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Despite the increasing need of new antituberculosis drugs, the number of agents approved for the market has fallen to an all-time low. In response to the emerging drug resistance followed, structurally unique chemical entities will be highlighted. decaprenylphosphoryl-β-d-ribose oxidase (DprE1) participating in the biosynthesis of mycobacterium cell wall is a highly vulnerable and validated antituberculosis target. On the basis of it, a systematic strategy was applied to identify a high-quality lead compound (compound 50) that inhibits the essential enzyme DprE1, thus blocking the synthesis of the mycobacterial cell wall to kill M. tuberculosis in vitro and in vivo. Correspondingly, the rational design and synthetic strategy for compound 50 was reported. Notably, the compound 50 has been confirmed to be no toxicity. Altogether, our data suggest the compound 50 targeting DprE1 is a promising candidate for the tuberculosis (TB) therapy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Context: According to guideline recommendations, barbiturates and neuromuscular relaxants are the recommended drugs for euthanasia., Objectives: To describe changes over time in drugs used to perform euthanasia and differences in case characteristics according to the drugs used., Methods: Repeated population-based mortality follow-back study among physicians attending a large representative sample of deaths in 1998, 2007, and 2013 in Flanders, Belgium., Results: In 1998, we identified 25 euthanasia cases (1.2% of all deaths), 142 cases in 2007 (2.0% of all deaths), and 349 cases in 2013 (4.6% of all deaths). Use of recommended drugs to perform euthanasia increased from 11.9% of euthanasia cases in 1998 to 55.3% in 2007 and 66.8% in 2013 (P < 0.001). In 2013, cases with recommended drugs compared with nonrecommended drugs more often involved requests expressed both orally and in writing (86.8%/14.1%; P < 0.001), consultation with colleague physicians (93.8%/69.1%; P < 0.001), and administration in the presence of another physician (98.3%/54.3%; P < 0.001), and were more often self-labeled by physicians as euthanasia (95.5%/0.9%; P < 0.001) and reported to the euthanasia review committee (92.3%/3.8%; P < 0.001). Between 2007 and 2013, physicians consistently labeled cases in which nonrecommended drugs were used as palliative sedation (72.8%/78.4%; P = 0.791) or alleviation of pain and symptoms (13.2%/15.0%; P > 0.999)., Conclusion: Physicians in Flanders are increasingly using the recommended drugs for euthanasia. This suggests that guidelines and training regarding the conduct and pharmacological aspects of euthanasia may have had important effects on the practice of euthanasia. However, the declining but persisting use of nonrecommended drugs requires further attention., (Copyright © 2018 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: Although revascularization surgery for patients with moyamoya disease can effectively prevent ischemic events and thus improve the long-term clinical outcome, the incidence of postoperative ischemic complications affects patients' quality of life. This study aimed to clarify the risk factors associated with postoperative ischemic complications and to discuss the appropriate perioperative management., Methods: Fifty-eight revascularization operations were performed in 37 children with moyamoya disease. Patients with moyamoya syndrome were excluded from this study. Magnetic resonance imaging was performed within 7 days after surgery. Postoperative cerebral infarction was defined as a diffusion-weighted imaging high-intensity lesion with or without symptoms. We usually use fentanyl and dexmedetomidine as postoperative analgesic and sedative drugs for patients with moyamoya disease. We used barbiturate coma therapy for pediatric patients with moyamoya disease who have all postoperative cerebral infarction risk factors., Results: Postoperative ischemic complications were observed in 10.3% of the children with moyamoya disease (6 of 58). Preoperative cerebral infarctions (P = 0.0005), younger age (P = 0.038), higher Suzuki grade (P = 0.003), and posterior cerebral artery stenosis/occlusion (P = 0.003) were related to postoperative ischemic complications. Postoperative cerebral infarction occurred all pediatric patients using barbiturate coma therapy., Conclusions: The risk factors associated with postoperative ischemic complications for children with moyamoya disease are preoperative infarction, younger age, higher Suzuki grade, and posterior cerebral artery stenosis/occlusion. Barbiturate coma therapy for pediatric patients with moyamoya disease who have the previous risk factors is insufficient for prevention of postoperative cerebral infarction. More studies are needed to identify the appropriate perioperative management., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Benzodiazepine-resistant cases of alcohol withdrawal syndrome are common, and therefore alternate treatments are needed., Objective: Our aim was to conduct a systematic review of published reports on the use of barbiturates for alcohol withdrawal syndrome., Methods: We performed a systematic literature search of PUBMED for relevant citations that described the use of barbiturates either alone or in conjunction with other pharmacological agents to treat alcohol withdrawal syndrome., Results: A total of 15 citations were identified; 2 citations looked at barbiturates alone; 1 found barbiturates effective in an emergency department setting at treating seizures and preventing return visits. A second showed that barbiturates caused a relatively low rate of respiratory depression. Further, 5 citations compared barbiturates with benzodiazepines; 1 suggested that they were better at treating severe withdrawal, and another showed they were more effective at preventing seizures; 4 citations found they were as effective as benzodiazepines, but 1 found a higher rate of respiratory depression. Also, 3 citations compared a combination of barbiturates and benzodiazepines to benzodiazepines alone; 1 showed decreased ventilation, another showed fewer intensive care unit admissions, and a third showed better symptom control; 3 citations described detailed reports of barbiturate protocols. Lastly, 2 citations compared barbiturates with other agents and found them equivalent., Conclusion: Barbiturates provide effective treatment for alcohol withdrawal syndrome. In particular, they show promise for use in the emergency department and for severe withdrawal in the intensive care unit. Respiratory depression does not appear to be exceedingly common. Additional studies are needed to clarify the role of barbiturates in alcohol withdrawal syndrome., (Copyright © 2016 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.)

The GABAA receptor (GABAAR) is a major target of antiseizure drugs (ASDs). A variety of agents that act at GABAARs s are used to terminate or prevent seizures. Many act at distinct receptor sites determined by the subunit composition of the holoreceptor. For the benzodiazepines, barbiturates, and loreclezole, actions at the GABAAR are the primary or only known mechanism of antiseizure action. For topiramate, felbamate, retigabine, losigamone and stiripentol, GABAAR modulation is one of several possible antiseizure mechanisms. Allopregnanolone, a progesterone metabolite that enhances GABAAR function, led to the development of ganaxolone. Other agents modulate GABAergic "tone" by regulating the synthesis, transport or breakdown of GABA. GABAAR efficacy is also affected by the transmembrane chloride gradient, which changes during development and in chronic epilepsy. This may provide an additional target for "GABAergic" ASDs. GABAAR subunit changes occur both acutely during status epilepticus and in chronic epilepsy, which alter both intrinsic GABAAR function and the response to GABAAR-acting ASDs. Manipulation of subunit expression patterns or novel ASDs targeting the altered receptors may provide a novel approach for seizure prevention., (Copyright © 2013 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objective: Bispectral index (BIS) may be used in traumatic brain-injured patients (TBI) with intractable intracranial hypertension to adjust barbiturate infusion but it is obtained through a unilateral frontal electrode. The objective of this study was to evaluate differences in BIS between hemispheres in two groups: unilateral frontal (UFI) and diffuse (DI) injured., Patients and Methods: Prospective monocenter observational study in 24 TBI treated with barbiturates: 13 UFI and 11 DI. Simultaneous BIS and EEG was recorded for 1h. Goal of monitoring was a left BIS between 5 and 15. Biases in BIS were considered as clinically relevant if greater than 5. Differences in biases were interpreted from both statistical (Mann-Whitney test) and clinical points of view., Results: Mean BIS in the two hemispheres remained in the same monitoring range. There were statistic and clinical differences in some values in the two groups of patients (15% of bias greater than I5I in UFI group and 10% in DI group). BIS monitoring allowed the adequate number of bursts/minutes to be predicted in 18 patients and did not detect an overdosage in 2., Conclusions: While asymmetric BIS values in TBI patients occur whatever the kind of injury, they were not found to be clinically relevant in most of these heavily sedated patients. Asymmetrical BIS monitoring might be sufficient to monitor barbiturate infusion in TBI provided that the concordance between BIS and EEG is regularly checked., (Copyright © 2012 Société française d’anesthésie et de réanimation (Sfar). Published by Elsevier SAS. All rights reserved.)

Background: The Japanese Society of Neurotraumatology announced guidelines for management of severe traumatic brain injury (TBI) in 2000. To evaluate subsequent implementation of these guidelines, we investigated current severe TBI practices in Japan., Methods: A questionnaire regarding management of severe TBI was sent to each of the 384 Japanese Neurosurgical Society specialist training medical centers and answers were received by mail from 233 centers (60.7%)., Results: Of the medical centers, 29% have neurosurgeons in their emergency department. Initial TBI treatment responsibility resided in the Departments of Neurosurgery in 34% of the medical centers, in the emergency department in 29%, and in 36% responsibility is assigned to both departments. Surgery was performed by neurosurgeons in 90% of the centers and postoperative management was assigned to neurosurgeons in 76%. Acute stage magnetic resonance imaging was done in 52% of the centers. An intracranial pressure sensor was inserted in 55%, and jugular venous oxygen saturation was measured in 21%. Hypothermia therapy was performed in 47%, positive normothermia therapy was administered in 76%, and barbiturate therapy was administered in 70%. Of the centers, 94% acknowledged the guidelines but only 72% of the centers implemented protocols that conformed to the guidelines., Conclusions: Neurosurgeons in Japan are positively involved in management of severe TBI, but few medical centers monitor TBI patients. Many medical centers find it difficult to conform to the guidelines due to lack of neurosurgeons and equipment. These problems can be addressed by consolidation of neurosurgeons into centralized centers and improvement of the medical insurance system., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: In emergency care of patients with severe blunt head injury, uncontrollable high intracranial pressure is one of major causes of morbidity and mortality. The purpose of this study was to evaluate the efficacy of aggressive surgical treatment in managing uncontrollable elevated intracranial pressure coupled with early skull reconstruction., Methods: This was a prospective study on a series of 147 consecutive patients, managed according to the same protocol by five different neurosurgical units, for severe head injuries (Glasgow coma scale score ≤8/15 and high intracranial pressure >25 mm Hg) during a five-year period. All patients received a wide decompressive craniectomy and duroplasty in the acute phase, and a cranioplasty was also performed within 12 weeks (median 6 weeks, range 4-12 weeks)., Results: The emergency decompressive surgery was performed within 28 hours (median 16 hours, range 6-28 hours) after sustaining the head injury. The median preoperative Glasgow coma scale score was 6/15 (range 3-8/15). At a mean follow-up of 26 months (range 14-74 months) 14 patients were lost to long-term follow-up, leaving only 133 patients available for the study. The outcome was favorable in 89 (67%, Glasgow outcome score 4 or 5), it was not favorable in 25 (19%, Glasgow outcome score 2 and 3), and 19 patients (14%) died. A younger age (<50 years) and earlier operation (within 9 hours from trauma) had a significant effect on positive outcomes (P < 0.0001 and P < 0.03, respectively)., Conclusions: A prompt aggressive surgery, including a wide decompressive craniectomy coupled with early cranioplasty, could be an effective treatment method to improve the outcome after a severe closed head injury reducing, perhaps, many of the complications related to decompressive craniectomy., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The objective of the treatment of intracranial hypertension is to decrease intracranial pressure (ICP) while maintaining cerebral blood flow (CBF). Despite numerous treatments, none of them associates total efficiency and security. Systemic secondary cerebral injuries, which are responsible for cerebral ischemia, lead us to administer non specific treatments in order to optimize CBF and cerebral oxygenation. Thus, the goals are: 1) to maintain cerebral perfusion pressure> or =70 mmHg; 2) to control metabolic status by preventing hyperglycaemia, anaemia and hyperthermia; 3) to maintain normoxia and normocapnia (hypercapnia increases ICP and hypocapnia decreases CBF). Beside the neurosurgical evacuation of extra- and intraparenchymatous haematomas, osmotherapy and cerebrospinal fluid (CSF) evacuation are the two specific treatments of intracranial hypertension. Osmotherapy consists in an administration of a hypertonic solution which induces a decrease in cerebral water and finally in ICP. Mannitol (20%), which is the reference, associates osmotic and rheologic effects, and decreases CSF production too. Recent data conduct us to administer larger doses, between 0.7 and 1 g/kg in 15 minutes. Hypertonic saline solution associates osmotic effects and plasma volume loading. Thus, this solution is particularly appropriate in severe head injury with arterial hypotension. CBF evacuation decreases rapidly ICP without any major side-effect. Until now, there is no proof of a superior efficiency of a treatment for intracranial hypertension compared to another. Considering their mechanism of action, all of them are efficient but potentially dangerous too. Indeed, the choice between treatments depends on data which are issued from the multimodal monitoring. General non specific treatments are always necessary. Specific treatments are indicated if ICP is above 20-25 mmHg. Maintaining cerebral perfusion pressure represents the first therapeutic goal. If intracranial hypertension persists, evacuation of CBF or osmotherapy may be advocated. In case of refractory intracranial hypertension, it may be useful to deepen neurosedation. Controlled hypocapnia and barbiturates remain a third line therapy providing to monitor and maintain an appropriate CBF and cerebral oxygenation. Controlled hypothermia and decompressive craniectomy must be individually discussed.

Secondary brain injury is a complicated, multifactorial process that results from hypoxemia, hypercapnia or hypocapnia, and increased ICP. Implementation of a traumatic brain injury protocol for patients with head injury including hemodynamic management, pulmonary care, maintenance of body temperature, control of the environment, positioning of patients, and seizure prophylaxis provides critical care nurses a proactive means to prevent or minimize the development of secondary brain injury in the emergency department.

Intracranial and systemic mechanisms of the secondary brain lesion are the targets of specific therapy for the head-injured patient. Recommendations for good clinical practice have recently defined the role of the main therapeutic measures. There is no indication for corticosteroids in head injury. Mannitol is the first-choice therapy for increased intracranial pressure, and barbiturates are still considered as a rescue therapy in case of refractory intracranial hypertension. The place of hypothermia remains to be defined. Although controversial, optimized hyperventilation, induced systemic hypertension and vasoconstrictive therapy are optimally used under multimodal monitoring. New therapeutic perspectives, aimed at controlling biochemical disorders at a cellular level, are under investigation, but are still inconclusive at the present time.

Barbiturates have been demonstrated to reduce the cerebral metabolic rate (CMR) in a dose-dependent manner but investigations of a dose-response relationship for their neuroprotective efficacy are scant. It has been suggested that barbiturates possess other mechanism of action that may be critical to their protective effect. If so, it is conceivable that the peak effect of such mechanisms does not parallel the reduction in CMR. Thus, maximal neuroprotection may be achieved with a substantially lower dose of the drug. Thirty Sprague-Dawley rats were subjected to 2 h of middle cerebral artery occlusion while either anesthetized with (1) halothane (control) or (2) intravenous thiopental titrated to cause mild EEG suppression or (3) thiopental titrated to maintain EEG burst suppression. Cortical blood flow was recorded by continuous bilateral laser Doppler flowmetry (LDF). Infarct volume was assessed after 3 h of reperfusion. Low-dose thiopental decreased blood flow to 80% of baseline and high-dose thiopental to 70% of baseline. LDF did not indicate improvement of blood flow by thiopental in the ischemic area. Compared to controls, low-dose thiopental significantly decreased infarct volume by 28% and high-dose thiopental by 29%. The results of this study and a review of literature indicate that barbiturates provide cerebral protection but that the magnitude of this effect has been overestimated. Other mechanisms than CMR reduction seem to contribute to their beneficial effects, and high doses administered to the point of burst suppression may not be required to obtain maximal protection.

More than 50% of severely head-injured patients develop increased intracranial pressure, risking exacerbating ischaemic insults to the already injured brain. In approximately 10% of these cases, intracranial pressure may become unresponsive to medical or surgical treatment, with a resulting mortality of over 90%. The main emphasis should be on full intensive care, based on the prophylaxis of the devastating effects of secondary insults to the injured brain. Specific treatment should be directed towards controlling intracranial pressure and maintaining a cerebral perfusion pressure over 70 mmHg, while avoiding, where feasible, treatment modalities at risk of exacerbating cerebral ischaemia. Recently, an algorithm for treating intracranial hypertension under three different therapeutic situations has been suggested, based on the successive application of effective agents with increasing associated risks. Therapeutic modalities of this protocol are discussed.

There remains nearly a twofold increase in blacks compared with whites for stroke mortality. The death rate from cerebral hemorrhage in blacks approximates twice that of whites. Subarachnoid hemorrhage is a frequent cause of mortality and morbidity in stroke and is also about twice as frequent in blacks. Lacunar strokes occur more in blacks reflecting increased incidence of hypertension and are leading causes of multi-infarct encephalopathy and dementia. Therefore, the concomitant occurrence of hypertension and stroke is most common in African Americans and requires diagnosis of the type of stroke, which then defines the rationale of blood pressure control. Cerebral vascular changes associated with acute, chronic, and reactive hypertension are operative. When to treat, when not to treat, and the appropriateness of specific antihypertensive agents in acute stroke are relevant. A common misconception is that the increased blood pressure is the cause of the stroke when it is likely the result of the stroke. Lowering the blood pressure in all acute stroke patients with elevated blood pressure may worsen the neurologic deficit. Thus, the judicious control of blood pressure is to be stressed in the concomitant occurrence of hypertension and stroke.

A research program in cerebral ischemia was initiated by our laboratory to determine optimal strategies for cerebroprotection. Four studies relating to cerebroprotection using nuclear magnetic resonance spectroscopy in a sheep model of hypothermic cardiopulmonary bypass are summarized. These showed, first, that low-flow bypass, with a flow as low as 10 mL.kg-1 x min-1, maintained normal cerebral metabolism; second, that hypothermia increases the high-energy phosphate content and the intracellular pH of the brain; third, that hyperglycemia causes a profound intracellular acidosis; and, finally, that barbiturates prevent the normal increase in high-energy phosphates associated with hypothermia.

A neurological and electroencephalographic (EEG) prospective study was performed in 34 leukemic patients receiving busulfan (BU) plus cyclophosphamide (CY) before bone marrow autologous transplant. During BU treatment and briefly thereafter, all patients were given anticonvulsant prophylaxis with phenobarbital. Neurological evaluations were performed daily and EEGs, recorded one week before and soon after the end of the BU regimen, were re-evaluated two months later. Basal EEGs were normal in 23 of the 34 patients, focal abnormalities were detected in 9 cases, and generalized epileptic discharges were present in one (one subject was not studied). EEGs performed at the end of BU administration showed generalized spike/polyspike-and-wave discharges in 21 of the 34 patients, with associated myoclonic epilepsy in 10 subjects appearing on the 3rd or 4th day of treatment. Focal abnormalities were present in 6 patients and constant EEG normality in 7. It is known that myoclonic epilepsy can be induced by drugs. Oral administration of high-dose BU is followed by a high-dose cerebrospinal fluid concentration of the drug. Therefore, myoclonic epilepsy and/or paroxysmal epileptiform EEG discharges may be observed in leukemic patients undergoing high-dose BU therapy.

Ischaemic brain damage can follow global cerebral hypoxia, localized cerebral hypoxia and global cerebral anoxia as it occurs after circulatory arrest. The calcium-ion-mediated mechanism is one of the main routes to cerebral deterioration. Barbiturates are restricted for treatment of increased intracranial pressure and seizures. Calcium channel blockers cannot yet be recommended. Therapy remains mainly symptomatic. Hyperglycaemia should be avoided.

The effect of barbiturate treatment on post-ischemic cerebral protein biosynthesis was studied in gerbils subjected to 5 min transient occlusion of carotid arteries followed by 2 h or 48 h recirculation. Ischemia induced a remarkable decline of amino acid incorporation into brain proteins in most forebrain structures. The initial inhibition recovered to near normal after 2 days recirculation in all regions except the vulnerable CA1 sector. Barbiturate treatment, which previously has been shown to prevent delayed neuronal death in CA1 sector, did not ameliorate the initial inhibition of protein synthesis but it significantly improved subsequent recovery, especially in the vulnerable CA1 sector of hippocampus. These observations indicate that delayed neuronal death in CA1 sector of hippocampus results from selective failure of post-ischemic recovery and not from selective ischemic injury of the protein synthesizing machinery. This explains that delayed neuronal death can be prevented by therapeutic interventions which are initiated during the post-ischemic recirculation phase.

We examined the hypothesis that G-6-PD deficiency associated with fava bean ingestion confers resistance to malaria by studying the in vitro interactions between malaria parasites (Plasmodium falciparum), human erythrocytes with varying degrees of G-6-PD deficiency, and isouramil (IU), a fava bean extract that is known to cause oxidant stress and hemolysis of G-6-PD-deficient erythrocytes. Untreated G-6-PD-deficient and normal erythrocytes supported the in vitro growth of P. falciparum equally well. However, after pretreatment with IU, G-6-PD-deficient erythrocytes did not support parasite growth in vitro, whereas growth remained high in normal erythrocytes. Parasite growth was proportional to the G-6-PD activity of the IU-treated erythrocytes. In contrast, when parasitized erythrocytes were exposed to IU, parasites even in normal erythrocytes were destroyed. Ring forms were much less sensitive than late trophozoites and schizonts. The results suggest that there are two modes by which IU affects the development of P. falciparum and demonstrate in vitro that G-6-PD deficiency confers resistance against malaria under conditions of fava-bean-associated oxidant stress.

Concurrent burst suppression and alpha pattern coma developed in the EEG of a 2-year-old child who suffered a cardiac arrest secondary to hypoxemia from Haemophilus influenza epiglottis. The neurophysiological implications of this association are discussed and the literature pertaining to the role of barbiturates in the production of post-anoxic coma with an alpha pattern and experimental post-resuscitative alpha frequencies is reviewed.

There was a progressive intensification (kindling) of the motor seizure pattern when electroconvulsive shocks (ECSs) were administered to rats at 3-day intervals, but not when the inter-ECS interval was 1 hr. Similarly, the incidence of convulsive symptoms elicited by subsequent alcohol exposure and withdrawal was a function of the number of antecedent ECSs administered at 3-day, but not at 1-hr, intervals. Significant ECS-produced intensification of the alcohol withdrawal syndrome persisted for 3 weeks following ten periodic ECSs and occurred even when the motor seizures elicited by the antecedent ECSs were pharmacologically suppressed.

This review has indicated that barbiturates are useful in controlling ICP during anaesthesia in patients with intracranial hypertension. While laboratory data indicate that intraoperative administration of barbiturates during episodes of transient cerebral ischaemia, associated with surgical revascularization procedures, should be efficacious, current intraoperative results claiming benefit are anecdotal. Continuous high-dose barbiturate therapy (induced barbiturate coma) for occlusive stroke and persistently increased intracranial pressure is currently undergoing clinical trials. While it is clear that this therapy can often reduce increased ICP in head injured patients, its influence on neurological outcome remains to be determined by a multicentre trial at present in progress. Despite evidence that high-dose barbiturate therapy can reduce the area of infarction in occlusive stroke in the laboratory, organized clinical trials have not yet commenced. Until more definitive knowledge is available concerning the influence of high-dose barbiturate therapy in treating different forms of cerebral ischaemia, its application should be viewed sceptically and limited to centres willing to create an organized data base for inter-institutional evaluation of this form of treatment. If barbiturate therapy proves successful and the mechanisms involved are better understood, drugs with fewer side-effects and risks may become available to combat cerebral ischaemia.

A high-performance liquid chromatographic (HPLC) assay for the identification and quantification of barbiturates in blood at therapeutic levels had been developed. An ODS-silica column is used with an eluent of 40% methanol at pH 8.5. The barbiturates are detected at 240 nm. The sample preparation procedure involves extraction of unfractionated blood (100 microliter) with hexane-diethyl ether (50 : 50, v/v) ang is very rapid. Talbutal is used as an internal standard. The method has been applied to the determination of five barbiturates (amylobarbitone, butobarbitone, cyclobarbitone, pentobarbitone and quinalbarbitone) in blood after therapeutic doses of the drugs. An application of the HPLC assay to forensic casework is demonstrated.