Publications by authors named "Jodi L Smith"

Article Synopsis
  • Traumatic brain injury (TBI) is a growing global concern with severe long-term effects, including dizziness, sleep issues, headaches, seizures, and mental health problems like depression and anxiety.
  • The prognosis for TBI outcomes is complicated due to the varied nature of the injuries, and research is increasingly focusing on genetics, such as the role of brain-derived neurotrophic factor (BDNF) and molecular biomarkers like the inflammatory protein IL1-β.
  • The review highlights not only the complications associated with TBI, such as cognitive decline and the risk of neurodegenerative diseases but also discusses current and future medical treatments aimed at alleviating these debilitating symptoms.
View Article and Find Full Text PDF

NMDA receptor antagonists have potential for therapeutics in neurological and psychiatric diseases, including neurodegenerative diseases, epilepsy, traumatic brain injury, substance abuse disorder (SUD), and major depressive disorder (MDD). ()-ketamine was the first of a novel class of antidepressants, rapid-acting antidepressants, to be approved for medical use. The stereoisomer, ()-ketamine (arketamine), is currently under development for treatment-resistant depression (TRD).

View Article and Find Full Text PDF

Spinal cord injury (SCI) afflicts millions of individuals globally. There are few therapies available to patients. Ascending and descending excitatory glutamatergic neural circuits in the central nervous system are disrupted by SCI, making α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) a potential therapeutic drug target.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

KRM-II-81 (1) is an imidazodiazepine GABA 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.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

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).

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

Imidazodiazepine (5-(8-ethynyl-6-(pyridin-2-yl)-4-benzo[]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole or KRM-II-81) is a potentiator of GABA 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.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF
Article Synopsis
  • * The leading theory suggests that tinnitus stems from compromised inhibitory mechanisms in the brain, specifically involving impaired GABA (a neurotransmitter) function, which leads researchers to explore GABA-enhancing drugs (GABAkines) for symptom relief.
  • * Although there is limited data, some studies indicate that traditional benzodiazepines have shown effectiveness, and there is potential for new GABAkines targeting extrasynaptic GABA receptors to provide additional therapeutic options worth investigating.
View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF
Article Synopsis
  • GABAkines are positive allosteric modulators of GABA receptors, used to treat conditions like anxiety, epilepsy, and sleep disorders; however, the development of new GABAkines had slowed down due to safety and side-effect concerns.
  • Recently, there has been renewed interest and progress in bringing new GABAkines to market, with the FDA approving brexanolone for post-partum depression in 2019 and several others currently in clinical development.
  • KRM-II-81 is highlighted as a promising new GABAkine with potential effectiveness against pharmacoresistant epilepsy, traumatic brain injury, and neuropathic pain, showing low sedation, no tolerance development, and anxiolytic and antidepressant-like
View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF
Article Synopsis
  • Positive allosteric modulators of GABA receptors (GABAkines) have been used for over 70 years to treat various disorders, but traditional options like diazepam have significant side effects such as sedation and dependence.
  • New compounds, including neuroactive steroids (like brexanolone), KRM-II-81, and darigabat, are currently in development to address issues like post-partum depression and epilepsy with potentially fewer side effects.
  • Ongoing research in medicinal chemistry aims to discover improved GABAkines, highlighting a need for better understanding of their molecular pharmacology to enhance their therapeutic effects in neurology and psychiatry.
View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

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.

View Article and Find Full Text PDF

R-(-)-ketamine has emerged as a potentially improved medication over that of the (S)-isomer (marketed as Spravato for depression). Recent data have suggested (R)-ketamine could have value in the treatment of substance use disorder. The present set of experiments was undertaken to examine whether (R)-ketamine might prevent tolerance development.

View Article and Find Full Text PDF