Is there a biochemical basis for purinergic P2X3 and P2X4 receptor antagonists to be considered as anti-seizure medications?

Patients with epilepsy require improved medications. Purinergic receptors were identified as late as 1976 and are slowly emerging as potential drug targets for the discovery of antiseizure medications. While compounds interacting with these receptors have been approved for use as medicines (e.g., gefapixant for cough) and continue to be explored for a number of diseases (e.g., pain, cancer), there have been no purinergic receptor antagonists that have been advanced for epilepsy. There are very few studies on the channel conducting receptors, P2X3 and P2X4, that suggest their possible role in seizure generation or control. However, the limited data available provides some compelling reasons to believe that they could be valuable antiseizure medication drug targets. The data implicating P2X3 and P2X4 receptors in epilepsy includes the role played by ATP in neuronal excitability and seizures, receptor localization, increased receptor expression in epileptic brain, the involvement of these receptors in seizure-associated inflammation, crosstalk between these purinergic receptors and neuronal processes involved in seizures (GABAergic and glutamatergic neurotransmission), and the significant attenuation of seizures and seizure-like activity with P2X receptor blockade. The discovery of new and selective antagonists for P2X3 and P2X4 receptors is ongoing, armed with new structural data to guide rational design. The availability of safe, brain-penetrant compounds will likely encourage the clinical exploration of epilepsy as a disease entity.

Mechanistic and therapeutic relationships of traumatic brain injury and γ-amino-butyric acid (GABA).

Traumatic brain injury (TBI) is a highly prevalent medical condition for which no medications specific for the prophylaxis or treatment of the condition as a whole exist. The spectrum of symptoms includes coma, headache, seizures, cognitive impairment, depression, and anxiety. Although it has been known for years that the inhibitory neurotransmitter γ-amino-butyric acid (GABA) is involved in TBI, no novel therapeutics based upon this mechanism have been introduced into clinical practice. We review the neuroanatomical, neurophysiological, neurochemical, and neuropharmacological relationships of GABA neurotransmission to TBI with a view toward new potential GABA-based medicines. The long-standing idea that excitatory and inhibitory (GABA and others) balances are disrupted by TBI is supported by the experimental data but has failed to invent novel methods of restoring this balance. The slow progress in advancing new treatments is due to the complexity of the disorder that encompasses multiple dynamically interacting biological processes including hemodynamic and metabolic systems, neurodegeneration and neurogenesis, major disruptions in neural networks and axons, frank brain lesions, and a multitude of symptoms that have differential neuronal and neurohormonal regulatory mechanisms. Although the current and ongoing clinical studies include GABAergic drugs, no novel GABA compounds are being explored. It is suggested that filling the gap in understanding the roles played by specific GABAA receptor configurations within specific neuronal circuits could help define new therapeutic approaches. Further research into the temporal and spatial delivery of GABA modulators should also be useful. Along with GABA modulation, research into the sequencing of GABA and non-GABA treatments will be needed.

New Imidazodiazepine Analogue, 5-(8-Bromo-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole, Provides a Simplified Synthetic Scheme, High Oral Plasma and Brain Exposures, and Produces Antiseizure Efficacy in Mice, and Antiepileptogenic Activity in Neural Networks in Brain Slices from a Patient with Mesial Temporal Lobe Epilepsy.

KRM-II-81 (1) is an imidazodiazepine GABAA receptor (GABAAR) potentiator with broad antiseizure efficacy and a low sedative burden. A brominated analogue, DS-II-73 (5), was synthesized and pharmacologically characterized as a potential backup compound as KRM-II-81 moves forward into development. The synthesis from 2-amino-5-bromophenyl)(pyridin-2yl)methanone (6) was processed in five steps with an overall yield of 38% and without the need for a palladium catalyst. GABAAR binding occurred with a Ki of 150 nM, and only 3 of 41 screened binding sites produced inhibition ≥50% at 10 µM, and the potency to induce cytotoxicity was ≥240 mM. DS-II-73 was selective for α2/3/5- over that of α1-containing GABAARs. Oral exposure of plasma and brain of rats was more than sufficient to functionally impact GABAARs. Tonic convulsions in mice and lethality induced by pentylenetetrazol were suppressed by DS-II-73 after oral administration and latencies to clonic and tonic seizures were prolonged. Cortical slice preparations from a patient with pharmacoresistant epilepsy (mesial temporal lobe) showed decreases in the frequency of local field potentials by DS-II-73. As with KRM-II-81, the motor-impairing effects of DS-II-73 were low compared to diazepam. Molecular docking studies of DS-II-73 with the α1ß3γ2L-configured GABAAR showed low interaction with α1His102 that is suggested as a potential molecular mechanism for its low sedative side effects. These findings support the viability of DS-II-73 as a backup molecule for its ethynyl analogue, KRM-II-81, with the human tissue data providing translational credibility.

KRM-II-81 suppresses epileptifom activity across the neural network of cortical tissue from a patient with pharmacoresistant epilepsy.

A clinical case of a 19-year-old male patient with pharmacoresistant seizures occurring following parieto-occipital tumor-resection at age 6 is described. Seizure surgery work-up included prolonged video EEG monitoring and head CT without contrast. Seizure focus was localized to the left temporal lobe, and we felt that the patient was an excellent candidate for seizure surgery. The patient underwent a left frontotemporal craniotomy for removal of the seizure focus with intraoperative electrocorticography (ECoG) conducted pre and post resection. ECoG recordings pre- and post-resection confirmed resolution of seizure generation. Imaging obtained immediately postoperatively showed complete resection of the residual tumor with no evidence of recurrence in follow-ups. A year after the surgery the patient is seizure-free but remains on seizure medication. With the patient's consent the excised epileptogenic tissue was used for ex-vivo research studies. The microelectrode recordings confirmed epileptiform activity in the excised tissue incubated in excitatory artificial cerebrospinal fluid. The epileptiform activity in the epileptogenic tissue was suppressed by addition of KRM-II-81, a novel α2/3 subtype preferring GABAA receptor (GABAAR) potentiator with previously demonstrated antiepileptic efficacy in multiple animal models of epilepsy and with reduced potential for CNS side-effects compared to classical benzodiazepine GABAAR potentiators. These findings support the proposition that KRM-II-81 might reduce seizure burden in pharmacoresistant patients.

Clinical pharmacological innovation in the treatment of depression.

INTRODUCTION: Deficiencies in standard of care antidepressants are driving novel drug discovery. A new age of antidepressant medications has emerged with the introduction of rapid-acting antidepressants with efficacy in treatment-resistant patients. AREAS COVERED: The newly approved medicines and those in clinical development for major depressive disorder (MDD) are documented in this scoping review of newly approved and emerging antidepressants. Compounds are evaluated for clinical efficacy, tolerability, and safety and compared to those of standard of care medicines. EXPERT OPINION: A new age of antidepressant discovery relies heavily on glutamatergic mechanisms. New medicines based upon the model of ketamine have been delivered and are in clinical development. Rapid onset and the ability to impact treatment-resistant depression, raises the question of the best first-line medicines for patients. Drugs with improvements in tolerability are being investigated (e.g. mGlu2/3 receptor antagonists, AMPA receptor potentiators, and novel NMDA receptor modulators). Multiple companies are working toward the identification of novel psychedelic drugs where the requirement for psychedelic activity is not fully known. Gaps still exist - methods for matching patients with specific medicines are needed, and medicines for the prevention of MDD and its disease progression need research attention.

Structural Analogs of the GABAkine KRM-II-81 Are Orally Bioavailable Anticonvulsants without Sedation.

To provide back-up compounds to support the development of the GABAA receptor (GABAAR) potentiator KRM-II-81, three novel analogs were designed: replacing the pyridinyl with 2'-Cl-phenyl (FR-II-60), changing the positions of the N and O atoms in the oxazole ring with addition of an ethyl group (KPP-III-34 and KPP-III-51), or substituting a Br atom for the ethynyl of KRM-II-81 (KPP-III-34). The compounds bound to brain GABAARs. Intraperitoneal administration of FR-II-60 and KPP-III-34 produced anticonvulsant activity in mice [maximal electroshock (MES)-induced seizures or 6 Hz-induced seizures], whereas KPP-III-51 did not. Although all compounds were orally bioavailable, structural changes reduced the plasma and brain (FR-II-60 and KPP-III-51) exposures relative to KRM-II-81. Oral administration of each compound produced dose-dependent increases in the latency for both clonic and tonic seizures and the lethality induced by pentylenetetrazol (PTZ) in mice. Since KPP-III-34 produced the highest brain area under the curve (AUC) exposures, it was selected for further profiling. Oral administration of KPP-III-34 suppressed seizures in corneal-kindled mice, hippocampal paroxysmal discharges in mesial temporal lobe epileptic mice, and PTZ-induced convulsions in rats. Only transient sensorimotor impairment was observed in mice, and doses of KPP-III-34 up to 500 mg/kg did not produce impairment in rats. Molecular docking studies demonstrated that all compounds displayed a reduced propensity for binding to α1His102 compared with the sedating compound alprazolam; the bromine-substituted KPP-III-34 achieved the least interaction. Overall, these findings document the oral bioavailability and anticonvulsant efficacy of three novel analogs of KRM-II-81 with reduced sedative effects. SIGNIFICANCE STATEMENT: A new non-sedating compound, KRM-II-81, with reduced propensity for tolerance is moving into clinical development. Three new analogs were orally bioavailable, produced anticonvulsant effects in rodents, and displayed low sensorimotor impairment. KPP-III-34 demonstrated efficacy in models of pharmacoresistant epilepsy. Docking studies demonstrated a low propensity for compound binding to the α1His102 residue implicated in sedation. Thus, three additional structures have been added to the list of non-sedating imidazodiazepine anticonvulsants that could serve as backups in the clinical development of KRM-II-81.

Comparative anticonvulsant activity of the GABAkine KRM-II-81 and a deuterated analog.

A series of imidazodiazepines has been developed that possess reduced sedative liabilities but retain efficacy in anticonvulsant screening models. The latest of these compounds, (5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole known as KRM-II-81) is currently awaiting advancement into the clinic. A deuterated structural analog (D5-KRM-II-81) was made as a potential backup compound and studied here in comparison to KRM-II-81. In the present study, both compounds significantly prevented seizures in mice induced by 6 Hz (44 mA) electrical stimulation without significantly altering motoric function on a rotarod after intraperitoneal administration. Both compounds also significantly prevented clonic seizures, tonic seizures, and lethality induced by pentylenetetrazol in mice when given orally. D5-KRM-II-81 had a slightly longer duration of action against clonic and tonic seizures than KRM-II-81. Oral administration of 100 mg/kg of either KRM-II-81 or D5-KRM-II-81 was significantly less disruptive of sensorimotor function in mice than diazepam (5 mg/kg, p.o.). The present report documents that D5-KRM-II-81 represents another in this series of imidazodiazepines with anticonvulsant activity at doses that do not impair sensorimotor function.

Mortality of adolescents with isolated traumatic brain injury does not vary with type of level I trauma center.

BACKGROUND: Pediatric patients with isolated severe traumatic brain injury (TBI) treated at pediatric trauma centers (PTCs) have lower mortality than those treated at adult trauma centers (ATCs) or mixed trauma centers (MTCs). The primary objective of this study was to determine if adolescent patients (15-17 years) with isolated severe TBI also benefited from treatment at PTCs. METHODS: This was a cross-sectional analysis using a national sample of adolescent trauma patients obtained from the American College of Surgeons' Trauma Quality Program Participant Use Files for 2013 to 2017 (n = 3,524). Mortality, the primary outcome variable, was compared between Level I PTCs, ATCs, and MTCs using multiple logistic regression controlling for patient characteristics and injury severity. Secondary outcomes included discharge disposition, utilization of craniotomy, intensive care unit (ICU) utilization, ICU length of stay (LOS), and hospital LOS. RESULTS: Prior to adjustment, patients treated at ATCs (odds ratio [OR], 2.76; p = 0.032) and MTCs (OR, 2.36; p = 0.070) appeared to be at greater risk of mortality than those treated at PTCs. However, after adjustment, this difference disappeared (ATC OR, 1.21; p = 0.733; MTC OR, 0.95; p = 0.919). Patients treated at ATCs and MTCs were more severely injured than those treated at PTCs and more likely to be admitted to an ICU (ATC OR, 2.12; p < 0.001; MTC OR, 1.91; p < 0.001). No other secondary outcome differed between center types. CONCLUSION: Adolescent patients with isolated severe TBI treated at ATCs and MTCs had similar mortality risk as those treated at PTCs. The difference in injury severity across center types warrants additional research. LEVEL OF EVIDENCE: Prognostic/Epidemiological; Level III.

Where do we go next in antidepressant drug discovery? A new generation of antidepressants: a pivotal role of AMPA receptor potentiation and mGlu2/3 receptor antagonism.

INTRODUCTION: Major depressive disorder remains a prevalent world-wide health problem. Currently available antidepressant medications take weeks of dosing, do not produce antidepressant response in all patients, and have undesirable ancillary effects. AREAS COVERED: The present opinion piece focuses on the major inroads to the creation of new antidepressants. These include N-methyl-D-aspartate (NMDA) receptor antagonists and related compounds like ketamine, psychedelic drugs like psilocybin, and muscarinic receptor antagonists like scopolamine. The preclinical and clinical pharmacological profile of these new-age antidepressant drugs is discussed. EXPERT OPINION: Preclinical and clinical data have accumulated to predict a next generation of antidepressant medicines. In contrast to the current standard of care antidepressant drugs, these compounds differ in that they demonstrate rapid activity, often after a single dose, and effects that outlive their presence in brain. These compounds also can provide efficacy for treatment-resistant depressed patients. The mechanism of action of these compounds suggests a strong glutamatergic component that involves the facilitation of AMPA receptor function. Antagonism of mGlu2/3 receptors is also relevant to the antidepressant pharmacology of this new class of drugs. Based upon the ongoing efforts to develop these new-age antidepressants, new drug approvals are predicted in the near future.

Clinical investigations of compounds targeting metabotropic glutamate receptors.

Pharmacological modulation of glutamate has long been considered to be of immense therapeutic utility. The metabotropic glutamate receptors (mGluRs) are potential targets for safely altering glutamate-driven excitation. Data support the potential therapeutic use of mGluR modulators in the treatment of anxiety, depression, schizophrenia, and other psychiatric disorders, pain, epilepsy, as well as neurodegenerative and neurodevelopmental disorders. For each of the three mGluR groups, compounds have been constructed that produce either potentiation or functional blockade. PET ligands for mGlu5Rs have been studied in a range of patient populations and several mGlu5R antagonists have been tested for potential efficacy in patients including mavoglurant, diploglurant, basimglurant, GET 73, and ADX10059. Efficacy with mGlu5R antagonists has been reported in trials with patients with gastroesophageal reflux disease; data from patients with Parkinson's disease or Fragile X syndrome have not been as robust as hoped. Fenobam was approved for use as an anxiolytic prior to its recognition as an mGlu5R antagonist. mGlu2/3R agonists (pomaglumated methionil) and mGlu2R agonists (JNJ-40411813, AZD 8529, and LY2979165) have been studied in patients with schizophrenia with promising but mixed results. Antagonists of mGlu2/3Rs (decoglurant and TS-161) have been studied in depression where TS-161 has advanced into a planned Phase 2 study in treatment-resistant depression. The Group III mGluRs are the least developed of the mGluR receptor targets. The mGlu4R potentiator, foliglurax, did not meet its primary endpoint in patients with Parkinson's disease. Ongoing efforts to develop mGluR-targeted compounds continue to promise these glutamate modulators as medicines for psychiatric and neurological disorders.

Hydrochloride Salt of the GABAkine KRM-II-81.

Imidazodiazepine (5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole or KRM-II-81) is a potentiator of GABAA receptors (a GABAkine) undergoing preparation for clinical development. KRM-II-81 is active against many seizure and pain models in rodents, where it exhibits improved pharmacological properties over standard-of-care agents. Since salts can be utilized to create opportunities for increased solubility, enhanced absorption, and distribution, as well as for efficient methods of bulk synthesis, a hydrochloride salt of KRM-II-81 was prepared. KRM-II-81·HCl was produced from the free base with anhydrous hydrochloric acid. The formation of the monohydrochloride salt was confirmed by X-ray crystallography, as well as 1H NMR and 13C NMR analyses. High water solubility and a lower partition coefficient (octanol/water) were exhibited by KRM-II-81·HCl as compared to the free base. Oral administration of either KRM-II-81·HCl or the free base resulted in high concentrations in the brain and plasma of rats. Oral dosing in mice significantly increased the latency to both clonic and tonic convulsions and decreased pentylenetetrazol-induced lethality. The increased water solubility of the HCl salt enables intravenous dosing and the potential for higher concentration formulations compared with the free base without impacting anticonvulsant potency. Thus, KRM-II-81·HCl adds an important new compound to facilitate the development of these imidazodiazepines for clinical evaluation.

Hydrocephalus surveillance following CSF diversion: a modified Delphi study.

OBJECTIVE: Long-term follow-up is often recommended for patients with hydrocephalus, but the frequency of clinical follow-up, timing and modality of imaging, and duration of surveillance have not been clearly defined. Here, the authors used the modified Delphi method to identify areas of consensus regarding the modality, frequency, and duration of hydrocephalus surveillance following surgical treatment. METHODS: Pediatric neurosurgeons serving as institutional liaisons to the Hydrocephalus Clinical Research Network (HCRN), or its implementation/quality improvement arm (HCRNq), were invited to participate in this modified Delphi study. Thirty-seven consensus statements were generated and distributed via an anonymous electronic survey, with responses structured as a 4-point Likert scale (strongly agree, agree, disagree, strongly disagree). A subsequent, virtual meeting offered the opportunity for open discussion and modification of the statements in an effort to reach consensus (defined as ≥ 80% agreement or disagreement). RESULTS: Nineteen pediatric neurosurgeons participated in the first round, after which 15 statements reached consensus. During the second round, 14 participants met virtually for review and discussion. Some statements were modified and 2 statements were combined, resulting in a total of 36 statements. At the conclusion of the session, consensus was achieved for 17 statements regarding the following: 1) the role of standardization; 2) preferred imaging modalities; 3) postoperative follow-up after shunt surgery (subdivided into immediate postoperative imaging, delayed postoperative imaging, routine clinical surveillance, and routine radiological surveillance); and 4) postoperative follow-up after an endoscopic third ventriculostomy. Consensus could not be achieved for 19 statements. CONCLUSIONS: Using the modified Delphi method, 17 consensus statements were developed with respect to both clinical and radiological follow-up after a shunt or endoscopic third ventriculostomy. The frequency, modality, and duration of surveillance were addressed, highlighting areas in which no clear data exist to guide clinical practice. Although further studies are needed to evaluate the clinical utility and cost-effectiveness of hydrocephalus surveillance, the current study provides a framework to guide future efforts to develop standardized clinical protocols for the postoperative surveillance of patients with hydrocephalus. Ultimately, the standardization of hydrocephalus surveillance has the potential to improve patient care as well as optimize the use of healthcare resources.

Can GABAkines quiet the noise? The GABAA receptor neurobiology and pharmacology of tinnitus.

Tinnitus is a highly prevalent and disabling disorder in which sound is perceived in the absence of an external auditory energy source. The disorder is complex and can arise from multiple etiologies. Co-morbid symptoms of anxiety, depression, and sleep loss are prevalent. There are no approved medications and the treatments that have been studied produce marginal improvements in symptoms. A major hypothesis of the etiology and maintenance of tinnitus is that inhibitory input mechanisms become compromised where impaired γ-aminobutyric acid (GABA) synaptic transmission has been implicated. This general idea lends support to the potential for enhanced inhibition by drugs that enhance GABA function (GABAkines) to dampen symptoms of tinnitus. Convergent evidence from neurochemical, anatomical, physiological, and pharmacological studies support the GABAA hypothesis. Although there is surprising a relatively sparse data set, examples of therapeutic efficacy have been reported with GABAkines. These studies have relied primarily on classical benzodiazepine anxiolytics like alprazolam and clonazepam. However, the possibility that novel GABAkines with unique activities might be effective have yet to be intensively explored. For example, data implicating extrasynaptic GABAAreceptors in the control of tinnitus suggests the potential for extrasynaptic GABAA receptor modulators. The large medical need, a basis for further testing of the GABAA hypothesis, and the recent reinvigoration of the drug development pipeline of new GABAkines, combine to give impetus and promise for further inquiry.

Metabolism, pharmacokinetics, and anticonvulsant activity of a deuterated analog of the α2/3-selective GABAkine KRM-II-81.

The imidazodiazepine, (5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo [f]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole or KRM-II-81) is a new α2/3-selective GABAkine (gamma aminobutyric acid A receptor potentiator) with anticonvulsant, anxiolytic, and antinociceptive activity in preclinical models. Reducing metabolism was utilized as a means of potentially extending the half-life of KRM-II-81. In vitro and in vivo studies were conducted to evaluate metabolic liabilities. Incubation of KRM-II-81 in hepatocytes revealed sites of potential metabolism on the oxazole and the diazepine rings. These sites were targeted in the design of a deuterated analog (D5-KRM-II-81) that could be evaluated as a potentially longer-acting analog. In contrast to computer predictions, peak plasma concentrations of D5-KRM-II-81 in rats were not significantly greater than those produced by KRM-II-81 after oral administration. Furthermore, brain disposition of KRM-II-81 was higher than that of D5-KRM-II-81. The half-life of the two compounds in either plasma or brain did not statistically differ from one another but the tmax for D5-KRM-II-81 occurred slightly earlier than for KRM-II-81. Non-metabolic considerations might be relevant to the lack of increases in exposure by D5-KRM-II-81. Alternative sites of metabolism on KRM-II-81, not targeted by the current deuteration process, are also possible. Despite its lack of augmented exposure, D5-KRM-II-81, like KRM-II-81, significantly prevented seizures induced by pentylenetetrazol when given orally. The present findings introduce a new orally active anticonvulsant GABAkine, D5-KRM-II-81.

The imidazodiazepine, KRM-II-81: An example of a newly emerging generation of GABAkines for neurological and psychiatric disorders.

GABAkines, or positive allosteric modulators of γ-aminobutyric acid-A (GABAA) receptors, are used for the treatment of anxiety, epilepsy, sleep, and other disorders. The search for improved GABAkines, with reduced safety liabilities (e.g., dependence) or side-effect profiles (e.g., sedation) constituted multiple discovery and development campaigns that involved a multitude of strategies over the past century. Due to the general lack of success in the development of new GABAkines, there had been a decades-long draught in bringing new GABAkines to market. Recently, however, there has been a resurgence of efforts to bring GABAkines to patients, the FDA approval of the neuroactive steroid brexanolone for post-partum depression in 2019 being the first. Other neuroactive steroids are in various stages of clinical development (ganaxolone, zuranolone, LYT-300, Sage-324, PRAX 114, and ETX-155). These GABAkines and non-steroid compounds (GRX-917, a TSPO binding site ligand), darigabat (CVL-865), an α2/3/5-preferring GABAkine, SAN711, an α3-preferring GABAkine, and the α2/3-preferring GABAkine, KRM-II-81, bring new therapeutic promise to this highly utilized medicinal target in neurology and psychiatry. Herein, we also discuss possible conditions that have enabled the transition to a new age of GABAkines. We highlight the pharmacology of KRM-II-81 that has the most preclinical data reported. KRM-II-81 is the lead compound in a new series of orally bioavailable imidazodiazepines entering IND-enabling safety studies. KRM-II-81 has a preclinical profile predicting efficacy against pharmacoresistant epilepsies, traumatic brain injury, and neuropathic pain. KRM-II-81 also produces anxiolytic- and antidepressant-like effects in rodent models. Other key features of the pharmacology of this compound are its low sedation rate, lack of tolerance development, and the ability to prevent the development of seizure sensitization.

GABAkines - Advances in the discovery, development, and commercialization of positive allosteric modulators of GABAA receptors.

Positive allosteric modulators of γ-aminobutyric acid-A (GABAA) receptors or GABAkines have been widely used medicines for over 70 years for anxiety, epilepsy, sleep, and other disorders. Traditional GABAkines like diazepam have safety and tolerability concerns that include sedation, motor-impairment, respiratory depression, tolerance and dependence. Multiple GABAkines have entered clinical development but the issue of side-effects has not been fully solved. The compounds that are presently being developed and commercialized include several neuroactive steroids (an allopregnanolone formulation (brexanolone), an allopregnanolone prodrug (LYT-300), Sage-324, zuranolone, and ganaxolone), the α2/3-preferring GABAkine, KRM-II-81, and the α2/3/5-preferring GABAkine PF-06372865 (darigabat). The neuroactive steroids are in clinical development for post-partum depression, intractable epilepsy, tremor, status epilepticus, and genetic epilepsy disorders. Darigabat is in development for epilepsy and anxiety. The imidazodiazepine, KRM-II-81 is efficacious in animal models for the treatment of epilepsy and post-traumatic epilepsy, acute and chronic pain, as well as anxiety and depression. The efficacy of KRM-II-81 in models of pharmacoresistant epilepsy, preventing the development of seizure sensitization, and in brain tissue of intractable epileptic patients bodes well for improved therapeutics. Medicinal chemistry efforts are also ongoing to identify novel and improved GABAkines. The data document gaps in our understanding of the molecular pharmacology of GABAkines that drive differential pharmacological profiles, but emphasize advancements in the ability to successfully utilize GABAA receptor potentiation for therapeutic gain in neurology and psychiatry.

Socioeconomic and demographic factors in the diagnosis and treatment of Chiari malformation type I and syringomyelia.

OBJECTIVE: The goal of this study was to assess the social determinants that influence access and outcomes for pediatric neurosurgical care for patients with Chiari malformation type I (CM-I) and syringomyelia (SM). METHODS: The authors used retro- and prospective components of the Park-Reeves Syringomyelia Research Consortium database to identify pediatric patients with CM-I and SM who received surgical treatment and had at least 1 year of follow-up data. Race, ethnicity, and insurance status were used as comparators for preoperative, treatment, and postoperative characteristics and outcomes. RESULTS: A total of 637 patients met inclusion criteria, and race or ethnicity data were available for 603 (94.7%) patients. A total of 463 (76.8%) were non-Hispanic White (NHW) and 140 (23.2%) were non-White. The non-White patients were older at diagnosis (p = 0.002) and were more likely to have an individualized education plan (p < 0.01). More non-White than NHW patients presented with cerebellar and cranial nerve deficits (i.e., gait ataxia [p = 0.028], nystagmus [p = 0.002], dysconjugate gaze [p = 0.03], hearing loss [p = 0.003], gait instability [p = 0.003], tremor [p = 0.021], or dysmetria [p < 0.001]). Non-White patients had higher rates of skull malformation (p = 0.004), platybasia (p = 0.002), and basilar invagination (p = 0.036). Non-White patients were more likely to be treated at low-volume centers than at high-volume centers (38.7% vs 15.2%; p < 0.01). Non-White patients were older at the time of surgery (p = 0.001) and had longer operative times (p < 0.001), higher estimated blood loss (p < 0.001), and a longer hospital stay (p = 0.04). There were no major group differences in terms of treatments performed or complications. The majority of subjects used private insurance (440, 71.5%), whereas 175 (28.5%) were using Medicaid or self-pay. Private insurance was used in 42.2% of non-White patients compared to 79.8% of NHW patients (p < 0.01). There were no major differences in presentation, treatment, or outcome between insurance groups. In multivariate modeling, non-White patients were more likely to present at an older age after controlling for sex and insurance status (p < 0.01). Non-White and male patients had a longer duration of symptoms before reaching diagnosis (p = 0.033 and 0.004, respectively). CONCLUSIONS: Socioeconomic and demographic factors appear to influence the presentation and management of patients with CM-I and SM. Race is associated with age and timing of diagnosis as well as operating room time, estimated blood loss, and length of hospital stay. This exploration of socioeconomic and demographic barriers to care will be useful in understanding how to improve access to pediatric neurosurgical care for patients with CM-I and SM.

Pineal gland hypermetabolic involvement without central nervous system symptoms in a pediatric patient with primary nodular sclerosis subtype classical Hodgkin Lymphoma.

This case report presents the first reported pediatric case of primary classical nodular sclerosing Hodgkin Lymphoma (HL) with pineal gland involvement, presenting without CNS symptoms, which completely resolved after 2 cycles of chemotherapy. The 12 year-old male first presented with a right inguinal mass and external iliac lymphadenopathy accompanied by B symptoms. He was diagnosed with stage IV B classical HL, and as part of the staging work-up, a full-body PET/CT scan was performed. In addition to the right inguinal mass, the PET/CT demonstrated increased FDG uptake at the pineal gland along with level II lymph nodes. The patient was treated with ABVE-PC chemotherapy (Doxorubicin, Bleomycin, Vincristine, Etoposide, Prednisone, and Cyclophosphamide) as per standard arm of AHOD1331 COG protocol for newly diagnosed high-risk HL patients, which resolved the pineal mass after 2 cycles without requiring radiation therapy. Following 5 cycles, a full-body PET/CT showed no brain or neck activity, along with decreased size and activity of the right groin mass. To our knowledge, there are no other documented cases of primary HL with specific pineal involvement, and no cases that lack CNS symptoms altogether like this one did. Additionally, this is the third published pediatric case of primary CNS-HL, both of the previous cases were treated with radiotherapy and presented with CNS symptoms. Thus, this case demonstrates the importance of ordering a full-body PET/CT as part of the initial HL work-up and provides evidence that chemotherapy alone is a treatment option for some patients with primary intracranial HL.

N-Substituted-3-alkoxy-derivatives of dextromethorphan are functional NMDA receptor antagonists in vivo: Evidence from an NMDA-induced seizure model in rats.

Interest in developing NMDA receptor antagonists with reduced side-effects for neurological and psychiatric disorders has been re-energized by the recent introduction of esketamine into clinical practice for treatment-resistant depression. Structural analogs of dextromethorphan bind with low affinity to the NMDA receptor ion channel, have functional effects in vivo, and generally display a lower propensity for side-effects than that of ketamine and other higher affinity antagonists. As such, the aim of the present study was to determine whether a series of N-substituted-3-alkoxy-substituted dextromethorphan analogs produce their anticonvulsant effects through NMDA receptor blockade. Compounds were studied against NMDA-induced seizures in rats. Compounds were administered intracerebroventricularly in order to mitigate confounds of drug metabolism that arise from systemic administration. Comparison of the anticonvulsant potencies to their affinities for NMDA, σ1, and σ2 binding sites were made in order to evaluate the contribution of these receptors to anticonvulsant efficacy. The potencies to block convulsions were positively associated with their affinities to bind to the NMDA receptor ion channel ([3H]-TCP binding) (r = 0.71, p < 0.05) but not to σ1 receptors ([3H]-SKF 10047 binding) (r = -0.31, p = 0.46) or to σ2 receptors ([3H]-DTG binding) (p = -0.38, p = 0.36). This is the first report demonstrating that these dextromethorphan analogs are functional NMDA receptor antagonists in vivo. Given their potential therapeutic utility and favorable side-effect profiles, such low affinity NMDA receptor antagonists could be considered for further development in neurological (e.g., anticonvulsant) and psychiatric (e.g., antidepressant) disorders.