Search

The molecular environment around supramolecular bonding systems significantly affects their stability and the assembly of host–guest complexes, most prominent for hydrogen bonds (H‐bonds). Hamilton receptor‐barbiturate host–guest complexes are well‐known in solution, typically forming a 1 : 1 molar ratio complex. However, within a polymer matrix, these complexes can form higher‐order assemblies, deviating from the standard 1 : 1 complex, which are challenging to characterize and often require lab‐intensive methods. In this study, a novel Hamilton receptor (H) was equipped with cyclopentene moieties and used as a host to form host–guest complexes (H−B) with allobarbital (B), followed by covalent crosslinking. UV‐Vis spectroscopy titration experiments in different solvents and at various temperatures revealed that polar solvents containing additional H‐bonding sites significantly reduce the formation of the 1 : 1 H−B complex, as indicated by a reduced association constant. Higher‐order aggregates (HH‐dimer, HHH‐trimer) were subsequently detected via an alkene cross‐metathesis (CM) reaction to fix the assemblies covalently, followed by analysis via electrospray ionization mass spectrometry (ESI MS). This two‐step method, firstly via CM fixation followed by ESI MS, was extended to study the H−B model complex within a polyisobutylene (PIB) matrix, presenting a direct method to analyze the complex host–guest assembly in solvent‐free (polymer) environments. [ABSTRACT FROM AUTHOR]

The two-component compound formed by codeine and cyclopentobarbital was produced using grinding techniques and through evaporation from alcoholic solutions. The cocrystal nature of this phase was established unequivocally through single crystal X-ray structure determination. The asymmetric unit contains one formula unit. In the cyclopentobarbital molecule, the cyclopentenyl ring is disordered over two positions related by a rotation of approximately 180° about its C—C bond to the pyrimidine ring. The two NH groups of the cyclopentobarbital molecule form N—H⋯N and N—H⋯O bonds to piperidine and hydroxyl groups, respectively, belonging to different codeine molecules. In addition, the hydroxyl and methoxy groups of neighboring codeine molecules are linked by O—H⋯O interactions, resulting in a H-bonded framework structure of codeine and cyclopentobarbital molecules. The cocrystal was also characterized using thermal analysis, X-ray powder diffraction and IR spectroscopy. [ABSTRACT FROM AUTHOR]

Ultraviolet nonlinear optical (NLO) crystals are the key materials to realize the development of ultraviolet solid-state lasers. At present, NLO crystals mainly rely on borate crystals, but the existing NLO crystals could not meet the applications fully. While it is increasingly difficult to find new NLO crystals, so it is particularly urgent to develop new material systems. From the relationship between borate structures and optical and nonlinear optical properties, it can be known that borates which containing planar conjugated groups have the characteristics of large frequency doubling coefficient, suitable birefringence and short UV cut-off edge. Group with planar conjugated configuration is the core functional unit of borate NLO crystals. The study of expanding planar conjugated groups based on geometric configuration is an important idea for exploring new systems of UV nonlinear optical materials. Based on these, our team proposes to expand the exploration scope of UV NLO crystals by studying CO3, NO3, C(NH2)3 groups with planar triangular conjugated structures and HC3N3O3, H2C4N2O3 groups with planar six-member ring conjuated structures. The research results obtained by our team in the exploration of UV crystals of carbonate, nitrate, guanidine, cyanurate and barbiturate in recent years are mainly introduced in this paper. [ABSTRACT FROM AUTHOR]

Background: Febrile status epilepticus is the most common form of status epilepticus in children. No previous reports compare the effectiveness of treatment strategies using fosphenytoin (fPHT) or phenobarbital (PB) and those using anesthetics as second-line anti-seizure medication for benzodiazepine-resistant convulsive status epilepticus (CSE). We aimed to examine the outcomes of various treatment strategies for febrile convulsive status epilepticus (FCSE) in a real-world setting while comparing the effects of different treatment protocols and their presence or absence.Methods: This was a single-center historical cohort study that was divided into three periods. Patients who presented with febrile convulsive status epilepticus for ≥60 min even after the administration of at least one anticonvulsant were included. During period I (October 2002-December 2006), treatment was performed at the discretion of the attending physician, without a protocol. During period II (January 2007-February 2013), barbiturate coma therapy (BCT) was indicated for FCSE resistant to benzodiazepines. During period III (March 2013-April 2016), BCT was indicated for FCSE resistant to fPHT or PB.Results: The rate of electroencephalogram monitoring was lower in period I than period II+III (11.5% vs. 85.7%, p<0.01). Midazolam was administered by continuous infusion more often in period I than period II+III (84.6% vs. 25.0%, p<0.01), whereas fPHT was administered less often in period I than period II+III (0% vs. 27.4%, p<0.01). The rate of poor outcome, which was determined using the Pediatric Cerebral Performance Category scale, was higher in period I than period II+III (23.1% vs. 7.1%, p=0.03). The rate of poor outcome did not differ between periods II and III (4.2% vs. 11.1%, p=0.40).Conclusions: While the presence of a treatment protocol for FCSE in children may improve outcomes, a treatment protocol using fPHT or PB may not be associated with better outcomes. [ABSTRACT FROM AUTHOR]

There are many nonopioid central nervous system depressant substances that share a gamma‐aminobutyric acid (GABA) receptor–related mechanism of action. These sedatives‐hypnotics can be indicated to treat anxiety, seizures, depression, and insomnia but are also used as substances of abuse and used to facilitate sexual assault. Barbiturates, methaqualone, and glutethimide were among the first type A GABA receptor–mediated sedative‐hypnotics. Their clinical use was limited for most indications by serious adverse events and strong abuse potential but continue to be used illicitly around the world. The benzodiazepines supplanted barbiturates for most indications because they were less likely to cause severe adverse events in monotherapy. Flunitrazepam is a newer benzodiazepine that is preferentially used recreationally and to facilitate sexual assault. Flunitrazepam has greater potency and higher affinity for the type A GABA receptor than most benzodiazepines. Gamma‐hydroxybutyric acid is sought illicitly for its hypnotic, euphoric and anabolic effects as well as to facilitate sexual assault. When any of these GABAergic drugs are used in high doses or with other sedative hypnotic agents, respiratory depression, coma, and death have occurred. Chronic use of these GABAergic drugs can lead to significant withdrawal syndromes. Phenibut and selank are poorly studied Russian drugs with GABAergic mechanisms that are inexplicably sold to US consumers as dietary supplements. Poison control center calls regarding phenibut have increased substantially over the past 5 years. Desired euphoriant effects account for the recreational and illicit use of many GABA‐modulating agents. However, illicit use can lead to significant toxicities related to abuse, dependence, and subsequent withdrawal syndromes. Significant evaluation of developing agents with GABA properties should be conducted to determine abuse potential before public access ensues. [ABSTRACT FROM AUTHOR]

Introduction: Seizures are seen in 13% of cases in palliative care. Phenobarbital is a drug from the barbiturates' family most used for its anticonvulsant and sedative properties, and therefore the drug of choice in palliative care suitable for the management of seizures and agitation. The study aimed to evaluate the role of phenobarbital in palliative care settings. Methods: A systematic literature review was conducted using predetermined keywords. Data was compiled and inclusion and exclusion criteria were established concerning the role of phenobarbital in palliative care. Five case studies met these criteria and were evaluated. Retrospective analysis of the data in the studies, along with randomized clinical trial about the use of at the end of life were reviewed by two independent reviewers. Results: Results of this review showed that phenobarbital is efficacious in the management of seizures and agitation, can be easily administered via different routes and utilized in various palliative care settings. No serious adverse skin reactions were noted with the use of phenobarbital and it did not abruptly end a patient's life when used at appropriate doses. Conclusions: Although phenobarbital is an old drug and is an approved anticonvulsant, its sedating properties make it to be useful not only for seizure management, but also in patients experiencing agitation, physical and psychological distress, and restlessness. More studies are warranted in the sole practice of using phenobarbital and further explore its role in palliative care. [ABSTRACT FROM AUTHOR]

Intracranial pressure (ICP) has to be maintained quite constant, because increased ICP caused by cerebrovascular disease and head trauma is fatal. Although controlling ICP is clinically critical, only few therapeutic methods are currently available. Barbiturates, a group of sedative-hypnotic drugs, are recognized as secondary treatment for controlling ICP. We proposed a novel "step-down infusion" method, administrating barbiturate (thiamylal) after different time point from the start of treatment under normothermia, at doses of 3.0 (0-24 h), 2.0 (24-48 h), 1.5 (48-72 h), and 1.0 mg/ kg/h (72-96 h), and evaluated its safety and effectiveness in clinical. In 22 patients with severe traumatic brain injury or severe cerebrovascular disease (Glasgow coma scale ≤8), thiamylal concentrations and ICP were monitored. The step-down infusion method under normothermia maintained stable thiamylal concentrations (<26.1 µg/ ml) without any abnormal accumulation/elevation, and could successfully keep ICP <20 mmHg (targeted management value: ICP <20 mmHg) in all patients. Moreover the mean value of cerebral perfusion pressure (CPP) was also maintained over 65 mmHg during all time course (targeted management value: CPP >65 mmHg), and no threatening changes in serum potassium or any hemodynamic instability were observed. Our novel "step-down infusion" method under normothermia enabled to maintain stable, safe thiamylal concentrations to ensure both ICP reduction and CPP maintenance without any serious side effects, may provide a novel and clinically effective treatment option for patients with increased ICP. [ABSTRACT FROM AUTHOR]

• The barbituric acid-based 1,3-dimethyl-2,4,6-trioxo-hexahydro-pyrimidine-5-(2,6-dimethylphenylamino)methylene, 1,3-dimethyl-2,4,6-trioxo-hexahydro-pyrimidine-5-(8-quinolylamino)methylene as ligands and six novel copper(II) and nickel(II) complexes were synthesized and characterized by elemental analysis, FT-IR spectroscopy. • Single crystal X-ray crystallography was performed to determine all molecules' crystal structures. • All molecules demonstrate essential molecular arrangements. • The Hirshfeld surface analysis method was used to explore the intermolecular interactions. It is well known that solvent molecules and additional agents significantly impact crystal structures. In relation to this, the barbituric acid-based 1,3-dimethyl-2,4,6-trioxo-hexahydro-pyrimidine-5-(2,6-dimethylphenylamino)methylene (HL1) as ligand and three novel copper(II) complexes, 2[Cu(L1) 2 ] (1), 2[Cu(L1) 2 (4,4′bpy)] (2), Cu(L1) 2 (CH 3) 2 SO (3), (where H is the deprotonatable hydrogen) were synthesized and characterized by elemental analysis, FT-IR spectroscopy. As a comparison, a potentially tridentate barbituric acid-based ligand, 1,3-dimethyl-2,4,6-trioxo-hexahydro-pyrimidine-5-(8-quinolylamino)methylene (HL2), and its three new copper(II) and nickel(II) complexes, Cu(L2) 2 (4), Cu(L2) 2 (5) and Ni(L2) 2 (6), were also synthesized and characterized by elemental analysis, FT-IR spectroscopy. The crystal structures of the ligands and their complexes were determined based on an X-ray diffraction study. X-ray diffraction studies have shown that the ligands HL1 and HL2 exist in keto-enamine form. The crystal structure of complexes of HL1 revealed that Cu center is distorted square-planar in 2[Cu(L1) 2 ] (1), while it is found in distorted square-pyramidal in relation to additional agent (4,4′ bpyridine) and solvent (DMSO) conditions in 2[Cu(L1) 2 (4,4′bpy)] (2) and Cu(L1) 2 (CH 3) 2 SO (3), respectively. In the crystal structure, [M(L2) 2 ] (M = Cu (4 and 5), Ni (6)), metal ions possess a distorted octahedral environment, and the HL2 ligands coordinate with a meridional geometry. Structures of all complexes reveal a tendency to form C–H···O, C–H···π and π···π interactions, except for molecule Cu(L1) 2 (CH 3) 2 SO (3) in terms of C–H···O bonds which was not observed. Exploring noncovalent interactions indicates similar molecular structures in [M(L2) 2 ] (M = Cu (4 and 5), Ni (6)) suggesting the difference in packing due to the solvent of crystallization (CH 2 Cl 2) in the lattice of Cu(L2) 2 (5) and the different metal ion in the molecular structure of Ni(L2) 2 (6). The packing in the structures of HL1 complexes is found to be strongly dependent on the additional agent (4,4′ bpyridine) and solvent (DMSO) fused in molecular structure with different supramolecular assemblies such as 1D chains, π···π dimers, 2D sheets, etc. In addition, Hirshfeld surface analysis and 2D fingerprint plots were employed to verify intermolecular interactions in both ligands and their complexes. [Display omitted] [ABSTRACT FROM AUTHOR]

Barbiturate-related deaths have increased in Australia in two major demographic groups: older people with physical health problems and younger people with mental health problems. The former are the intended beneficiaries of laws that allow euthanasia. The latter have been described as collateral damage from increased access to barbiturates, a class of drug often used for euthanasia, regardless of its legality or illegality. [ABSTRACT FROM AUTHOR]

Human prolyl hydroxylases are involved in the modification of transcription factors, procollagen, and ribosomal proteins, and are current medicinal chemistry targets. To date, there are few reports on inhibitors selective for the different types of prolyl hydroxylases. We report a structurally informed template‐based strategy for the development of inhibitors selective for the human ribosomal prolyl hydroxylase OGFOD1. These inhibitors did not target the other human oxygenases tested, including the structurally similar hypoxia‐inducible transcription factor prolyl hydroxylase, PHD2. Humans have 60–70 2OG‐dependent oxygenases, of which some are important therapeutic targets. A priority in the development of oxygenase inhibitors is to identify scaffolds selective for a particular enzyme, made challenging by the highly conserved oxygenase active sites. This work reports the development of potent inhibitors for the oxygenase OGFOD1, which do not inhibit related enzymes, such as the physiologically important oxygenase PHD2. [ABSTRACT FROM AUTHOR]

A fatal concentration of pentobarbital found in a coroner's case where the history had not indicated use of this drug prompted a review of fatalities in Ontario from 2012 to 2015. Coroner's case files, including police and toxicology reports, were reviewed in twenty deaths, in which pentobarbital was identified as the primary cause of death. In all of the deaths (11 females, 9 males), the blood concentration of pentobarbital was greater than 10 mg/L. There were three to eight deaths per year and each was classified as suicide. In 11 cases, there was clear evidence that the drug was purchased over the internet from Mexico or China and imported into Canada. In four cases, it appears that the pentobarbital was labeled as a different, innocuous chemical to facilitate crossing the border without scrutiny. The findings underscore the value of a thorough scene investigation, including details of evidence that may be considered unrelated. [ABSTRACT FROM AUTHOR]

The developing brain is uniquely susceptible to drug-induced increases in programmed cell death or apoptosis. Many compounds, including anticonvulsant drugs, anesthetic agents, and ethanol, when administered in a narrow postnatal window in rodents, result in increased pruning of neurons. Here, we report that dimethyl sulfoxide (DMSO) triggers widespread neurodegeneration in the immature (postnatal day, P7) rat brain, an effect consistent with a prior report in neonatal mice. We found that the synthetic cannabinoid receptor agonist WIN 55,212-2 (WIN) exerts a neuroprotective effect against DMSO-induced cell death. We extended these findings to determine if WIN is neuroprotective against another drug class known to increase developmental cell death, namely antiseizure drugs. The antiseizure drug phenobarbital (PB) remains the primary treatment for neonatal seizures, despite significantly increasing cell death in the developing rodent brain. WIN exerts antiseizure effects in immature rodent seizure models, but increases the toxicity associated with neonatal ethanol exposure. We thus sought to determine if WIN would protect against or exacerbate PB-induced cell death. Unlike either the prior report with ethanol or our present findings with DMSO, WIN was largely without effect on PB-induced cell death. WIN alone did not increase cell death over levels observed in vehicle-treated rats. These data suggest that WIN has a favorable safety profile in the developing brain and could potentially serve as an adjunct therapy with phenobarbital (albeit one that does not attenuate PB-induced toxicity). [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Multicomponent reaction (MCR) access to perfluoroalkylated cis -spiropyrido[2,1- a ]isoquinoline-1,5'-pyrimidine derivatives. • The proton-promoted transformation of trans -isomer to cis -isomer. • Regioselectivity of the 1,4-dipolar cycloaddition. Abstract The 1,4-dipoles derived from isoquinolines and methyl perfluoroalk-2-ynoates reacted readily with arylidene-substituted N , N -dimethylbarbituric acids resulting in the first diastereoselective synthesis of perfluoroalkylated cis -spiropyrido[2,1- a ]isoquinoline-1,5'-pyrimidine derivatives in good to excellent yields under mild conditions. The reaction mechanism was proposed to illustrate the formation of the diastereoisomers and proton-promoted transformation of trans -spiropyrido[2,1- a ]isoquinoline-1,5'-pyrimidines to the more thermodynamically stable cis -isomers. The DFT calculation demonstrated the diastereoselectivity of the reaction. [ABSTRACT FROM AUTHOR]

In the past two decades, the solvomorphism phenomenon in organic materials has attracted much attention, especially in the pharmaceutical and materials industries. Cocrystallization with solvent molecules can lead to modified physical and chemical properties of materials. We present here two new solvomorphs (pseudopolymorphs) of tyraminium 5,5‐diethylbarbiturate [2‐(4‐hydroxyphenyl)ethanaminium 5,5‐diethyl‐2,4,6‐trioxotetrahydro‐2H‐pyrimidin‐1‐ide, C8H12NO+·C8H11N2O3−] with unusual structural features. Pseudopolymorph (I) follows the symmetry of the P21/n space group and has four tyraminium cations, four barbitalate anions and four molecules of chloroform in the asymmetric unit. Pseudopolymorph (II) crystallizes in the space group Rc with one tyraminium cation, one barbitalate anion and a small amount of disordered solvent (ethanol and water) located in the cavities. Hirshfeld surface analysis and the Non‐Covalent Interaction (NCI) index were used to examine and compare the crystal packing features and intermolecular interactions in (I) and (II). Both materials crystallize with large unit cells and contain nontypical barbitalate ions formed through deprotonation of the barbital N3 position. Pseudopolymorph (I) is an example of a crystal structure with a rarely observed value of Z′ = 4. Analysis of the hydrogen‐bond patterns in (II) showed an unusual arrangement of three barbitalate anions in R33(12) rings, which is the first example of such a hydrogen‐bond motif in barbital structures. The mutual arrangement of the ions in the crystal structure of (II) leads to the formation of specific cavities along the c direction. A tyraminium barbitalate solvomorph (pseudopolymorph) contains disordered chloroform molecules and its Z′ value is 4. A second solvomorph, a rare example of a crystal structure with a hydrogen‐bonded (12) ring motif, exhibits a layered structure, with cavities containing disordered water and ethanol molecules. [ABSTRACT FROM AUTHOR]

Abstract In chronic pruritic diseases such as atopic dermatitis, pruritus is exacerbated during nocturnal sleep; however, the underlying mechanism remains unclear. We previously demonstrated that acute administration of the sedative-hypnotics ethanol markedly enhanced itch-associated spontaneous scratching in a diet-induced mouse model of atopic dermatitis. In the present study, to expand our previous finding and provide a general mechanism for the central modulation of chronic itch, we examined whether other hypnotic drugs, such as barbiturates and benzodiazepines, also enhance scratching, and further investigated the underlying mechanism. Barbiturates markedly enhanced spontaneous scratching in the atopic dermatitis model but not controls. However, unexpectedly, benzodiazepines only slightly increased scratching, and the selective γ-aminobutyric acid type A (GABA A ) receptor agonist, muscimol, had no effect. Local injection studies have demonstrated that barbiturates act at the supraspinal level to enhance scratching. Barbiturate-induced scratching was inhibited not only by GABA A receptor antagonists but also by an L-type voltage-dependent calcium channel (L-VDCC) agonist and an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor agonist. An intracisternally injected AMPA receptor antagonist alone or in combination with an L-VDCC antagonist sufficiently enhanced scratching. Barbiturate-induced scratching enhancement was observed in another atopic dermatitis model, NC/Nga, but not in histamine-induced acute itch model in normal healthy mice. Overall, our results suggest that a synergistic effect among AMPA receptor inhibition, GABA A receptor activation, and L-VDCC inhibition in the brain mediates barbiturate-induced scratching in atopic dermatitis mice. This observation may provide a novel clue to understanding a supraspinal itch mechanism in chronic diseases such as atopic dermatitis. [ABSTRACT FROM AUTHOR]

Synthetic hydrogen-bonding receptors are described, which incorporate a central electroactive ferrocene moiety grafted with two adjacent bis(amido)pyridine motifs and an aliphatic tether (14 and 18 methylene units for 1 and 2, respectively) completing the macrocycle. The crystallographic structure, barbiturate guest-binding studies and electrochemical data are provided for the more strongly-binding macrocycle 2. [ABSTRACT FROM AUTHOR]

A combined experimental and DFT studies on molecular structure along with spectral investigation on the title compound which is a barbiturate derivative with the formula [C 34 H 40 N 2 O 5 ], 5,5-diethyl-1,3-Bis(2-(3-methyl-3-phenylcyclobutyl)-2-oxoethyl)pyrimidine-2,4,6(1H,3H,5H)-trione, has been reported. The crystal and molecular structures of compound were uncovered by single-crystal X-ray diffraction (SCXRD) technique. The starting geometry was obtained from the X-ray structure determination was optimized using density functional theory (DFT/B3LYP) method with the 6-31G(d) and 6-31G(d, p) basis sets in ground state. From the optimized geometry of the molecule, geometric parameters (bond lengths and bond angles), vibrational assignments and chemical shifts of the title compound have been calculated theoretically and compared with the experimental data(SCXRD, FT-IR and NMR). Molecular Electrostatic Potential (MEP) map and Hirshfeld surfaces of the compound are obtained by using the optimized structures and Crystal Explorer software, respectively. [ABSTRACT FROM AUTHOR]

Three new complexes of barbituric acid (H 2 BA), a discrete molecular complex [Co(H 2 O) 4 (HBA) 2 ] ( 1 ), a barbiturate-bridged 1 D Co(II) coordination polymer [Co(H 2 O) 2 (μ 2 -HBA) 2 ] ( 2 ) and a 3 D Co(II) coordination polymer [Co(μ 3 -HBA) 2 ] ( 3 ) were synthesized and structurally characterized by X-ray powder diffraction. In 1 – 3 , the HBA − ions are coordinated to Co(II) only through O atoms with cobalt ions in an octahedral environment. In 1 , Co(II) is coordinated to four terminal water molecules and two HBA − ions. In compound 2 , Co(II) is bonded to two terminal water molecules and two μ 2 -HBA − ions forming polymer chains. In the 3 D -polymeric form 3, a bridging μ 3 -HBA ligand is connected through three oxygen atoms of the carbonyl groups with three Co(II) ions. All three structures are stabilized by intermolecular hydrogen bonds and π–π stacking interactions between HBA − ions. The IR spectroscopic data supports the results of the X-ray diffraction analysis. The thermal decomposition of the compounds comprises the dehydration steps and the organic ligand oxidation to form cobalt oxides. [ABSTRACT FROM AUTHOR]

The management of phenobarbital overdose using hemodialysis in a cat with suspected portosystemic shunt is described. An 8 year old British blue intact male cat was referred due to convulsions and stupor. The cat had a lifelong history of abnormal behavior and convulsions every approximately 6 months. The cat was tentatively diagnosed with portosystemic shunt based on high serum ammonia concentrations and abdominal ultrasound. The cat was hospitalized for further diagnosis and treatment, and was accidentally overdosed with phenobarbital at 25 mg/kg IM. Hemodialysis was performed in an attempt to enhance clearance of the drug. Phenobarbital levels decreased gradually during the treatment, however, there was no improvement in the neurological status of the cat and the owners elected euthanasia. To the best of the author's knowledge, this is the first report demonstrating the utility of hemodialysis in the management of phenobarbital overdose in small animals. [ABSTRACT FROM AUTHOR]

A continuous isoelectric electroencephalogram reflects an interruption of endogenously-generated activity in cortical networks and systematically results in a complete dissolution of conscious processes. This electro-cerebral inactivity occurs during various brain disorders, including hypothermia, drug intoxication, long-lasting anoxia and brain trauma. It can also be induced in a therapeutic context, following the administration of high doses of barbiturate-derived compounds, to interrupt a hyper-refractory status epilepticus. Although altered sensory responses can be occasionally observed on an isoelectric electroencephalogram, the electrical membrane properties and synaptic responses of individual neurons during this cerebral state remain largely unknown. The aim of the present study was to characterize the intracellular correlates of a barbiturate-induced isoelectric electroencephalogram and to analyse the sensory-evoked synaptic responses that can emerge from a brain deprived of spontaneous electrical activity. We first examined the sensory responsiveness from patients suffering from intractable status epilepticus and treated by administration of thiopental. Multimodal sensory responses could be evoked on the flat electroencephalogram, including visually-evoked potentials that were significantly amplified and delayed, with a high trial-to-trial reproducibility compared to awake healthy subjects. Using an analogous pharmacological procedure to induce prolonged electro-cerebral inactivity in the rat, we could describe its cortical and subcortical intracellular counterparts. Neocortical, hippocampal and thalamo-cortical neurons were all silent during the isoelectric state and displayed a flat membrane potential significantly hyperpolarized compared with spontaneously active control states. Nonetheless, all recorded neurons could fire action potentials in response to intracellularly injected depolarizing current pulses and their specific intrinsic electrophysiological features were preserved. Manipulations of the membrane potential and intracellular injection of chloride in neocortical neurons failed to reveal an augmented synaptic inhibition during the isoelectric condition. Consistent with the sensory responses recorded from comatose patients, large and highly reproducible somatosensory-evoked potentials could be generated on the inactive electrocorticogram in rats. Intracellular recordings revealed that the underlying neocortical pyramidal cells responded to sensory stimuli by complex synaptic potentials able to trigger action potentials. As in patients, sensory responses in the isoelectric state were delayed compared to control responses and exhibited an elevated reliability during repeated stimuli. Our findings demonstrate that during prolonged isoelectric brain state neurons and synaptic networks are dormant rather than excessively inhibited, conserving their intrinsic properties and their ability to integrate and propagate environmental stimuli. [ABSTRACT FROM AUTHOR]

Background: Seizure duration in electroconvulsive therapy (ECT) is positively related with patients' outcome. This study sought to investigate the impact of anesthetic management on seizure duration, and the impact of selected drugs (theophylline, remifentanil, S-ketamine) on seizure duration. Methods: Retrospective analysis of all patients undergoing ECT at our institution from January 2011 to April 2012 was performed based on electronic medical chart and review of existing quality improvement data. Patient data (N = 78), including gender, age, height, weight, and administered drugs, energy levels, and electroencephalic seizure duration were analyzed. Statistical analysis was performed using a generalized linear model. Results: A total of 78 patients (male = 39, female = 39, age 51 ± 12 years) were included. Average number of session was 10 ± 6 (1-30). In our patient population, theophylline administration was the only parameter, which significantly prolonged seizure duration, whereas S-ketamine, remifentanil, thiopental, age, sex, session or energy level had no significant effect. Conclusion: Theophylline can be a useful adjunct for patients with inadequate seizure duration. If there is a concomitant beneficial effect on patients' outcome needs to be investigated in further studies. [ABSTRACT FROM AUTHOR]

By combining the structural features of indole and barbituric acid, new hybrid molecules were designed and synthesized. Hydroxy(indolyl)barbiturates and bis(indolyl)barbiturates were selectively prepared via the reaction of indoles with alloxan derivatives in various conditions. Graphical Abstract: [ABSTRACT FROM AUTHOR]

Catatonia, a motor dysfunction of acute onset, expressed as mutism, negativism, posturing, staring, repetitive speech and others, was demarcated in 1874. Useful barbiturate treatments were described in 1930 and the benefits of inducing grand mal seizures (ECT today) was described in 1934. Many forms of the illness are now recognized: stupor, mutism, malignant catatonia, delirious mania, self injurious behavior in autism. The diagnosis is made when subjects exhibit two or more signs for 24 hours or longer. The diagnosis is verified by the acute relief afforded by a benzodiazepine test. Treatment is by increasing dosages of benzodiazepines, and when this fails, ECT is effective. Optimized treatment algorithms are described. Once thought to be a form of schizophrenia, this is no longer accepted in the latest DSM-5 classification where it is classified as "Catatonia secondary to a general medical condition". Catatonia is a recognizable, verifiable, and treatable behavior syndrome that is found in up to 10% of hospitalized psychiatric patients and unkown additional patients on medical and surgical services. [ABSTRACT FROM AUTHOR]

• The components of anesthesia muscle relaxation, unconsciousness, and immobility were examined by grip strength, righting reflex, and the loss of motor response in mice. • The change in each behavior induced by pentobarbital was roughly consistent with that in EEG and EMG power. • A low dose of the indirect GABA receptor agonist gabaculine alone did not affect these components, but it enhanced all components induced by pentobarbital. • This suggests that pentobarbital-induced components of anesthesia are mediated by GABAergic neurons. • Moreover, muscle relaxation or immobility induced by the agent might be partially involved in NMDA receptor antagonism or glycinergic neuron activation, respectively. Pentobarbital-induced anesthesia is believed to be mediated by enhancement of the inhibitory action of γ-aminobutyric acid (GABA)ergic neurons in the central nervous system. However, it is unclear whether all components of anesthesia induced by pentobarbital, such as muscle relaxation, unconsciousness, and immobility in response to noxious stimuli, are mediated only through GABAergic neurons. Thus, we examined whether the indirect GABA and glycine receptor agonists gabaculine and sarcosine, respectively, the neuronal nicotinic acetylcholine receptor antagonist mecamylamine, or the N-methyl- d -aspartate receptor channel blocker MK-801 could enhance pentobarbital-induced components of anesthesia. Muscle relaxation, unconsciousness, and immobility were evaluated by grip strength, the righting reflex, and loss of movement in response to nociceptive tail clamping, respectively, in mice. Pentobarbital reduced grip strength, impaired the righting reflex, and induced immobility in a dose-dependent manner. The change in each behavior induced by pentobarbital was roughly consistent with that in electroencephalographic power. A low dose of gabaculine, which significantly increased endogenous GABA levels in the central nervous system but had no effect on behaviors alone, potentiated muscle relaxation, unconsciousness, and immobility induced by low pentobarbital doses. A low dose of MK-801 augmented only the masked muscle-relaxing effects of pentobarbital among these components. Sarcosine enhanced only pentobarbital-induced immobility. Conversely, mecamylamine had no effect on any behavior. These findings suggest that each component of anesthesia induced by pentobarbital is mediated through GABAergic neurons and that pentobarbital-induced muscle relaxation and immobility may partially be associated with N-methyl- d -aspartate receptor antagonism and glycinergic neuron activation, respectively. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The purpose of this study was to identify the clinical aspects leading to overdose of multiple psychotropic drugs, in order to determine areas which need attention in the proper treatment of overdose patients. METHODS: Patients who were treated for overdose of psychotropic drugs at our emergency and critical center over two years were targeted. The clinical data was gathered from the medical records and database of all patients, including age, gender, vital signs, and laboratory data, drugs, and medical complications during hospital stay. In addition primary patient care at the emergency department was examined. RESULTS: Among the 277 patients treated during this study period, 255 (74.0%) used two or more types of psychotropic drugs. Risk factors associated with endotracheal intubation and aspiration pneumonitis included the use of antipsychotics and/or barbiturates as types of overdose drugs. The mean number of days in the ICU was 3.4 days. Seventy-four patients (26.7%) stayed 4 days or more in the ICU of which 16 patients (5.8%) still had suicidal thoughts. A significantly higher incidence of extended ICU stay or endotracheal intubation and aspiration pneumonitis was observed in the group who overdosed on more than 50 or 60 tablets of psychotropic drugs, respectively. CONCLUSIONS: Patients who ingested an overdose of more than 60 tablets of psychotropic drugs should be considered a high-risk group requiring intensive care with extended ICU stay. In case of including antipsychotics and/or barbiturates, the patient should be observed carefully due to a higher risk of medical complications. [ABSTRACT FROM AUTHOR]

Date-rape drugs have the potential to be used in drug-facilitated sexual assault, organ theft and property theft. Since they are colorless, tasteless and odorless, victims can drink without noticing, when added to the beverages. These drugs must be detected in time, before they are cleared up from the biofluids. A simultaneous extraction and determination method in urine for GHB, ketamine, norketamine, phenobarbital, thiopental, zolpidem, zopiclone and phenytoin (an anticonvulsant and antiepileptic drug) with LC–MS/MS was developed for the first time with analytically acceptable recoveries and validated. A 4 steps liquid-liquid extraction was applied, using only 1.000 mL urine. A new age commercial C 18 poroshell column with high column efficiency was used for LC–MS/MS analysis with a fast isocratic elution as 5.5 min. A new MS transition were introduced for barbital. 222.7 > 179.8 with the effect of acetonitrile. Recoveries (%) were between 80.98–99.27 for all analytes, except for GHB which was 71.46. LOD and LOQ values were found in the ranges of 0.59–49.50 and 9.20–80.80 ngmL −1 for all the analytes (except for GHB:3.44 and 6.00 μgmL −1 ). HorRat values calculated (between 0.25–1.21), revealed that the inter-day and interanalist precisions (RSD% ≤ 14.54%) acceptable. The simultaneous extraction and determination of these 8 analytes in urine is challenging because of the difficulty arising from the different chemical properties of some. Since the procedure can extract drugs from a wide range of polarity and p K a , it increases the window of detection. Group representatives from barbiturates, z-drugs, ketamine, phenytoin and polar acidic drugs (GHB) have been successfully analyzed in this study with low detection limits. The method is important from the point of determining the combined or single use of these drugs in crimes and finding out the reasons of deaths related to these drugs. [ABSTRACT FROM AUTHOR]

Background: Butalbital is a small molecule (approximately 220 Da), with 26% protein binding, a 0.8 L/kg volume of distribution, and is eliminated nearly 80% unchanged in the urine. Although hemodialysis has been used to treat overdoses of other barbiturates, the extracorporeal clearance of butalbital is unknown. The objective of this case is to describe the use of extracorporeal therapy to augment elimination of butalbital after an overdose of aspirin 325 mg-butalbital 50 mg-caffeine 40 mg with codeine 30 mg (Fiorinal with Codeine). Methods: This is a case report of a single patient. Results: A 67-year-old female was admitted to the medical intensive care unit approximately 3 h after ingestion of 40 tablets of Fiorinal with Codeine. Her presentation was notable for a decline in mental status, preserved renal function and a relatively low peak salicylate concentration at 46.4 mg/dL (3.4 mmol/L). Approximately 8 h after ingestion of 2000 mg of butalbital, our patient’s serum concentration was 26.9 mg/L (normal <10 mg/L). At the end of a four-hour hemodialysis session, the total body elimination of butalbital was approximately 60% which corresponded to an intradialytic clearance of 233-300 mL/min. Conclusions: The extracorporeal clearance of butalbital observed in this case demonstrates the utility of dialysis to augment drug elimination in a Fiorinal with Codeine overdose. [ABSTRACT FROM AUTHOR]

Activation of taste buds triggers the release of several neurotransmitters, including ATP and serotonin (5-hydroxytryptamine; 5-HT). Type III taste cells release 5-HT directly in response to acidic (sour) stimuli and indirectly in response to bitter and sweet tasting stimuli. Although ATP is necessary for activation of nerve fibers for all taste stimuli, the role of 5-HT is unclear. We investigated whether gustatory afferents express functional 5-HT3 receptors and, if so, whether these receptors play a role in transmission of taste information from taste buds to nerves. In mice expressing GFP under the control of the 5-HT3A promoter, a subset of cells in the geniculate ganglion and nerve fibers in taste buds are GFP-positive. RT-PCR and in situ hybridization confirmed the presence of 5-HT3A mRNA in the geniculate ganglion. Functional studies show that only those geniculate ganglion cells expressing 5-HT3A-driven GFP respond to 10µM5-HT and this response is blocked by 1µM ondansetron, a 5-HT3 antagonist, and mimicked by application of 10µM m-chlorophenylbiguanide, a 5-HT3 agonist. Pharmacological blockade of 5-HT3 receptors in vivo or genetic deletion of the 5-HT3 receptors reduces taste nerve responses to acids and other taste stimuli compared with controls, but only when urethane was used as the anesthetic. We find that anesthetic levels of pentobarbital reduce taste nerve responses apparently by blocking the 5-HT3 receptors. Our results suggest that 5-HT released from type III cells activates gustatory nerve fibers via 5-HT3 receptors, accounting for a significant proportion of the neural taste response. [ABSTRACT FROM AUTHOR]

Background: During the last decade nanoparticles have gained attention as promising drug delivery agents that can transport through the blood brain barrier. Recently, several studies have demonstrated that specifically targeted nanoparticles which carry a large payload of therapeutic agents can effectively enhance therapeutic agent delivery to the brain. However, it is difficult to draw definite design principles across these studies, owing to the differences in material, size, shape and targeting agents of the nanoparticles. Therefore, the main objective of this study is to develop general design principles that link the size of the nanoparticle with the probability to cross the blood brain barrier. Specifically, we investigate the effect of the nanoparticle size on the probability of barbiturate coated GNPs to cross the blood brain barrier by using bEnd.3 brain endothelial cells as an in vitro blood brain barrier model. Results: The results show that GNPs of size 70 nm are optimal for the maximum amount of gold within the brain cells, and that 20 nm GNPs are the optimal size for maximum free surface area. Conclusions: These findings can help understand the effect of particle size on the ability to cross the blood brain barrier through the endothelial cell model, and design nanoparticles for brain imaging/therapy contrast agents. [ABSTRACT FROM AUTHOR]

Barbiturates and benzodiazepines are GABA A -receptor agonists and potent antiseizure medications. We reported that exposure of neonatal macaques to combination of phenobarbital and midazolam (Pb/M) for 24 h, at clinically relevant doses and plasma levels, causes widespread apoptosis affecting neurons and oligodendrocytes. Notably, the extent of injury was markedly more severe compared to shorter (8 h) exposure to these drugs. We also reported that, in the infant macaque, mild hypothermia ameliorates the apoptosis response to the anesthetic sevoflurane. These findings prompted us explore whether mild hypothermia might protect infant nonhuman primates from neuro- and gliotoxicity of Pb/M. Since human infants with seizures may receive combinations of benzodiazepines and barbiturates for days, we opted for 24 h treatment with Pb/M. Neonatal rhesus monkeys received phenobarbital intravenously, followed by midazolam infusion over 24 h under normothermia (T > 36.5 °C-37.5 °C; n = 4) or mild hypothermia (T = 35 °C-36.5 °C; n = 5). Medication doses and blood levels measured were comparable to those in human infants. Animals were euthanized at 36 h and brains examined immunohistochemically and stereologically. Treatment was well tolerated. Extensive degeneration of neurons and oligodendrocytes was seen at 36 h in both groups within neocortex, basal ganglia, hippocampus and brainstem. Mild hypothermia over 36 h (maintained until terminal perfusion) conferred no protection against the neurotoxic and gliotoxic effects of Pb/M. This is in marked contrast to our previous findings that mild hypothermia is protective in the context of a 5 h-long exposure to sevoflurane in infant macaques. These findings demonstrate that brain injury caused by prolonged exposure to Pb/M in the neonatal primate cannot be ameliorated by mild hypothermia. • Administration of phenobarbital and midazolam over 24 h triggers profound apoptosis of neurons in the neonatal primate brain; • Neurotoxicity occurs at plasma concentrations relevant to the treatment of human infants; • Mild hypothermia did not reduce neurotoxicity of prolonged exposure to phenobarbital/midazolam; • Antiseizure medications given to neonates during whole-body cooling likely maintain their full neurotoxic potential. [ABSTRACT FROM AUTHOR]

Patron saints act as facilitators between God and humans. Humans appeal to patron saints for support in devastating, often futile situations in life. Patron saints may intercede for trade and professional guilds, every so often they hold a protective hand over objects. Saint Barbara is venerated as the patron saint of surgeons. In anesthesia she also oversees barbiturates, protects anesthetized patients, anesthetists and anesthesia nursing personnel. Within the Anglo-American language area Saint René is venerated by anesthetists and anesthesia nursing personnel. During anesthesia or critical care treatment patient safety and welfare are entirely in the hands of anesthetists and intensivists. Especially in the borderland of critical illness and imminent death, it may be reassuring for religiously or spiritually orientated physicians and nurses that they can turn to 'their' patron saints to intercede so that upcoming anesthetic procedures or intensive care interventions will meet with success. Hereby, the heavy burden of responsibility may be borne more easily and equanimously. [ABSTRACT FROM AUTHOR]

Objectives: Decompressive craniectomy and barbiturate coma are often used as second-tier strategies when intracranial hypertension following severe traumatic brain injury is refractory to firstline treatments. Uncertainty surrounds the decision to choose either treatment option. We investigated which strategy is more economically attractive in this context. Design: We performed a cost-utility analysis. A Markov Monte Carlo microsimulation model with a life-long time horizon was created to compare quality-adjusted survival and cost of the two treatment strategies, from the perspective of healthcare payer. Model parameters were estimated from the literature. Two-dimensional simulation was used to incorporate parameter uncertainty into the model. Value of information analysis was conducted to identify major drivers of decision uncertainty and focus future research. Setting: Trauma centers in the United States. Subjects: Base case was a population of patients (mean age = 25 yr) who developed refractory intracranial hypertension following traumatic brain injury. Interventions: We compared two treatment strategies: decompressive craniectomy and barbiturate coma. Measurements and Main Results: Decompressive craniectomy was associated with an average gain of 1.5 quality-adjusted life years relative to barbiturate coma, with an incremental costeffectiveness ratio of $9,565/quality-adjusted life year gained. Decompressive craniectomy resulted in a greater quality-adjusted life expectancy 86% of the time and was more cost-effective than barbiturate coma in 78% of cases if our willingness-to-pay threshold is $50,000/quality-adjusted life year and 82% of cases at a threshold of $100,000/quality-adjusted life year. At older age, decompressive craniectomy continued to increase survival but at higher cost (incremental cost-effectiveness ratio = $197,906/ quality-adjusted life year at mean age = 85 yr). Conclusions: Based on available evidence, decompressive craniectomy for the treatment of refractory intracranial hypertension following traumatic brain injury provides better value in terms of costs and health gains than barbiturate coma. However, decompressive craniectomy might be less economically attractive for older patients. Further research, particularly on natural history of severe traumatic brain injury patients, is needed to make more informed treatment decisions. [ABSTRACT FROM AUTHOR]

Introduction: Posterior reversible encephalopathy syndrome (PRES) is a largely reversible disease with long-term favorable outcome. A minority of patients, however, may develop progressive cerebral edema and ischemia resulting in severe disability or death. We report a case of severe intracranial hypertension associated with PRES that was successfully treated according to intracranial pressure (ICP)- and cerebral perfusion pressure (CPP)-driven therapy. Methods: Case report. Results: A 42-year-old woman underwent bilateral lung transplantation for severe bronchiectasis. Her immunosuppressive regimen consisted of azathioprine, prednisone, and tacrolimus. She acutely developed an aggressive form of PRES that rapidly resulted in severe refractory intracranial hypertension despite discontinuation of potentially causative medications and adequate supportive therapy. Accordingly, second-tier therapies, including barbiturate infusion, were instituted and immunosuppression was switched to anti-thymocyte globulin followed by mycophenolate mofetil. Within 10 h of barbiturate administration, ICP dropped to 20 mmHg. Thiopental was administered for two days and then rapidly tapered because of severe urosepsis. Six months after discharge from the intensive care unit the patient returned to near-normal life, her only complaint being short-term amnesia. Conclusions: The decision to undertake ICP monitoring in medical conditions in which no clear recommendations exist greatly relies on physicians’ judgment. This case suggests that ICP monitoring may be considered in the setting of acute PRES among selected patients, when severe intracranial hypertension is suspected, provided that a multidisciplinary team of neurocritical care specialists is readily available. [ABSTRACT FROM AUTHOR]

A new type of barbiturate (a pyrimidine derivative) has been prepared through one pot synthesis from the ethanolic solution of 1-chloro-2,4,6-trinitrobenzene, barbituric acid and 2-methylpyridine. The mechanism of the formation of the reported barbiturate involves an intermediate sigma complex formation and proton abstraction reactions. The structure of the title barbiturate has been identified from UV-Vis, FT-IR, H NMR, C NMR and elemental analysis data. Single crystal XRD studies further confirm the formation of the reported barbiturate. The anticonvulsant activity of the synthesized barbiturate has been tested by Maximal Electro Shock method on albino rats. The title barbiturate showed notable anticonvulsant activity even at low concentration (dose, 25 mg/kg). It also induces hypnosis in albino mice (dose, 100 mg/kg) for a duration of 47 min. Acute toxicity studies on albino mice indicate that LD value is >1,500 mg/kg and the animals do not show any behavioral changes. Graphical Abstract: Figure 1 ORTEP view of 2-Methylpyridinium 2,6-dioxo-5-(2,4,6-trinitrophenyl)-1,2,3,6-tetrahydropyrimidin-4-olate. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Objective To assess the influence of switching acute treatment on headache-related disability in a population sample of individuals with migraine using acute triptan therapy. Background Acute treatments for migraine are often modified in clinical practice. The effect of changes in treatment from one triptan to another or from a triptan to another medication class has rarely been studied. Methods Patterns of acute treatment for migraine were monitored from 1 year to the next in the American Migraine Prevalence and Prevention (AMPP) Study for the following couplets (2005-2006, 2006-2007, 2007-2008, and 2008-2009). Changes in medication regimens were classified as follows: (1) switch within the triptan class; (2) switch to combination analgesics containing opioids or barbiturates; (3) switch to non-steroidal anti-inflammatory drug ( NSAID) agents; (4) maintaining current therapy (consistent use, 'control'). We assessed change in migraine disability assessment scale score from the first to the second year of a couplet contrasting those with consistent use with those who changed acute treatment. Each individual contributed only 1 couplet to the analysis. Persons who added an acute treatment are considered in a separate manuscript. We modeled change in migraine disability assessment scale score as a function of change in medication regimen with consistent users as the control group. Results We identified 81 individuals who switched to another triptan, with a referent of 619 who remained consistent, 31 cases who switched to an opioid or barbiturate with a referent of 666 who remained consistent, and 20 cases who switched to an NSAID with a referent of 667 cases who remained consistent. In cell-mean coded analyses of covariance (ANCOVA), switching from one triptan to another or switching from a triptan to an opioid/barbiturate was never associated with significant improvements in headache-related disability compared with consistent treatment. Switching from a triptan to an NSAID was associated with significant increases in headache-related disability among those with high-frequency episodic/chronic migraine (HFEM/CM) compared with those with low-frequency episodic migraine (LFEM) (interaction = 34.81, 95% confidence interval 10.61 to 59.00). The same was true comparing high-frequency episodic/chronic migraine with those with moderate-frequency episodic migraine (interaction = 48.73, 95% confidence interval 2.63 to 94.83). Conclusions In this observational study, switching triptan regimens does not appear to be associated with improvements in headache-related disability and in some cases is associated with increased headache-related disability. [ABSTRACT FROM AUTHOR]

Zoo animals, including tigers, have been reported to suffer from barbiturate intoxication, with pentabarbitone being most commonly recorded. Clinical signs range from mild ataxia to general anaesthesia with recovery over hours to days with several factors affecting hepatic barbiturate metabolism and tissue partitioning. Botulism is an often fatal intoxication in man, animals, birds and certain fish. The occurrence in carnivores is uncommon to rare, with only 2 reports found of botulism in felids. This report relates to 3 adult captive cohabiting tigers that simultaneously developed signs of abdominal discomfort, progressive ataxia, recumbency and comatose sleep resembling stage 2 anaesthesia, alternating with periods of distracted wakefulness and ataxic movements. These signs occurred 4 days after being fed the carcass of a horse that had ostensibly died of colic and not been euthanased. The male tiger that was the dominant animal in the feeding hierarchy was worst affected and had to be given intravenous fluids. The female that was lowest in hierarchy was unaffected. After 48-72 hours of treatment at the Onderstepoort Veterinary Academic Hospital the females could eat and made an uneventful recovery. The male tiger showed partial recovery but died during the night a few hours after drinking water on his return to the owner. Necropsy revealed severe oesophageal dilation and impaction with decaying grass; some of this material and water were present in the pharynx and trachea, and had been aspirated causing acute widespread bronchopneumonia. Colon content tested negative for common pesticides but, together with liver, tested positive for barbiturate. Serum taken on the day of admission had tested negative for barbiturate and the residual serum from the 3 animals later tested negative for botulinum toxin. Colon and oesophageal content from the male at necropsy were positive for Clostridium botulinum toxin type C by the mouse bioassay neutralisation test, confirming that this male had had concomitant barbiturate toxicity and botulism, and had succumbed to aspiration bronchopneumonia secondary to pharyngeal, laryngeal and oesophageal paralysis and oesophageal impaction. [ABSTRACT FROM AUTHOR]

Background: Barbiturate coma therapy is a useful method to control increased intracranial pressure (ICP) in patients with severe brain damage if standard measures have failed to lower ICP. Pentobarbital (not available in Germany) and thiopental (in Germany only approved for induction of anesthesia) have frequently been used in patients with intracranial hypertension and the effects and side-effects are well-described. However, little is known about the effect of methohexital (the only barbiturate in Germany approved for maintaining anesthesia) in lowering increased ICP. Therefore, the effect of methohexital on ICP was studied in patients where standard measures had failed to control intracranial hypertension. Method: A retrospective observational study was carried out with the inclusion criteria of patient age ≥18 years and methohexital therapy for 12 h or more with ICP monitoring in place. Methohexital was administered following a standardized algorithm to patients for whom standard measures, such as deep anesthesia, normoventilation, cerebral perfusion pressure (CPP) >65 mmHg, osmotherapy, neurosurgical evacuation of mass lesions, had failed to lower ICP. Methohexital was used if the ICP had risen above 20-25 mmHg for more the 20-30 min and otherwise manageable causes for the ICP increase had been ruled out. Methohexital was given continuously in addition to standard analgesia and sedation in doses of 2-4-6 mg/kg body weight (BW), depending on the ICP lowering effect. The records of the patient data management system from the years 2008/2009 were used to compare the ICP and CPP before and during methohexital administration. For statistical analyses Student's t-test was applied for measured values and the χ-test was applied for percentage values whereby p<0.05 was defined as being statistically significant. Results: During the study period 36 patients required methohexital therapy and 30 fulfilled the inclusion criteria. In 26 out of 30 patients the data were complete and these 26 patients were included in the data analyses. Of the patients 6 (23%) died due to elevated intracranial hypertension and 20 patients (77%) survived. In all patients methohexital lowered the ICP from 25.2 mmHg (standard deviation, SD ±4.3 mmHg) to 19.8 mmHg (SD ±12.5 mmHg) within the first 24 h, this result closely failed to reach a level of significance. In the 20 survivors methohexital lowered the ICP from 25.88 mmHg (SD ±4.8 mmHg) to 14.25 mmHg (SD ±6.9 mmHg) within the first 24 h, which is statistically highly significant. In non-survivors the ICP had risen from 24 mmHg (SD ±2.6 mmHg) to 32 mmHg (SD ±16.3 mmHg) within the first 24 h despite all efforts. Due to the CPP driven volume and vasopressor therapy no significant changes in the CPP during methohexital administration were observed. No significant changes in brain temperature (as possible cause for the decrease of the ICP) were observed. Non-survivors received significantly more methohexital due to increased ICP and required significantly more vasopressor therapy to maintain a sufficient CPP. Conclusions: Methohexital showed a clear trend for decreasing ICP in patients with intracranial hypertension refractory to standard therapeutic measures. In survivors the effect was highly significant. Patients not responding to methohexital therapy seemed to have an unfavorable outcome. [ABSTRACT FROM AUTHOR]

Abstract: Matrix metalloproteinases are implicated in a wide range of pathophysiological processes and potent selective inhibitors for these enzymes continue to be eagerly sought. 5,5-Disubstituted barbiturates hold promise as inhibitor types being stable in vivo and relatively selective for the gelatinases (MMP-2 and MMP-9). In this paper we describe the synthesis of 5-piperazine and -homopiperazine substituted barbiturates. The activity of these compounds as gelatinase inhibitors was evaluated using supernatants from 12-O-tetradecanoylphorbol-13-acetate (PMA)-stimulated HT-1080 cells as well as using recombinant human MMPs. N-Acyl homopiperazine compounds were found to be potent inhibitors of the gelatinases (range in nM) and generally more potent than the corresponding piperazine analogues. The panel of N-acyl homopiperazines was enlarged in order to exploit differences between the gelatinases at the S2′ site in order to design MMP-2- or MMP-9-selective inhibitors. Compounds in this group exhibited single digit nano-molar potency and some selectivity between the two enzymes. Representative potent compounds were effective inhibitors of cancer cell migration. [Copyright &y& Elsevier]

The 1960s were a time of social upheaval, wars, vibrant creativity and missed opportunity. Mainstream culture and a psychedelic drug-using counterculture shared a belief in "better living through cheniistry' but they disagreed about the particular chemistry. The Vietnam war and the cold war with the Soviet Union, racial discrimination, and gender roles fueled political activism. "Yes we can" was not a slogan of the time but political activists clearly believed they could change the beliefs, attitudes and behavior of mainstream culture; and they did. Hippie counterculture on the other hand was largely alienated and strove primarily to develop a separate culture with its own mores, beliefs and lifestyles. Although there was some overlap between hippies and activists, hippies didn't generally have the same sense of political empowerment. Hippie enclaves developed in New York; Boston; Seattle; Austin, Texas and elsewhere; but the epicenter was arguably the Haight-Asbury District of San Francisco. Psychedelic drugs, marijuana and the Vietnam war were among many wedge issues. This paper conjures up a personal history related to the evolution of the hippie counterculture, changing drug use patterns in the Haight-Ashbury, and the origins of a technique of withdrawing patients from barbiturates and other sedative-hypnotics using phenobarbital variously known as the "Phenobarbital Withdrawal Protocol, or the "Smith and Wesson Protocol." [ABSTRACT FROM AUTHOR]

Context. Despite a worldwide decline in barbiturate use, cases of acute poisoning with severe toxicity are still noted, particularly in developing countries. Severe poisonings often require prolonged admission to an intensive care unit, so enhanced elimination might be useful to hasten recovery. Information regarding the efficacy of these techniques for individual barbiturates is not available in standard textbooks. Objective. To determine the evidence supporting the effect of enhanced elimination and its role in the management of acute barbiturate poisoning. Methods. A systematic review was conducted using broad search criteria in three databases. All potentially relevant articles were obtained, and reference lists were manually reviewed. Ninety-four publications fulfilling inclusion criteria were located. Studies were classified as controlled or uncontrolled, and clinical and pharmacokinetic end points were manually extracted. If not directly stated, standard pharmacokinetic methods were used to calculate the clearance and efficiency of enhanced elimination techniques for each barbiturate and tabulated for direct comparison. Prospective controlled clinical trials. Two of the 94 publications were prospective controlled studies (only one stated that allocation was via blinded randomisation), and both assessed the effect of multiple-dose activated charcoal for acute phenobarbital poisoning. These studies demonstrated enhanced elimination with a decrease in elimination of half-life from approximately 80 to 40 h, but only one study reported clinical benefits. Uncontrolled series and single case reports. Sufficient data to determine the clearance due to enhanced elimination were available in only 52 of these papers. Barbiturate clearances by enhanced elimination varied markedly among studies. While extracorporeal modalities appeared to increase the direct clearance of many barbiturates, there was insufficient information to confirm a clinical benefit. Conclusions. There is limited evidence to support the use of enhanced elimination in the treatment of poisoning with most barbiturates. There is no role for urine alkalinisation, while multiple-dose activated charcoal may be useful for most phenobarbital and possibly primidone poisonings. Extracorporeal techniques appear to enhance elimination, but the clinical benefits, relative to the potential complications and cost, are poorly defined. Extracorporeal techniques such as haemodialysis and haemoperfusion can be considered for patients with life-threatening barbiturate toxicity such as refractory hypotension. [ABSTRACT FROM AUTHOR]

Novel oxospirobicyclic γ-butenolides containing barbiturate moiety have been synthesised by the Michael-addition of primary amines to dialkyl acetylenedicarboxylates followed by aldol-like reaction with alloxan derivatives, and then γ-lactonisation. Subsequent 1,4-addition of water and elimination of the amine group completes the sequence. This tandem reaction sequence represents a rapid and unprecedented route to the described biologically interesting molecules. [ABSTRACT FROM AUTHOR]

Abstract: A three-component domino reaction approach between a primary amine, a dialkyl acetylenedicarboxylate, and 1,3-dimethylalloxan that affords novel oxaspirobicyclic γ-butenolidobarbiturate derivatives is reported. The reaction sequence consists of an initial Michael-addition of primary amines to dialkyl acetylenedicarboxylates, followed by aldol-like reaction with 1,3-dimethylalloxan, and then γ-lactonization to afford the products. This cascade reaction sequence represents a rapid and unprecedented route to the described biologically interesting molecules. [Copyright &y& Elsevier]

Abstract: Plasticity at corticostriatal synapses is thought to underlie both normal and aberrant forms of reinforcement-driven learning. Studies in brain slices have found bidirectional, spike-timing dependent plasticity in striatum; however it is not known whether similar rules govern corticostriatal plasticity in awake behaving animals. To assess whether behavioral state is a key regulator of plasticity in this pathway, we examined the effects of 5 Hz cortical stimulation trains on evoked striatal field potentials, in either anesthetized or awake, unrestrained rats. Consistent with prior studies we observed long-term potentiation in intact, barbiturate-anesthetized animals. However, when an identical stimulation pattern was applied to the same animals while awake, long-term depression was observed instead. Our results demonstrate that the rules governing corticostriatal plasticity depend critically on behavioral state, and suggest that the dynamic context of cortical-basal ganglia loops must be considered while investigating synaptic mechanisms underlying reinforcement learning and neurological disorders. [Copyright &y& Elsevier]

Abstract: Hypoxia-inducible factor 1 (HIF-1) is a master transcription factor of hypoxia-induced gene expression. Anesthetics and perioperative drugs have been reported to affect HIF-1 activity. However, the effect of barbiturates on HIF-1 activity has not been reported. In this study, we investigated the effect of thiopental and thiamylal on HIF-1 activity using the neuronal SH-SY5Y cells, the non-neuronal HEK293 cells, and the macrophage-differentiated THP-1 cells. Cells were exposed to 20% or 1% O2 conditions with or without thiopental or thiamylal treatment. The cell lysate were subjected to Western blot analysis using anti-HIF-1α and -HIF-1β antibodies. HIF-1-dependent gene expression was investigated by semi-quantitative real-time RT-PCR and luciferase assay. Hydroxylation of HIF-1α protein was evaluated by in vitro pulldown assay using recombinant protein. Both thiopental and thiamylal reversibly suppressed hypoxia-induced HIF-1 activation in the neuronal and the non-neuronal cells in a dose-dependent manner. Moreover, the barbiturates inhibited lipopolysaccharide-induced HIF-1α expression in THP-1 cells. The HIF-1-downstream gene expression was also inhibited by the barbiturates. HIFα-hydroxylases activity and HIF-1α stability were not affected but the HIF-1α protein neosynthesis was inhibited by the barbiturates. Our experimental results indicate that barbiturates inhibit induced HIF-1 activation and downstream genes expression. [Copyright &y& Elsevier]

The suprachiasmatic nucleus (SCN) controls the timing of the preovulatory luteinizing hormone (LH) surge in laboratory rodents. Barbiturate administrator during a critical period on proestrus delays the surge and prolongs the estrous cycle I day. Because a nonphotic timing signal (zeitgeber) during the critical period that phase advances activity rhythms, can also induce the latter effect, we hypothesized that barbiturates delay the LH surge by phase-advancing its circadian timing signal beyond the critical period. In experiment 1, locomotor rhythms and estrous cycles were monitored in hamsters for 2-3 wk preinjection and postinjection of vehicle or phenobarbital and after transfer to darkness at zeitgeber time (ZT) 6 on proestrus. Phenobarbital delayed estrous cycles in five of seven hamsters, which exhibited phase shifts that averaged twofold greater than those exhibited by vehicle controls or phenobarbital-injected hamsters with normal cycles. Experiment 2 used a similar protocol, but injections were at ZT 5, and blood samples for LH determination were collected from 1200 to 1800 on proestrus and the next day via jugular cannulae inserted the day before proestrus. Phenobarbital delayed the LH surge I day in all six hamsters, but it occurred at an earlier circadian time, supporting the above hypothesis. Experiment 3 investigated whether phenobarbital, like other nonphotic zeitgebers, suppresses SCN Period1 and Period2 transcription. Two hours postinjection, phenobarbital decreased SCN expression of only Period] mRNA, as determined by in situ hybridization. These results suggest that phenobarbital advances the SCN pacemaker, governing activity rhythms and hormone release in part by decreasing its Period] gene expression. [ABSTRACT FROM AUTHOR]

• Neurogenic inflammation originates from local release of inflammatory mediators, such as substance P (SP), by primary afferent neurons after noxious stimuli like surgery. • Cultured dorsal root ganglion (DRG) neurons have both central and peripheral branches. • Pentobarbital significantly inhibited capsaicin-induced, but not high K+-induced, SP release from rat DRG cells. • However, a high concentration of ketamine did not block SP release. • Thus, the inhibitory effects of pentobarbital on SP release from peripheral terminals may protect against neurogenic inflammation after surgery. The inflammatory response related to surgery is considered surgical inflammation. Most anesthetic agents directly or indirectly suppress the immune response. However, the intravenous anesthetics pentobarbital and ketamine were reported to inhibit the lipopolysaccharide-induced inflammatory response such as cytokines formation. Neurogenic inflammation is inflammation originating from the local release of inflammatory mediators, such as substance P (SP), by primary afferent neurons after noxious stimuli like surgery. Thus, in this study, we examined whether pentobarbital and ketamine suppress SP release from cultured dorsal root ganglion (DRG) neurons. DRG cells were dissected from male Wistar rats. Released SP was measured by radioimmunoassay. We demonstrated that higher concentrations of pentobarbital (100–1,000 μM) significantly inhibited capsaicin (100 nM)-induced, but not high K+ (50 mM)-induced, SP release from DRG cells, although a high concentration of ketamine (1 mM) did not. This study revealed that pentobarbital functions between the activation of vanilloid receptor subtype 1 (TRPV1) receptors, to which capsaicin selectively binds, and the opening of voltage-operated Ca2+ channels (VOCC) in the nerve endings. Therefore, the anti-inflammatory action of pentobarbital is mediated through different mechanisms than those of ketamine. Thus, the inhibitory effect of pentobarbital on SP release from peripheral terminals may protect against neurogenic inflammation after surgery. [ABSTRACT FROM AUTHOR]

Abstract: A water-accelerated multicomponent synthesis of organic target molecules has been used as a key method for the preparation of novel barbiturate derivatives. The three-component condensation reactions of primary amines with alkyl propiolates in the presence of alloxan derivatives in water are developed as efficient and clean green synthetic procedures for the high-yielding preparation of alkyl 2-(5-hydroxy-2,4,6-trioxohexahydro-5-pyrimidinyl)-3-(alkyl or arylamino)-2-propenoates. The above synthetic protocol provides rapid access to novel and diversely substituted barbiturate derivatives. [Copyright &y& Elsevier]

Abstract: The aim of this study was to establish strategies for prophylaxis against status epilepticus (SE) associated with high fever and for management of ongoing SE in children with severe myoclonic epilepsy in infancy (SMEI). Methods: The investigation was performed retrospectively using a questionnaire, asking about medications, which was distributed to epilepsy specialists throughout Japan. All respondents were members of the Japan Epilepsy Society (JES) and/or the Japanese Society of Child Neurology (JSCN). Data from 109 SMEI patients (51 males and 58 females), 1–37 (M±SD, 10.7±6.53) years old, were used for this study. Of these 109 patients, 10 were excluded because they had not experienced SE, such that data from 99 patients were analyzed. Results: Among the anti-epileptic drugs (AEDs) used daily, excellent efficacy against SE evolution was obtained with the following: potassium bromide (KBr) (41.7%), zonisamide (ZNS) (13.5%), clobazam (CLB) (10.0%), valproate (VPA) (8.0%), phenobarbital (PB) (6.7%), and phenytoin (PHT) (2.6%). Excellent efficacy was not obtained with either clonazepam (CZP) or carbamazepine (CBZ). The diazepam (DZP) suppository was the most frequently given drug for prophylaxis against SE triggered by fever, but only 2 (2.4%) cases showed excellent results. Excellent efficacy in terminating ongoing SE was obtained with the following medications; intravenous barbiturates (75–100%), intravenous midazolam (MDZ) (68.8%), intravenous DZP (54.3%), intravenous lidocaine (Lid) (21.4%), and intravenous PHT (15.4%). Conclusions: Daily KBr was most efficacious for controlling seizures in SMEI patients. Early use of intravenous barbiturates is the most effective strategy in stopping SE in a subset of patients. Reliable efficacy in SE was not obtained with prophylactic DZP, intravenous benzodiazepines (BZPs), PHT and Lid. [Copyright &y& Elsevier]

Abstract: Mice with point-mutated α2 GABAA receptor subunits (rendering them diazepam insensitive) are resistant to the anxiolytic-like effects of benzodiazepines (BZs) in the conditioned emotional response (CER) test, but show normal anxiolytic effects of a barbiturate. We investigated the consequence of deleting the α2-subunit on acquisition of the CER with increasing intensity of footshock, and on the anxiolytic efficacy of a benzodiazepine, diazepam, and a barbiturate, pentobarbital. α2 knockout (KO) and wildtype (WT) mice were trained in a conditioned emotional response (CER) task, in which lever pressing for food on a variable interval (VI) schedule was suppressed during the presentation of a compound light/tone conditioned stimulus (CS+) that predicted footshock. The ability of diazepam and of pentobarbital to reduce suppression during the CS+ was interpreted as an anxiolytic response. There were no differences between the genotypes in shock sensitivity, as assessed by their flinch responses to increasing levels of shock. However, α2 KO mice showed a greater suppression of lever pressing than WT littermates in the presence of a compound cue signalling footshock. Diazepam (0, 0.5, 1 and 2 mg/kg) induced a dose-dependent anxiolytic-like effect in WT mice but no such effect was seen in KO mice. Similarly, although pentobarbital (20 mg/kg) reduced the ability of the CS+ to reduce lever pressing rates in WT mice, this effect was not seen in the KO. These findings suggest that α2-containing GABAA receptors mediate the anxiolytic effects of barbiturates, as well as benzodiazepines, and that they may be involved in neuronal circuits underlying conditioned anxiety. [Copyright &y& Elsevier]

Abstract: Indolenine and benzindolenine heptamethinecyanine dyes having barbiturate at meso position were synthesized by the substitution of corresponding meso chloro substituted dyes with barbituric acid, and their absorption spectra and crystal structures were investigated. All barbiturate dyes had absorption near 800nm and showed hypsochromic shift from the corresponding chloro dyes. Both barbiturate and chloro benzindolenine dyes showed bathochromic shift from the corresponding indolenine dyes. The crystal structures of barbiturate dyes indicated that barbiturate ring is sterically hindered by indolenine ring and cannot form adequate π-conjugation with cyanine main chromophore. [Copyright &y& Elsevier]