H. Steve White
VerifiedUniversity of Washington · Pharmacy
Active 1945–2025
About
H. Steve White, RpH, Ph.D, earned his baccalaureate degree in Pharmacy and a M.S. in Pharmacology at Idaho State University. He earned his Ph.D. in Pharmacology at the University of Utah where he joined the College of Pharmacy faculty in 1986 and advanced through the academic ranks. Before joining the University of Washington School of Pharmacy as Chair of the Department of Pharmacy, White was the principal investigator and scientific director of the NIH-sponsored Anticonvulsant Drug Development (ADD) Program, established in 1975 to identify novel anticonvulsant drugs using established animal seizure and epilepsy models. His research focuses on understanding the factors that contribute to the initiation, propagation, and amelioration of seizure activity, including early discovery of anti-seizure drugs, animal seizure and epilepsy models for drug discovery, pharmaco-resistant epilepsy, and the impact of adherence on seizure control. White has received significant research funding from the National Institute of Neurological Disorders and Stroke (NINDS) and the NIH, and has published over 170 original papers on the mechanism of action and pharmacology of antiepileptic drugs. He has served as Research Director of CURE, the largest non-governmental provider of epilepsy research funding, and continues to serve as a Research Advisor to its team-science initiatives. White has been actively engaged as a mentor for neuroscientists and epilepsy educators, and is frequently invited to speak at national and international congresses. In recognition of his contributions, he received an Honorary Doctor of Science from the University of Copenhagen in 2011 and the Epilepsy Foundation's Lifetime Accelerator Award in 2014. He was appointed Chair of the Department of Pharmacy at the University of Washington in January 2016.
Research topics
- Medicine
- Psychiatry
- Political Science
- Psychology
- Intensive care medicine
- Pharmacology
- Anesthesia
- Chemistry
- Internal medicine
- Neuroscience
- Medical physics
- Pathology
Selected publications
A review of the putative antiseizure and antiepileptogenic mechanisms of action for soticlestat
Epilepsia · 2025-02-18 · 8 citations
reviewOpen accessSenior authorSoticlestat (TAK-935) is a potent and selective inhibitor of cholesterol 24-hydroxylase (CYP46A1), an enzyme primarily expressed in the brain that catabolizes cholesterol to 24S-hydroxycholesterol (24HC). In the ELEKTRA phase II clinical trial, soticlestat reduced seizure frequency in patients with developmental and epileptic encephalopathies, and two phase III studies evaluating the safety and efficacy of soticlestat in Dravet syndrome (SKYLINE) and Lennox-Gastaut syndrome (SKYWAY) have recently been completed. The exact mechanism of action by which soticlestat exerts pharmacological benefits remains undetermined. In this review, we assess the available preclinical evidence and present a working hypothesis for the antiseizure effects of soticlestat. The data support three potential mechanisms of action: (1) normalization of the seizure threshold via reduction of 24HC levels in the brain; as 24HC acts as a potent and selective positive allosteric modulator of glutamate N-methyl-D-aspartate receptors, reduction of 24HC levels by soticlestat may lead to decreased hyperexcitability and elevated seizure thresholds; (2) restoration of glutamate sequestration from the synaptic cleft; accumulation of glutamate in the synaptic cleft enhances neural excitation and can contribute to neurotoxicity; soticlestat may inhibit conversion of cholesterol to 24HC in the membrane lipid raft microdomain and help to preserve it, consequently reducing excessive glutamate excitation; and (3) suppression of neuroinflammation via reduction of inflammatory cytokine release. These potential mechanisms of action warrant further investigation.
British Journal of Pharmacology · 2025-06-02 · 3 citations
articleOpen accessSenior authorBACKGROUND AND PURPOSE: Drug-resistant epilepsy affects 30% of patients who have uncontrolled seizures despite current antiseizure medications (ASMs). Preclinical drug screening often uses acute dosing and evoked seizures, which may not fully capture the complexities of drug resistance and human treatment regimens. We introduce a novel experimental paradigm that incorporates clinical treatment regimens, pharmacokinetic monitoring and behavioural tolerability assessments to accurately model drug-resistant epilepsy in animal models. EXPERIMENTAL APPROACH: Rats with epilepsy following kainic acid-induced status epilepticus were enrolled in a triple cross-over study to evaluate the dose-dependent efficacy and tolerability of three commonly used ASMs: - lamotrigine, levetiracetam and carbamazepine. Each medication was delivered in rodent chow for 2 weeks via our automated system, maintaining steady-state exposures measured by pharmacokinetic sampling. Seizure control was monitored via 24/7 videoEEG and behavioural tolerability was evaluated using minimal motor impairment and hyperexcitability assays. KEY RESULTS: Chronic oral dosing with carbamazepine and levetiracetam reduced seizure frequency by more than 50% in over half the animals at clinically relevant doses. Lamotrigine, however, was either ineffective or worsened seizures at toxic doses, increasing both convulsive and clustered seizures. Levetiracetam was well tolerated, while carbamazepine impaired motor function at the highest dose. Lamotrigine led to increased hyperactivity and aggressive behaviour at all doses. CONCLUSION AND IMPLICATIONS: This study highlights the need for preclinical models that better reflect human epilepsy, considering both efficacy and side effects in drug development. Our findings emphasize the complexity of drug responses and underscore the importance of improved models for drug development.
bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-08
preprintOpen accessABSTRACT/SUMMARY Objective Central to the development of novel antiseizure medications (ASMs) is testing of anticonvulsant activity in preclinical models. While various well-established models exist, their predictive validity across the spectrum of clinical epilepsies has been less clear. We sought to establish the translational concordance of commonly used preclinical models to define models with the highest predictive clinical validity for focal onset seizures (FOS). Methods The Praxis Analysis of Concordance (PAC) framework was implemented to assess the translational concordance between preclinical and clinical ASM response for 32 FDA-approved ASMs. Preclinical ASM responses in historically used seizure models were collected. Protective indices based on reported TD 50 and ED 50 values were calculated for each ASM in each preclinical model. A weighted scale representing relative anticonvulsant effect was used to grade preclinical ASM response for each seizure model. Data depth was further scored based on the number of evaluated ASMs with publicly available data. Established reports of clinical ASM use in patients with FOS were similarly evaluated and a weighted scale representing prescribing patterns and perceived efficacy used to grade clinical ASM response for each indication. To assess the predictive validity of preclinical models, a unified translational scoring matrix was developed to assign a concordance score spanning the spectrum of complete discordance (-1) to complete concordance (1) between preclinical and clinical ASM responses. Scores were summed and normalized to generate a global translational concordance score. Results The preclinical models with the highest translational concordance and greatest data depth for FOS were rodent maximal electroshock seizure (MES), mouse audiogenic seizure, mouse 6 Hz (32mA) and rat amygdala kindling. Significance The PAC-FOS framework highlights mouse MES, mouse audiogenic and mouse 6 Hz (32mA) as three acute seizure models consistently demonstrating high predictive validity for FOS. We provide a pragmatic decision tree approach to support efficient resource utilization for novel ASM discovery for FOS. KEY POINT BOX Using a newly developed translational scoring matrix, we provide novel insights into the clinical validity of common preclinical seizure models for FOS. The PAC-FOS Framework identifies mouse MES, audiogenic and 6-Hz 32 mA as three acute models with greatest predictive validity and versatility for FOS drug discovery. We present a pragmatic approach and decision tree to support efficient use of drug discovery resources and in consideration of the 3Rs of animal ethics. The work presented would allow for faster and more effective screening of ASMs, while potentially reducing future patient exposures to likely ineffective drugs.
Epilepsy & Behavior · 2025-07-08 · 1 citations
articlebioRxiv (Cold Spring Harbor Laboratory) · 2025-01-11
preprintOpen accessAbstract Antiseizure medicines (ASMs) cause both acute and chronic behavioral side effects in individuals with epilepsy. While clinical and preclinical studies often focus on chronic effects, the acute dose-related impact of ASMs on behavior is underreported, especially in rodent temporal lobe epilepsy (TLE) models. Investigating the acute effects of both therapeutic and behaviorally impairing doses may inform clinically relevant adverse effects, such as sedation, hyperactivity, and impaired coordination, which are essential for evaluating drug safety and tolerability. This study investigated the acute effects of anticonvulsant doses of carbamazepine (CBZ), valproic acid (VPA), levetiracetam (LEV), and cenobamate (CNB) on locomotor activity and exploratory behavior in rats 8-13 weeks after kainic acid-induced status epilepticus to elicit confirmed spontaneous recurrent seizures consistent (SRS) with TLE. Behavioral outcomes were quantified using an automated open field task (OFT) in both epileptic and non-epileptic (naïve) rats. Our findings revealed that anticonvulsant doses of CNB affected locomotor behavior while other ASMs did not alter exploratory behavior. However, the motor impairing doses of CBZ and CNB equally suppressed exploratory behavior, likely due to sedative effects, in both epileptic and non-epileptic rats. LEV was unique, showing no sedative effects even at high doses, while VPA exhibited an anxiolytic effect in SRS rats and a sedative effect in naïve rats at high dose. This study provides essential insight into the efficacy and tolerability profiles of a diversity of FDA-approved ASMs in a clinically relevant TLE model. Thus, SRS may influence ASM tolerability in preclinical TLE models that may inform clinical translation.
Potential for Therapeutic Alteration of the Underlying Biology of Epilepsy
Biomedicines · 2025-09-13 · 2 citations
reviewOpen accessApproximately 30-35% of people with epilepsy experience seizures despite taking antiseizure medications. Recurrent seizures that are independent of status epilepticus can be associated with neuronal injury and structural changes to the brain, as well as diminished cognitive function, mood, and quality of life. A treatment that alters the underlying biology of epilepsy, thereby reducing the seizure burden and its attendant consequences, would be of great value in preventing these detrimental effects. In this review, we summarize preclinical and clinical research on pharmacological treatments that may favorably alter the underlying biology of epilepsy (i.e., disease modification or antiepileptogenesis). A reduction in seizures over time (e.g., increase in responder rates) or prevention of epilepsy in susceptible individuals has been observed with therapies that target neurotransmission (cenobamate, cannabidiol, vigabatrin, and diazepam nasal spray) and inflammation (everolimus), though evidence is limited and in preliminary stages. Pharmacological treatments that target neuroinflammation and oxidative stress have the potential to modify seizure phenotype and 1 or more comorbidities in preclinical studies (e.g., stress/anxiety and depression). Gene therapies and stem-cell-derived treatments also hold promise in reducing seizure burden in preclinical models, with several therapeutic candidates having advanced to phase 1/2 and 3 clinical trials. Effective disease-modifying strategies in epilepsy might include seizure control with novel antiseizure medications in combination with therapeutic targeting of key pathophysiological mechanisms. Standard criteria and a definition of disease modification should be established. Importantly, given the heterogeneity of the epilepsies, syndrome- or seizure-specific methods and trial design would likely be required.
Epilepsia · 2025-08-06 · 1 citations
articleOpen accessOBJECTIVE: Central to the development of novel antiseizure medications (ASMs) is testing of antiseizure activity in preclinical models. Although various well-established models exist, their predictive validity across the spectrum of clinical epilepsies has been less clear. We sought to establish the translational concordance of commonly used preclinical models to define models with the highest predictive clinical validity for focal onset seizures (FOS). METHODS: The Praxis Analysis of Concordance (PAC) framework was implemented to assess the translational concordance between preclinical and clinical ASM response for 32 US Food and Drug Administration-approved ASMs. Preclinical ASM responses in historically used seizure models were collected. Protective indices based on reported median tolerability and median efficacy values were calculated for each ASM in each preclinical model. A weighted scale representing relative antiseizure effect was used to grade preclinical ASM response for each seizure model. Data depth was further scored based on the number of evaluated ASMs with publicly available data. Established reports of clinical ASM use in patients with FOS were similarly evaluated, and a weighted scale representing prescribing patterns and perceived efficacy was used to grade clinical ASM response. To assess the predictive validity of preclinical models, a unified translational scoring matrix was developed to assign a concordance score spanning the spectrum from complete discordance (-1) to complete concordance (1) between preclinical and clinical ASM responses. Scores were summed and normalized to generate a global translational concordance score. RESULTS: The preclinical models with the highest translational concordance and greatest data depth for FOS were rodent maximal electroshock seizure (MES), mouse audiogenic seizure, mouse 6 Hz (32 mA), and rat amygdala kindling. SIGNIFICANCE: The PAC-FOS framework highlights mouse MES, mouse audiogenic, and mouse 6 Hz (32 mA) as three acute seizure models consistently demonstrating high predictive validity for FOS. We provide a pragmatic decision tree approach to support efficient resource utilization for novel ASM discovery for FOS.
Epilepsia · 2025-03-15 · 1 citations
articleOpen accessAbstract Objective γ‐Aminobutyric acid type A (GABA A ) receptor positive allosteric modulators (PAMs) that lack α‐subunit selectivity, including benzodiazepines such as diazepam, exhibit antiseizure actions in animal models and in humans. ENX‐101 is a deuterated analog of the ⍺2,3,5‐selective GABA A receptor PAM L‐838,417. The purpose of this study was to characterize the α‐subunit selectivity of ENX‐101 and evaluate its antiseizure potential in preclinical seizure and epilepsy models. Methods ENX‐101 potentiation of GABA chloride current responses in cells expressing recombinant GABA A receptors were evaluated using an automated patch clamp assay. Antiseizure effects of ENX‐101 were examined in the mouse 6 Hz test at 32 and 44 mA, amygdala kindled rats, and Genetic Absence Epilepsy Rat from Strasbourg (GAERS). Results ENX‐101 displayed partial PAM activity with respect to diazepam at GABA A receptors containing α2, α3, or α5 subunits but did not enhance GABA responses of GABA A receptors containing α1 subunits. ENX‐101 (30, 100, and 300 mg/kg, i.p.) and diazepam protected most animals in the 6 Hz model at 32 mA but was less effective at 44 mA. In amygdala kindled rats, ENX‐101 (1–100 mg/kg, p.o.) reduced behavioral seizure severity and afterdischarge duration in a dose‐dependent manner. ENX‐101 (0.075–100 mg/kg, p.o.) caused dose‐dependent, persistent (>130 min) inhibition of spontaneous spike‐and‐wave discharges (SWDs) in GAERS, whereas diazepam transiently inhibited discharges. ENX‐101 did not cause motor impairment, as measured by performance in the rotarod assay. Significance ENX‐101 is an α2,α3,α5‐selective GABA A receptor PAM that has high potency and partial efficacy. The drug is highly effective in rodent seizure and epilepsy models. ENX‐101 is most potent in the GAERS model of absence epilepsy, and active in the 6 Hz model and amygdala kindled rats. These results demonstrate that a partial, subtype‐selective GABA A receptor PAM has activity in translationally validated preclinical epilepsy screening models. Clinical evaluation of ENX‐101 as a treatment for focal and generalized epilepsies is warranted.
Journal of Neurochemistry · 2024-08-26
articleOpen accessSenior authorThis is a tribute to Arne Schousboe, Professor Emeritus at the University of Copenhagen, an eminent neurochemist and neuroscientist who was a leader in the fields of GABA, glutamate, and brain energy metabolism. Arne was known for his keen intellect, his wide-ranging expertise in neurochemistry and neuropharmacology of GABA and glutamate and brain energy metabolism. Arne was also known for his strong leadership, his warm and engaging personality and his enjoyment of fine wine and great food shared with friends, family, and colleagues. Sadly, Arne passed away on February 27, 2024, after a short illness. He is survived by his wife Inger Schousboe, his two children, and three wonderful grandchildren. His death is a tremendous loss to the neuroscience community. He will be greatly missed by his friends, family, and colleagues. Some of the highlights of Arne's career are described in this tribute.
2024-12-11
preprintOpen accessSenior authorBackground & Purpose: Drug-resistant epilepsy affects 30% of patients who continue to have seizures despite current antiseizure medications (ASMs). Preclinical drug screening uses acute dosing and evoked seizures, which may not fully capture the complexities of drug resistance and human treatment regimens. We introduce a novel experimental paradigm that incorporates clinical treatment regimens, pharmacokinetic monitoring, and behavioral tolerability assessments to accurately model drug-resistant epilepsy in animal models. Experimental Approach: Rats with epilepsy following kainic acid induced status epilepticus were enrolled in a triple cross-over study to evaluate the dose-dependent efficacy and tolerability of three commonly used ASMs — lamotrigine, levetiracetam, and carbamazepine. Each medication was delivered in rodent chow for two weeks via our automated system, maintaining steady-state exposures measured by pharmacokinetic sampling. Seizure control was monitored via 24/7 videoEEG, and behavioral tolerability was evaluated using minimal motor impairment and hyperexcitability assays. Key Results: Chronic oral dosing with carbamazepine and levetiracetam reduced seizure frequency by more than 50% in over half the animals at clinically relevant doses. Lamotrigine, however, was either ineffective or worsened seizures at toxic doses, increasing both convulsive and clustered seizures. Levetiracetam was well tolerated, while carbamazepine impaired motor function at the highest dose. Lamotrigine led to increased hyperactivity and aggressive behavior at all doses. Conclusions: This study highlights the need for preclinical models that better reflect human epilepsy, considering both efficacy and side effects in drug development. Our findings emphasize the complexity of drug responses and underscore the importance of improved models for drug development.
Recent grants
NIH · $887k · 2015
NIH · $380k · 2008
Development of a galanin-based therapy for the treatment of refractory epilepsy
NIH · $3.4M · 2010–2015
NIH · $640k · 1993
Frequent coauthors
- 83 shared
Vivienne Shen
Lundbeck (United States)
- 83 shared
David M. Tworek
- 83 shared
James C. Cloyd
- 83 shared
Guangbin Peng
Shanghai University of Traditional Chinese Medicine
- 83 shared
Jouko Isojärvi
- 82 shared
Raman Sankar
- 82 shared
Georgia Montouris
Boston University
- 81 shared
Barry E. Gidal
University of Wisconsin–Madison
Labs
Education
Other, Pharmacy
not specified
M.S., Pharmacology
not specified
Ph.D., Pharmacology
not specified
Awards & honors
- Honorary Doctor of Science from The University of Copenhagen…
- 2014 recipient of the Epilepsy Foundation's Lifetime Acceler…
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