothermia, and barbiturates. We also discuss future perspectives for these management options.ConclusionsThe available evidence appears to show that mortality can be reduced when rescue interventions are used as last-tier therapy; however, this benefit comes at the cost of severe disability. The decision of whether to perform these interventions should always be patient-centred and made on an individual basis. The development and integration of different physiological variables through multimodality monitoring is of the utmost importance to provide more robust prognostic information to patients facing these challenging decisions.     

Recent trends in barbiturate detection in medicolegal deaths

A study was undertaken of 51 cases where barbiturates were detected in post-mortem blood samples from 2000 to 2019 at Forensic Science South Australia, Adelaide, Australia. The cause of death was drug toxicity in only 27 (53%) (M:F = 19:8; age range 19-74yrs, mean 46yrs). In 17 cases, barbiturate toxicity was the primary cause of death, 14 due to pentobarbitone and 3 to phenobarbitone. All were suicides. Barbiturates were obtained by online purchase from overseas sources in 9 cases (33%), and through veterinary practice in 2 cases (7%). Drug toxicity deaths where barbiturates were detected rose from 1 in 2000–2004 to 11 in 2015–2019, and those where deaths were primarily due to barbiturate toxicity rose from 1 in 2000–2004 to 9 in 2015–2019. However, the mere detection of barbiturates in post mortem samples did not equate with illicit use, as 23 of the deaths (45%) were due to natural causes in individuals prescribed barbiturates for epilepsy. The usefulness of examining subset populations separate from accrued national data is also demonstrated in the significantly younger age of decedents in South Australia dying from deliberately administered barbiturates (46 yrs) compared to the national average of 57.9 yrs. The reasons for this difference will require further investigation as this may impact upon local suicide prevention strategies.     

Depletion of brain norepinephrine: differential influence on anxiolyic treatment effects

Rationale: Previous studies have demonstrated that anxiolytic-like anticonflict effects can be produced by either (1) acute administration of traditional anti-anxiety compounds (benzodiazepines or barbiturates) or (2) chronic administration of tricyclic (TCA) or monoamine oxidase inhibitor (MAOI) antidepressants. Objective: The present study determined the effects of noradrenergic neuronal depletion on these distinct anticonflict treatments. Methods: After 3 weeks of training in a repeated measures drink suppression conflict paradigm, water-restricted rats consumed 11–14 ml water/session (unpunished responding) and accepted 25–40 shocks/session (punished responding) during control (i.e., non-drug) 10-min test sessions. The noradrenergic neurotoxin DSP4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride; 65 mg/kg, IP] or its vehicle (saline; 1 ml/kg) was administered after 3 weeks of conflict testing. Conflict behavior was then evaluated for 8 weeks post-treatment. In separate groups of DSP4- and vehicle-pretreated subjects, the effects of acute administration (10-min pretreatment) of phenobarbital (5–40 mg/kg) or alprazolam (0.3–2.5 mg/kg) were determined. In a third experiment, the effects of chronic treatment with the TCA desipramine (DMI; 5 mg/kg, twice daily for 8 weeks) or the non-selective MAOI phenelzine (4.0 mg/kg, twice daily for 8 weeks) on conflict behavior were determined in additional groups of DSP4- or vehicle-pretreated subjects. Results: DSP4 treatment produced a modest yet statistically significant decrease in punished responding (i.e., anxiogenic-like effect) relative to vehicle controls. DSP4 pretreatment did not alter the anticonflict effects of acute alprazolam or phenobarbital treatment. In contrast, DSP4 treatment completely abolished the anticonflict effects produced by chronic DMI or chronic phenelzine treatment. Conclusions: Thus, noradrenergic neuronal integrity appears to be required for the anxiolytic-like effects of chronic antidepressant treatment, but not for the anxiolytic-like effects of acute treatment with barbiturates and benzodiazepines. Received: 6 August 1998/Final version: 16 October 1998     

Membrane-ordering effects of barbiturates on pure phospholipid model membranes

Intramolecular excimer formation of 1,3-di(1-pyrenyl)propane (Py-3-Py) and fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene (DPH) were used to investigate the effects of barbiturates on the fluidity of model membranes of phosphatidylcholine (SPMVPC), phosphatidylserine (SPMVPS), and phosphatidylinositol (SPMVPI) fractions of synaptosomal plasma membrane vesicles (SPMV) isolated from bovine cerebral cortex. In a dose-dependent manner, barbiturates decreased the excimer to monomer fluorescence intensity ratio (I′/I) of Py-3-Py and increased the anisotropy(r), rotational relaxation time(φ), limiting anisotropy(r_∞), and order parameter (S) of DPH in SPMVPC, SPMVPS and SPMVPI. This indicates that barbiturates decreased both the lateral and rotational diffusion of the probes in SPMVPC, SPMVPS and SPMVPI. The relative potencies of barbiturates in ordering the membranes were in the order: pentobarbital>hexobarbital>amobarbital>phenobarbital. This order correlates well with the anesthetic potencies of barbiturates and the potencies for enhancement of γ-aminobutyric acid-stimulated chloride uptake. Thus, it is strongly suggested that a close relationship might exist between the membrane-ordering effects of barbiturates and the chloride fluxes across SPMV.     

Management of a giant intracranial aneurysm using surface-heparinized extracorporeal circulation and controlled deep hypothermic low flow perfusion. A case report

Extracorporeal circulation with controlled hypothermic low flow perfusion was introduced during the surgical treatment of a patient with a giant intracranial aneurysm of the anterior communicating artery. Heparin-coated equipment (Carmeda Bio-Active Surface; CBAS) was utilized, thus reducing the need for systemic heparinization. Direct cannulation of the right atrium and aorta was established through thoracotomy. Blood flow through the circuit was kept at 4.5 1/min during normothermia. Core cooling, in combination with external surface cooling, was performed for 30 min to a temperature of 18d?C (nasopharynx). During a period of 25 min, the time for surgical repair of the aneurysm, blood flow was minimized to 0.4 1 · min^-1, equilibrating central and peripheral blood pressures to approximately 5–10 mmHg (0.65–1.3 kPa). Reper-fusion was started immediately after the low flow period concomitantly with rewarming, aiming at a temperature of 36d?C following 150 min. The patient could be weaned off the extracorporeal circulation with minimal inotropic support. The postoperative course was uneventful apart from a left-sided hemiparesis, probably due to an infarction in the area of the right pericallosal artery (A2). The patient was weaned off the ventilator after 6 days. He recovered and the hemiparesis regressed slowly.     

The use of a simple test of attention as a measure of drug effects in schizophrenic patients

This is a brief review of the use of the Continuous Performance Test (CPT), a simple test of attention, in assessing drug effects in schizophrenic patients. Results of experiments are reviewed showing the sensitivity of the procedure to both acute and chronic administration of phenothiazine drugs. In single doses the drug impairs performance while after chronic administration of medication performance improves. Impairment in performance on the CPT is found in approximately 40–45 per cent of testable patients who show no deficit in performance on a simple cognitive test. In patients with a deficit on the CPT their performance after chronic drug therapy covaries with rating scales of clinical state. Patients who perform poorly on the CPT are more likely to have a history of mental illness in the family than those patients whose performance is indistinguishable from that of normal subjects.Paper presented at the meetings of the American College of Neuropsychopharmacology, December 10–11, 1970, San Juan, Puerto Rico, as part of a symposium, Behavioral Mechanisms of Drug Action in Schizophrenia, Solomon C. Goldberg, Chairman.Many of the experiments described in this paper were supported by Grants MH 03312 & MH 12568 from the National Institute of Mental Health.Career Scientist Awardee MH 1759 from the National Institute of Mental Health.     

Cross-tolerance to centrally injected barbiturates.

Hypnotic responses to intracerebroventricular (i.c.v) injections of either barbital, pentobarbital, R(-) and S(+) mephorbarbital, or racemic metharbital were compared to those produced by phenobarbital. Dose--response relationships were obtained for all except S(+) mephorbarbital and metharbital. Chronic i.c.v. phenobarbital administration resulted in tolerance to the drug's hypnotic effects. However, chronic barbital administration using an identical regimen did not produce tolerance, nor were phenobarbital tolerant rats cross-tolerant to barbital. Chronic i.c.v pentobarbital resulted in an irreversible decrease in responsiveness to its own effects and to those of other barbiturates. This was attributed to the high alkalinity of the solution (pH 9.6) since i.c.v. injection of saline adjusted to the same pH also reduced responsiveness to i.c.v. barbiturates. However, rats tolerant to i.c.v. phenobarbital were tolerant to acute i.c.v. injection of pentobarbital. Similar cross-tolerance was observed on systemic administration of the barbiturates. The efflux rates of i.c.v. phenobarbital or barbital and their distribution to different brain areas were identical in tolerant and nontolerant rats. Awakening phenobarbital brain levels of the tolerant rats were approximately three times higher than those in nontolerant controls. The conclusion is reached that central administration of phenobarbital provides a valid model for studying functional tolerance.