Barbiturate-sulfonate hybrids as potent cholinesterase inhibitors: design, synthesis and molecular modeling studies.

Aim: Design and synthesis of a series of 5-benzylidene(thio)barbiturates 3a-r. Methodology: Evaluation of the inhibitory activity of the new chemical entities on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using Donepezil as the standard reference. Results & Conclusion: Compound 3r emerged as the most potent AChE inhibitor (IC50 = 9.12 µM), while compound 3q exhibited the highest inhibitory activity against BChE (IC50 = 19.43 µM). Toxicological bioassays confirmed the absence of cytotoxicity for the most potent compounds at the tested doses. Molecular docking analysis demonstrated that the tested derivatives effectively bind to the active sites of both enzymes. Overall, this study sheds light on the potential of barbiturate-sulfonate conjugates as promising drug candidates.

[Box: see text].

Evaluation of the Use of Phenobarbital and Benzodiazepines in the Management of Alcohol Withdrawal Syndrome in Patients Requiring Neurological/Neurosurgical Critical Care: A Propensity-Matched Analysis.

Objective There is growing interest in the use of phenobarbital for alcohol withdrawal syndrome in critically ill patients, though experience in neurologically injured patients is limited. The purpose of this study was to compare the safety and effectiveness of phenobarbital-containing alcohol withdrawal regimens versus benzodiazepine monotherapy in the neurocritical care unit. Methods We conducted a retrospective cohort study of adult patients admitted to the neurocritical care unit from January 2014 through November 2021 who received pharmacologic treatment for alcohol withdrawal. Treatment groups were defined as benzodiazepine monotherapy versus phenobarbital alone or in combination with benzodiazepines. The primary outcome was the percentage of patients requiring intubation after receiving alcohol withdrawal treatment. Secondary outcomes included all-cause, in-hospital mortality, intensive care unit length of stay, discharge disposition, change in Glasgow Coma Scale (GCS) score, and the use of adjunctive agents. Results We analyzed data from 156 patients, with 77 (49%) in the benzodiazepine group and 79 (51%) in the phenobarbital combination group. The groups were well-balanced for baseline characteristics, though more males (67, 85%) were in the phenobarbital group. Only three (1.9%) patients received phenobarbital monotherapy, and the rest (153, 98.1%) received combination therapy. The percentage of patients requiring mechanical ventilation was significantly higher in the phenobarbital combination group compared to benzodiazepine monotherapy (39% (n=31) versus 13% (n=10); OR: 4.33, 95% CI: 1.94-9.66; p<0.001). The use of adjunctive propofol and dexmedetomidine was higher in the phenobarbital group (propofol 35% (n= 28) versus 9% (n=7) and dexmedetomidine 30% (n=24) versus 5% (n=4), respectively). Patients in the phenobarbital group also had lower GCS scores and higher Clinical Institute Withdrawal Assessment of Alcohol (CIWA-Ar) scores during their intensive care unit admission, possibly suggesting more severe alcohol withdrawal. There was no difference in intensive care unit length of stay, all-cause, in-hospital mortality, discharge disposition, or therapeutic adjuncts. Conclusions Combination therapy of phenobarbital plus benzodiazepines was associated with higher odds of requiring mechanical ventilation. Few patients received phenobarbital monotherapy. Additional studies are needed to better compare the effects of phenobarbital monotherapy versus benzodiazepines in neurocritical patients.

Tuning the photophysical properties of cyanine by barbiturate functionalization and nanoformulation for efficient optoacoustics- guided phototherapy.

Cyanine derivatives are organic dyes widely used for optical imaging. However, their potential in longitudinal optoacoustic imaging and photothermal therapy remains limited due to challenges such as poor chemical stability, poor photostability, and low photothermal conversion. In this study, we present a new structural modification for cyanine dyes by introducing a strongly electron-withdrawing group (barbiturate), resulting in a new series of barbiturate-cyanine dyes (BC810, BC885, and BC1010) with suppressed fluorescence and enhanced stability. Furthermore, the introduction of BC1010 into block copolymers (PEG114-b-PCL60) induces aggregation-caused quenching, further boosting the photothermal performance. The photophysical properties of nanoparticles (BC1010-NPs) include their remarkably broad absorption range from 900 to 1200 nm for optoacoustic imaging, allowing imaging applications in NIR-I and NIR-II windows. The combined effect of these strategies, including improved photostability, enhanced nonradiative relaxation, and aggregation-caused quenching, enables the detection of optoacoustic signals with high sensitivity and effective photothermal treatment of in vivo tumor models when BC1010-NPs are administered before irradiation with a 1064 nm laser. This research introduces a barbiturate-functionalized cyanine derivative with optimal properties for efficient optoacoustics-guided theranostic applications. This new compound holds significant potential for biomedical use, facilitating advancements in optoacoustic-guided diagnostic and therapeutic approaches.

Ultrasensitive enantiomeric barbiturate analysis in body fluids through capillary electrophoresis with large volume sample stacking and ultrasound assisted dispersive liquid liquid microextraction.

A rapid, straightforward, and sensitive approach to quantifying enantiomeric barbiturates in serum was developed by integrating ultrasound-assisted dispersive liquid-liquid microextraction (UA-DLLME) with large-volume sample stacking (LVSS) in capillary electrophoresis (CE). UA-DLLME was employed for sample preparation, and on-column preconcentration by using LVSS with polarity switching was implemented to enhance sensitivity. We thoroughly investigated and optimized various parameters influencing extraction and stacking to achieve optimal detection performance with the highest enrichment efficiencies. Under optimal extraction conditions (injection of a mixed solution containing 40 µL of CHCl3 and 200 µL of tetrahydrofuran into 1 mL of a sample solution at pH 10.0), LVSS was performed using 600 mM Tris-boric acid (pH 9.5) containing 35 mM hydroxypropyl-ß-cyclodextrin and sodium taurodeoxycholate hydrate. A voltage of 20 kV was applied and a preinjection water plug was loaded at a height of 25 cm for 10 s. Subsequently, the sample solution was injected at a height of 25 cm for 480 s, after which a voltage of -20 kV was applied and the sample stacking was initiated. The stacking process was completed when 95 % of the separation current was attained. Under optimized conditions, the contraction folds of the four barbiturate analytes (R, S-Secobarbital, R, S-pentobarbital) were improved by approximately 6400-fold, achieving detection limits of 0.1 ng/mL. The limits of quantification for all analyte enantiomers were 0.5-50 ng/mL, demonstrating good linearity (r > 0.997). Migration times exhibited a relative standard deviation of less than 1.7 %, whereas peak areas for the four analytes exhibited a deviation of 8.7 %. Finally, the established method was effectively applied to the analysis of human serum samples.

A rare case of phenobarbital-induced leukocytoclastic vasculitis.

Drug hypersensitivity reactions (DHRs) manifested as vasculitis are rare. Antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs), sulphonamides, diuretics, immunosupressants and anticonvulsants are the most common culprits for drug-induced leukocytoclastic vasculitis (LCV) but there is scarce information about barbiturates. We present a case of 53-year-old female with severe vasculitis after phenobarbital- and NSAIDs-containing medications use. The preliminary diagnosis of drug-induced vasculitis was made based on anamnestic and clinical data. Further examinations confirmed the diagnosis of LCV and excluded other more common causes of vasculitis. The causative significance of used medications was assessed by long-term observation of the patient after the reaction, including the drug challenge series and Naranjo's Adverse Drug Reaction Probability Scale. It was concluded that phenobarbital is the most probable culprit drug. The patient's data were included in the Armenian Registry of Patients with Severe DHRs. Since then, the patient has avoided only barbiturate-containing drugs and no reactions were noted. Thus, the case indicates that even with limited diagnostic capabilities, the final diagnosis of rare drug-induced LCV and even rarer culprit drug can be established by comparing the available data. Awareness about phenobarbital and proper recording of the case are important in the management and prevention of DHRs manifested as vasculitis.

The dosage of thiopental as pharmacological cerebral protection during non-shunt carotid endarterectomy: A retrospective study.

Background: Thiopental has been used as a pharmacological cerebral protection strategy during carotid endarterectomy surgeries. However, the optimal dosage required to induce burst suppression on the electroencephalogram (EEG) remains unknown. This retrospective study aimed to determine the optimal dosage of thiopental required to induce burst suppression during non-shunt carotid endarterectomy. Methods: The Neurological Institute of Thailand Review Board approved the study. Data were collected from 2009 to 2019 for all non-shunt carotid endarterectomy patients who received thiopental for pharmacological cerebral protection and had intraoperative EEG monitoring. Demographic information, carotid stenosis severity, intraoperative EEG parameters, thiopental dosage, carotid clamp time, intraoperative events, and patient outcomes were abstracted. Results: The study included 57 patients. Among them, 24 patients (42%) achieved EEG burst suppression pattern with a thiopental dosage of 26.3±10.1 mg/kg/hr. There were no significant differences in perioperative events between patients who achieved burst suppression and those who did not. After surgery, 33.3% of patients who achieved burst suppression were extubated and awakened. One patient in the non-burst suppression group experienced mild neurological deficits. No deaths occurred within one month postoperative. Conclusions: The optimal dosage of thiopental required to achieve burst suppression on intraoperative EEG during non-shunt carotid endarterectomy was 26.3±10.1 mg/kg/hr.

Ultrasound and surfactant-assisted dispersive liquid-liquid microextraction prior to poly(ethylene oxide)-mediated stacking in CE for highly sensitive determination of barbiturates in human fluids.

This study developed a facile, highly sensitive technique for extracting and quantifying barbiturates in serum samples. This method combined ultrasound and surfactant-assisted dispersive liquid-liquid microextraction with poly(ethylene oxide)-mediated stacking in capillary electrophoresis. Factors influencing the extraction and stacking performance, such as the type and volume of extraction solvents, the type and concentration of surfactant, extraction time, salt additives, sample matrix, solution pH, and composition of the background electrolyte, were carefully studied and optimized to achieve the optimal detection sensitivity. Under the optimized extraction (injecting 140 µL C2 H4 Cl2 into 1 mL of sample with pH 4 (5 mM sodium phosphate containing 0.05 mM Tween 20 and sonication for 1 min) and separation conditions (150 mM tris(hydroxymethyl)aminomethane-borate with pH 8.5 containing 0.5% (m/v) poly(ethylene oxide)), the limits of detection (signal-to-noise ratio = 3) of five barbiturates ranged from 0.20 to 0.33 ng/mL, and the calculated sensitivity improvement ranged from 868- to 1700-fold. The experimental results revealed excellent linearity (R2  > 0.99), with relative standard deviations of 2.1%-3.4% for the migration time and 4.3%-5.7% for the peak area. The recoveries of the spiked serum samples were 97.1% -110.3%. Our proposed approach offers a rapid and practical method for quantifying barbiturates in biological fluids.

[Methods of analgesia and euthanasia in backyard poultry]. / Methoden der Analgesie und Euthanasie in der Hobby-Hühnerhaltung.

INTRODUCTION: The keeping of chickens in the backyard is growing in popularity in urban and suburban areas, numbers of animals are increasing and as a result small animal practitioners are more and more frequently faced with chickens as patient. Clinical conditions in backyard poultry often require the treatment of pain. The challenges regarding the adequate use of analgesics include: 1. Recognition and assessment of pain, which necessitates good knowledge of chicken behaviour, 2. Selection of the adequate drug and dosage based on evidence that is often not available for chickens, but spread over different species of birds, and 3. Implementation of food safety regulations, which result from the dual use of backyard poultry as «food producing pets¼. Analgesics used in chickens include opiates, nonsteroidal anti-inflammatory drugs and local analgesics. The opiate butorphanol has been shown to have an analgesic effect of approximately two hours in chickens. Tramadol and methadone show some promise as analgesics, but more evidence is needed especially regarding bioavailability. The nonsteroidal anti-inflammatory drugs meloxicam and carprofen appear to have an analgesic effect. Variable metabolism between breeds of chickens and the risk of accumulation, especially when used for periods exceeding five consecutive days, need to be taken into account regarding dosage. Lidocaine and bupivacaine have successfully been used in chickens for nerve blocks and spinal anaesthesia and should be included as part of multimodal analgesia especially during surgery. In cases, where termination of life is necessary the preferred method consists of an injectable anaesthesia followed by intravenous application of a barbiturate.

INTRODUCTION: L'élevage de volailles de basse-cour est de plus en plus populaire dans les zones urbaines et suburbaines, le nombre d'animaux augmente et les praticiens pour petits animaux sont, par conséquent, de plus en plus souvent confrontés à ces animaux en tant que patients. Les conditions cliniques des volailles de basse-cour nécessitent souvent le traitement de la douleur. Les défis liés à l'utilisation adéquate des analgésiques sont les suivants 1. La reconnaissance et l'évaluation de la douleur, qui nécessitent une bonne connaissance du comportement des volailles, 2. la sélection du médicament et du dosage adéquats sur la base de preuves qui ne sont souvent pas disponibles pour les volailles mais sont réparties entre différentes espèces d'oiseaux, et 3. la mise en œuvre des réglementations en matière de sécurité alimentaire, qui résultent de la double utilisation des volailles de basse-cour en tant qu'«animaux de compagnie producteurs de denrées alimentaires¼. Les analgésiques utilisés chez les poulets comprennent les opiacés, les anti-inflammatoires non stéroïdiens et les analgésiques locaux. Il a été démontré que l'opiacé butorphanol a un effet analgésique chez les poulets, d'une durée d'environ deux heures. Le Tramadol et la méthadone sont des analgésiques prometteurs, mais des preuves supplémentaires sont nécessaires, notamment en ce qui concerne leur biodisponibilité. Les anti-inflammatoires non stéroïdiens Meloxicam et Carprofen semblent avoir un effet analgésique. En ce qui concerne la posologie, il convient de tenir compte du métabolisme variable selon les races de poules et du risque d'accumulation, en particulier en cas d'utilisation pendant des périodes supérieures à cinq jours consécutifs. La lidocaïne et la bupivacaïne ont été utilisées avec succès chez les poules pour les blocs nerveux ainsi que pour l'anesthésie spinale et devraient être incluses dans l'analgésie multimodale, en particulier pendant la chirurgie. Dans les cas où il est nécessaire de mettre fin à la vie de l'animal, la méthode de choix consiste en une anesthésie injectable suivie d'une application intraveineuse d'un barbiturique.

A Case of Barbiturate Poisoning From Pentobarbital in a Young Japanese Patient.

Concomitant prescriptions of psychotropic drugs such as sleeping pills, antidepressants, and anti-anxiety medications are common. The relationship between the number of psychotropic drug prescriptions and the incidence of drug overdose has not been reported. However, efforts have been made to reduce the number of concomitant prescriptions hoping that fewer prescriptions of multiple drugs will lower the incidence of drug overdoses. Furthermore, among sleeping pills, prescriptions of barbiturates have been gradually decreasing due to the risk of severe side effects and addiction. This report features a case of an overdose of pentobarbital tablets that caused the classic medical triad (impaired consciousness, hypotension, and hypothermia) of barbiturate intoxication under the characteristics of borderline personality disorder.

N-methyl-d-aspartate receptors and glycinergic transmission, respectively, mediate muscle relaxation and immobility of pentobarbital in mice.

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.

Intermolecular n→π* Interactions Based on a Tailored Multicarbonyl-Containing Macrocycle.

Towards unexplored intermolecular n→π* interactions, presented herein are the synthesis, structure, self-assembly and function of a multicarbonyl-containing macrocycle calix[2]arene[2]barbiturate 1. X-ray single crystal diffraction reveals the presence of Cl⋅⋅⋅C=O interactions in CH2 Cl2 ⊂1 host-guest complex and multiple intermolecular C=O⋅⋅⋅C=O interactions between molecules 1 in crystalline state. The intermolecular C=O⋅⋅⋅C=O interactions as attractive driving force led to unprecedented self-assembly of nanotube with diameter around 1.4 nm and inner surface engineered by aromatic rings. SEM and TEM images of the self-assembly of 1 demonstrated temperature-dependent morphologies which allows the observation of spheres at 25 °C and rods at 0 °C, respectively. XRD analysis indicated consistent hexagonal patterns in the self-assembly and single crystal lattice, indicating the nanotubes driven by C=O⋅⋅⋅C=O interactions constitute the basic structural architectures of both aggregates. The nanoscopic tubes (pores) formed in the rodlike single crystal engendering the separation of moving dyes were preliminarily investigated by a single-crystal chromatography and crystal-packed column chromatography.

Alcohol-related posterior reversible encephalopathy syndrome: a case report of a patient managed with a benzodiazepine-sparing regimen for alcohol withdrawal.

We report a case of posterior reversible encephalopathy syndrome (PRES) during treatment for alcohol withdrawal syndrome with gabapentin and clonidine. The patient developed severe hypertension, confusion and tremor, culminating in bilateral vision loss and a seizure. Imaging revealed posterior cerebral edema. Treatment with benzodiazepines, antihypertensives, and anti-seizure medications led to resolution. One year later, imaging showed resolution of the findings. We review the associated literature and propose the recognition of a PRES sub-entity, Alcohol-Related PRES (ARPRES), which can appear in the setting of alcohol withdrawal syndrome, chronic alcohol use, and acute alcohol intoxication, with or without hypertension.

Mild hypothermia fails to protect infant macaques from brain injury caused by prolonged exposure to Antiseizure drugs.

Barbiturates and benzodiazepines are GABAA-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.

Prognostic effects of treatment protocols for febrile convulsive status epilepticus in children.

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.

Pentobarbital may protect against neurogenic inflammation after surgery via inhibition of substance P release from peripheral nerves of rats.

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.

Anti-Inflammatory Effects of the Novel Barbiturate Derivative MHY2699 in an MPTP-Induced Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders, and is caused by the death of dopamine neurons and neuroinflammation in the striatum and substantia nigra. Furthermore, the inflammatory response in PD is closely related to glial cell activation. This study examined the neuroprotective effects of the barbiturate derivative, MHY2699 [5-(4-hydroxy 3,5-dimethoxybenzyl)-2 thioxodihydropyrimidine-4,6(1H,5H)-dione] in a mouse model of PD. MHY2699 ameliorated MPP⁺-induced astrocyte activation and ROS production in primary astrocytes and inhibited the MPP⁺-induced phosphorylation of MAPK and NF-κB. The anti-inflammatory effects of MHY2699 in protecting neurons were examined in an MPTP-induced mouse model of PD. MHY2699 inhibited MPTP-induced motor dysfunction and prevented dopaminergic neuronal death, suggesting that it attenuated neuroinflammation. Overall, MHY2699 has potential as a neuroprotective treatment for PD.

Combination of antiseizure medications phenobarbital, ketamine, and midazolam reduces soman-induced epileptogenesis and brain pathology in rats.

OBJECTIVE: Cholinergic-induced status epilepticus (SE) is associated with a loss of synaptic gamma-aminobutyric acid A receptors (GABAA R) and an increase in N-methyl-D-aspartate receptors (NMDAR) and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) that may contribute to pharmacoresistance when treatment with benzodiazepine antiseizure medication is delayed. The barbiturate phenobarbital enhances inhibitory neurotransmission by binding to a specific site in the GABAA R to increase the open state of the channel, decrease neuronal excitability, and reduce glutamate-induced currents through AMPA/kainate receptors. We hypothesized that phenobarbital as an adjunct to midazolam would augment the amelioration of soman-induced SE and associated neuropathological changes and that further protection would be provided by the addition of an NMDAR antagonist. METHODS: We investigated the efficacy of combining antiseizure medications to include a benzodiazepine and a barbiturate allosteric GABAA R modulator (midazolam and phenobarbital, respectively) to correct loss of inhibition, and ketamine to reduce excitation caused by increased synaptic localization of NMDAR and AMPAR, which are NMDA-dependent. Rats implanted with transmitters to record electroencephalographic (EEG) activity were exposed to soman and treated with atropine sulfate and HI-6 one min after exposure and with antiseizure medication(s) 40 minutes after seizure onset. RESULTS: The triple therapy combination of phenobarbital, midazolam, and ketamine administered at 40 minutes after seizure onset effectively prevented soman-induced epileptogenesis and reduced neurodegeneration. In addition, dual therapy with phenobarbital and midazolam or ketamine was more effective than monotherapy (midazolam or phenobarbital) in reducing cholinergic-induced toxicity. SIGNIFICANCE: Benzodiazepine efficacy is drastically reduced with time after seizure onset and inversely related to seizure duration. To overcome pharmacoresistance in severe benzodiazepine-refractory cholinergic-induced SE, simultaneous drug combination to include drugs that target both the loss of inhibition (eg, midazolam, phenobarbital) and the increased excitatory response (eg, ketamine) is more effective than benzodiazepine or barbiturate monotherapy.

Substance Use Disorders in Patients With Parkinson's Disease and Adverse Hospitalization Outcomes: A National Inpatient Study.

Objectives To understand the demographic pattern of substance use disorders (SUD) in Parkinson's disease (PD) inpatients and to evaluate the impact of SUD on hospitalization outcomes including the severity of illness, length of stay (LOS), total charges, and disposition to nursing facilities. Methods We used the nationwide inpatient sample and identified adult patients (age, ≥40 years) with PD as a primary diagnosis and comorbid SUD (N = 959) and grouped by co-diagnosis of alcohol (N = 789), cannabis (N = 46), opioid (N = 30), stimulants (N = 54) and barbiturate (N = 40) use disorders. We used a binomial logistic regression model to evaluate the odds ratio (OR) for major loss of functioning and disposition to nursing facilities in PD inpatients. All regression models were adjusted for demographics, including age, sex, race, and median household income. Results Alcohol, opioid, and stimulant use disorders were prevalent in old-age adults (60-79 years), males, and whites, but cannabis use was prevalent in middle-aged adults (40-59 years), and barbiturate use among older-age (>80 years). The severity of illness is statistically higher in PD inpatients with comorbid opioid and barbiturate use disorders with major loss of body functioning, closely seconded by alcohol and stimulant use disorder cohorts (27.6% and 25.9%, respectively). Disease severity and loss of body functioning increase with advancing age (>80 years adults, OR 5.8, 95%CI 5.32-6.37), and in blacks (OR 1.7, 95%CI 1.56-1.81), and those with opioid use disorder (OR 3.8, 95%CI 1.96-7.35). PD inpatients with barbiturate use disorder had a higher LOS and charges by 17.4 days and $68,922, and six-fold increased likelihood (95%CI 2.33-15.67) for disposition to nursing facilities. Conclusions SUD is prevalent among PD patients and is associated with more severe illnesses with body loss functioning and prolonged care. A multidisciplinary care model including collaborative neuropsychiatric and addiction management is required to manage SUD among PD patients to lessen disease severity, slow down the disease progression and potentially save medical costs.