COVID-2019 Alert

The latest information about the 2019 Novel Coronavirus, including vaccine clinics for children ages 6 months and older.

La información más reciente sobre el nuevo Coronavirus de 2019, incluidas las clínicas de vacunación para niños de 6 meses en adelante.


Lawrence Fung, MD, PhD

  • Lawrence Kwok-Kit Fung



Work and Education

Professional Education

George Washington University Office of the Registrar, Washington, DC, 05/17/2009


Stanford University Pain Management Fellowship, Redwood City, CA, 06/30/2010


Stanford University Pain Management Fellowship, Redwood City, CA, 06/30/2012


Stanford University Pain Management Fellowship, Redwood City, CA, 12/31/2014

Board Certifications

Child & Adolescent Psychiatry, American Board of Psychiatry and Neurology

Psychiatry, American Board of Psychiatry and Neurology

All Publications

NEURODIVERSITY: AN INVISIBLE STRENGTH? JOM Fung, L. K., Ulrich, T. L., Fujimoto, K. T., Taheri, M. 2022; 74 (9): 3200-3202
"Self-compassion changed my life": The self-compassion experiences of autistic and non-autistic adults and its relationship with mental health and psychological wellbeing. Journal of autism and developmental disorders Cai, R. Y., Gibbs, V., Love, A., Robinson, A., Fung, L., Brown, L. 2022


Self-compassion is a gentle way of relating to oneself, linked to a host of mental health benefits in non-autistic people. Although many autistic individuals report high anxiety and depression symptoms, no research to-date has examined the self-compassion experiences of autistic individuals and determined if self-compassion is associated with psychopathology. Therefore, the purpose of the current study was to address this research gap. The participants (153 autistic and 93 non-autistic adults) completed on online survey and 11 autistic participants were also interviewed. Autistic participants reported significantly lower self-compassion than non-autistic adults, and in both groups, those with higher self-compassion reported higher psychological wellbeing and lower depression symptoms. Demographic predictors of self-compassion were identified. These findings have both clinical and research implications.

View details for DOI 10.1007/s10803-022-05668-y

View details for PubMedID 35904649

The impact of autism-related training programs on physician knowledge, self-efficacy, and practice behavior: A systematic review. Autism : the international journal of research and practice Clarke, L., Fung, L. K. 2022: 13623613221102016


Autism spectrum disorder is estimated to impact 1.5 million children and almost 5.5 million adults. However, most physicians do not receive training on how to provide care to this increasingly large group of people. After performing a systematic review of the literature and screening over 4,500 unique articles focused on the effectiveness of autism-specific training programs designed for physicians and physician trainees, we determined that 17 studies met the pre-determined criteria for inclusion in this systematic review. The results reported by these studies suggest that by completing specialized training programs related to autism, physicians were more knowledgeable on topics related to the condition, more confident in their ability to provide care to autistic individuals, and more likely to screen their patients for autism spectrum disorder. However, further studies with higher quality data are needed to validate these findings and provide additional insight on the ability of these programs to improve physician behavior and patient outcomes. We are therefore advocating that medical educators develop and evaluate specialized autism training programs with an increased focus on improving physician behavior related to all aspects of providing care to autistic people.

View details for DOI 10.1177/13623613221102016

View details for PubMedID 35698749

Region-specific associations between gamma-aminobutyric acid A receptor binding and cortical thickness in high-functioning autistic adults. Autism research : official journal of the International Society for Autism Research James, D., Lam, V. T., Jo, B., Fung, L. K. 2022


The neurobiology of autism has been shown to involve alterations in cortical morphology and gamma-aminobutyric acid A (GABAA ) receptor density. We hypothesized that GABAA receptor binding potential (GABAA R BPND ) would correlate with cortical thickness, but their correlations would differ between autistic adults and typically developing (TD) controls. We studied 50 adults (23 autism, 27 TD, mean age of 27years) using magnetic resonance imaging to measure cortical thickness, and [18 F]flumazenil positron emission tomography imaging to measure GABAA R BPND . We determined the correlations between cortical thickness and GABAA R BPND by cortical lobe, region-of-interest, and diagnosis of autism spectrum disorder (ASD). We also explored potential sex differences in the relationship between cortical thickness and autism characteristics, as measured by autism spectrum quotient (AQ) scores. Comparing autism and TD groups, no significant differences were found in cortical thickness or GABAA R BPND . In both autism and TD groups, a negative relationship between cortical thickness and GABAA R BPND was observed in the frontal and occipital cortices, but no relationship was found in the temporal or limbic cortices. A positive correlation was seen in the parietal cortex that was only significant for the autism group. Interestingly, in an exploratory analysis, we found sex differences in the relationships between cortical thickness and GABAA R BPND , and cortical thickness and AQ scores in the left postcentral gyrus. LAY SUMMARY: The thickness of the brain cortex and the density of the receptors associated with inhibitory neurotransmitter GABA have been hypothesized to underlie the neurobiology of autism. In this study, we found that these biomarkers correlate positively in the parietal cortex, but negatively in the frontal and occipital cortical regions of the brain. Furthermore, we collected preliminary evidence that the correlations between cortical thickness and GABA receptor density are sexdependent in a brain region where sensory inputs are registered.

View details for DOI 10.1002/aur.2703

View details for PubMedID 35261207

A Scoping Review of Peer Mentoring Programs for Autistic College Students Review Journal of Autism and Developmental Disorders Morris, I. F., Matta, C., Fung, L. K. 2022
Thalamocortical connectivity is associated with autism symptoms in high-functioning adults with autism and typically developing adults. Translational psychiatry Ayub, R. n., Sun, K. L., Flores, R. E., Lam, V. T., Jo, B. n., Saggar, M. n., Fung, L. K. 2021; 11 (1): 93


Alterations in sensorimotor functions are common in individuals with autism spectrum disorder (ASD). Such aberrations suggest the involvement of the thalamus due to its key role in modulating sensorimotor signaling in the cortex. Although previous research has linked atypical thalamocortical connectivity with ASD, investigations of this association in high-functioning adults with autism spectrum disorder (HFASD) are lacking. Here, for the first time, we investigated the resting-state functional connectivity of the thalamus, medial prefrontal, posterior cingulate, and left dorsolateral prefrontal cortices and its association with symptom severity in two matched cohorts of HFASD. The principal cohort consisted of 23 HFASD (mean[SD] 27.1[8.9] years, 39.1% female) and 20 age- and sex-matched typically developing controls (25.1[7.2] years, 30.0% female). The secondary cohort was a subset of the ABIDE database consisting of 58 HFASD (25.4[7.8] years, 37.9% female) and 51 typically developing controls (24.4[6.7] years, 39.2% female). Using seed-based connectivity analysis, between-group differences were revealed as hyperconnectivity in HFASD in the principal cohort between the right thalamus and bilateral precentral/postcentral gyri and between the right thalamus and the right superior parietal lobule. The former was associated with autism-spectrum quotient in a sex-specific manner, and was further validated in the secondary ABIDE cohort. Altogether, we present converging evidence for thalamocortical hyperconnectivity in HFASD that is associated with symptom severity. Our results fill an important knowledge gap regarding atypical thalamocortical connectivity in HFASD, previously only reported in younger cohorts.

View details for DOI 10.1038/s41398-021-01221-0

View details for PubMedID 33536431

Neurobiology of Neurodiversity Neurodiversity: from Phenomenology to Neurobiology and Enhancing Technologies Fung, L. K. American Psychiatric Association Publishing. 2021


Autism spectrum disorder (ASD) has been associated with imbalance between excitatory and inhibitory (E/I) neurotransmission systems, as well as with neuroinflammation. Sitting at the crossroads between E/I imbalance and neuroinflammation is a class of endogenous hormones known as neurosteroids. Current literature points to dysregulated steroid metabolism and atypical neurosteroid levels in ASD as early as in utero. However, due to the complexity of neurosteroid metabolomics, including possible sex differences, the impact of neurosteroids on ASD symptomatology remains unclear. In this study, we assessed neurosteroid levels and ASD symptom severity of 21 males with ASD and 20 full-scale-IQ-matched typically developing (TD) males, all aged 18-39. Using liquid chromatography-tandem mass spectrometry, concentrations of allopregnanolone, cortisol, dehydroepiandrosterone, progesterone, and testosterone were measured in saliva and serum. With the exception of cortisol's, all neurosteroids' concentrations were found to have ASD vs. TD group differences in distribution, where one group was normally distributed and the other non-normally distributed. Serum allopregnanolone levels in males with ASD were found to negatively correlate with clinician-rated measures of restricted and repetitive behavior measures (ADOS-2 RRB and ADI-R RRSB domain scores). Additionally, lower serum allopregnanolone levels were found to predict more negative camouflaging scores, which represent greater differences in self- and clinician-rated symptom severity, of both ASD symptomatology overall and repetitive behaviors in particular. Taken together, our findings demonstrate that in adult males with ASD, decreased serum allopregnanolone levels are associated with more severe restricted and repetitive behaviors and with less insight into the severity of these behaviors.

View details for DOI 10.1016/j.psyneuen.2020.105039

View details for PubMedID 33161257

Strengths-Based Model of Attention Deficit Hyperactivity Disorder Neurodiversity: from Phenomenology to Neurobiology and Enhancing Technologies Fung, L. K. American Psychiatric Association Publishing. 2021


The gamma aminobutyric acid (GABA) neurotransmission system has been implicated in autism spectrum disorder (ASD). Molecular neuroimaging studies incorporating simultaneous acquisitions of GABA concentrations and GABAA receptor densities can identify objective molecular markers in ASD. We measured both total GABAA receptor densities by using [18F]flumazenil positron emission tomography ([18F]FMZ-PET) and GABA concentrations by using proton magnetic resonance spectroscopy (1H-MRS) in 28 adults with ASD and 29 age-matched typically developing (TD) individuals. Focusing on the bilateral thalami and the left dorsolateral prefrontal cortex (DLPFC) as our regions of interest, we found no differences in GABAA receptor densities between ASD and TD groups. However, 1H-MRS measurements revealed significantly higher GABA/Water (GABA normalized by water signal) in the left DLPFC of individuals with ASD than that of TD controls. Furthermore, a significant gender effect was observed in the thalami, with higher GABA/Water in males than in females. Hypothesizing that thalamic GABA correlates with ASD symptom severity in gender-specific ways, we stratified by diagnosis and investigated the interaction between gender and thalamic GABA/Water in predicting Autism-Spectrum Quotient (AQ) and Ritvo Autism Asperger's Diagnostic Scale-Revised (RAADS-R) total scores. We found that gender is a significant effect modifier of thalamic GABA/Water's relationship with AQ and RAADS-R scores for individuals with ASD, but not for TD controls. When we separated the ASD participants by gender, a negative correlation between thalamic GABA/Water and AQ was observed in male ASD participants. Remarkably, in female ASD participants, a positive correlation between thalamic GABA/Water and AQ was found.

View details for DOI 10.1038/s41380-020-0756-y

View details for PubMedID 32376999

Strengths-Based Model of Autism Neurodiversity: from Phenomenology to Neurobiology and Enhancing Technologies Fung, L. K. American Psychiatric Association Publishing. 2021
Neurodiversity: The New Diversity Neurodiversity: from Phenomenology to Neurobiology and Enhancing Technologies Fung, L. K., Doyle, N. American Psychiatric Association Publishing. 2021
Association of serum allopregnanolone with restricted and repetitive behaviors in adult males with autism. Psychoneuroendocrinology Chew, L., Sun, K. L., Sun, W., Wang, Z., Rajadas, J., Flores, R. E., Arnold, E., Jo, B., Fung, L. K. 2020; 123: 105039


The field of psychiatry is approaching a major inflection point. The basic science behind cognition, emotion, behavior, and social processes has been advancing rapidly in the past 20 years. However, clinical research supporting the classification system in psychiatry has not kept up with these scientific advances. To begin organizing the basic science of psychiatry in a comprehensive manner, we begin by selecting fragile X syndrome, a neurogenetic disease with cognitive-behavioral manifestations, to illustrate key concepts in an integrative, multidimensional model. Specifically, we describe key genetic and molecular mechanisms (e.g., gamma-aminobutyric acidergic dysfunction and metabotropic glutamate receptor 5-associated long-term depression) relevant to the pathophysiology of fragile X syndrome as well as neural correlates of cognitive-behavioral symptoms. We then describe what we have learned from fragile X syndrome that may be applicable to other psychiatric disorders. We conclude this review by discussing current and future opportunities in diagnosing and treating psychiatric diseases.

View details for DOI 10.1016/j.biopsych.2015.12.015

View details for Web of Science ID 000378530200007

View details for PubMedID 26868443

Thalamic and prefrontal GABA concentrations but not GABAA receptor densities are altered in high-functioning adults with autism spectrum disorder. Molecular psychiatry Fung, L. K., Flores, R. E., Gu, M. n., Sun, K. L., James, D. n., Schuck, R. K., Jo, B. n., Park, J. H., Lee, B. C., Jung, J. H., Kim, S. E., Saggar, M. n., Sacchet, M. D., Warnock, G. n., Khalighi, M. M., Spielman, D. n., Chin, F. T., Hardan, A. Y. 2020


White matter abnormalities have been described in autism spectrum disorder (ASD) with mounting evidence implicating these alterations in the pathophysiology of the aberrant connectivity reported in this disorder. The goal of this investigation is to further examine white matter structure in ASD using proton magnetic resonance spectroscopy ((1)H MRS). Multi-voxel, short echo-time in vivo(1)H MRS data were collected from 17 male children with ASD and 17 healthy age- and gender-matched controls. Key (1)H MRS metabolite ratios relative to phosphocreatine plus creatine were obtained from four different right and left white matter regions. Significantly lower N-acetylaspartate/creatine ratios were found in the anterior white matter regions of the ASD group when compared to controls. These findings reflect impairment in neuroaxonal white matter tissue and shed light on the neurobiologic underpinnings of white matter abnormalities in ASD by implicating an alteration in myelin and/or axonal development in this disorder.

View details for DOI 10.1016/j.pnpbp.2015.11.005

View details for PubMedID 26593330

Brief Report: Sex/Gender Differences in Symptomology and Camouflaging in Adults with Autism Spectrum Disorder JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Schuck, R. K., Flores, R. E., Fung, L. K. 2019; 49 (6): 25972604


Autism spectrum disorder (ASD) is increasingly recognized as a public health issue. Irritability and aggression (IA) often negatively affect the lives of people with ASD and their families. Although many medications have been tested for IA in ASDs in randomized controlled trials (RCTs), critical quantitative analyses of these trials are lacking in the literature.To systematically review and quantitatively analyze the efficacy and safety of pharmacologic treatments for IA in youth with ASD.Studies were identified from Medline, PsycINFO, Embase, and review articles.Original articles on placebo-controlled RCTs of pharmacologic treatments of IA in youth age 2 to 17 years with ASD were included. Data items included study design, study goals, details of study participants, details of intervention, study results, statistical methods, side effects, and risks of bias. The primary study outcome measure was the effect size of reduction in the Aberrant Behavioral Checklist-Irritability (ABC-I) scores in the medication group, as compared with placebo, in RCTs using parallel groups design.Forty-six RCTs were identified. Compared with placebo, 3 compounds resulted in significant improvement in ABC-I at the end of treatment. Risperidone and aripiprazole were found to be the most effective, with the largest effect sizes. Sedation, extrapyramidal sides effects, and weight gain were assessed quantitatively.Although risperidone and aripiprazole have the strongest evidence in reducing ABC-I in youth with ASD, a few other compounds also showed significant efficacy with fewer potential side effects and adverse reactions in single studies.

View details for DOI 10.1542/peds.2015-2851K

View details for PubMedID 26908468

A randomized placebo-controlled pilot trial shows that intranasal vasopressin improves social deficits in children with autism SCIENCE TRANSLATIONAL MEDICINE Parker, K. J., Oztan, O., Libove, R. A., Mohsin, N., Karhson, D. S., Sumiyoshi, R. D., Summers, J. E., Hinman, K. E., Motonaga, K. S., Phillips, J. M., Carson, D. S., Fung, L. K., Garner, J. P., Hardan, A. Y. 2019; 11 (491)


The objective of this study was to assess the tolerability and efficacy of pregnenolone in reducing irritability in adults with autism spectrum disorder (ASD). This was a pilot, open-label, 12-week trial that included twelve subjects with a mean age of 22.55.8years. Two participants dropped out of the study due to reasons unrelated to adverse effects. Pregnenolone yielded a statistically significant improvement in the primary measure, Aberrant Behavior Checklist (ABC)-Irritability [from 17.47.4 at baseline to 11.27.0 at 12weeks (p=0.028)]. Secondary measures were not statistically significant with the exception of ABC-lethargy (p=0.046) and total Short Sensory Profile score (p=0.009). No significant vital sign changes occurred during this study. Pregnenolone was not associated with any severe side effects. Single episodes of tiredness, diarrhea and depressive affect that could be related to pregnenolone were reported. Overall, pregnenolone was modestly effective and well-tolerated in individuals with ASD.

View details for DOI 10.1007/s10803-014-2144-4

View details for Web of Science ID 000343724000027

Moving Toward Integrative, Multidimensional Research in Modern Psychiatry: Lessons Learned From Fragile X Syndrome BIOLOGICAL PSYCHIATRY Fung, L. K., Reiss, A. L. 2016; 80 (2): 100-111


An imbalance in the excitatory/inhibitory systems with abnormalities in the glutamatergic pathways has been implicated in the pathophysiology of autism. Furthermore, chronic redox imbalance was also recently linked to this disorder. The goal of this pilot study was to assess the feasibility of using oral N-acetylcysteine (NAC), a glutamatergic modulator and an antioxidant, in the treatment of behavioral disturbance in children with autism.This was a 12-week, double-blind, randomized, placebo-controlled study of NAC in children with autistic disorder. Subjects randomized to NAC were initiated at 900 mg daily for 4 weeks, then 900 mg twice daily for 4 weeks and 900 mg three times daily for 4 weeks. The primary behavioral measure (Aberrant Behavior Checklist [ABC] irritability subscale) and safety measures were performed at baseline and 4, 8, and 12 weeks. Secondary measures included the ABC stereotypy subscale, Repetitive Behavior Scale-Revised, and Social Responsiveness Scale.Thirty-three subjects (31 male subjects, 2 female subjects; aged 3.2-10.7 years) were randomized in the study. Follow-up data was available on 14 subjects in the NAC group and 15 in the placebo group. Oral NAC was well tolerated with limited side effects. Compared with placebo, NAC resulted in significant improvements on ABC irritability subscale (F = 6.80; p < .001; d = .96).Data from this pilot investigation support the potential usefulness of NAC for treating irritability in children with autistic disorder. Large randomized controlled investigations are warranted.

View details for DOI 10.1016/j.biopsych.2012.01.014

View details for Web of Science ID 000303814800007

View details for PubMedID 22342106

A proton spectroscopy study of white matter in children with autism. Progress in neuro-psychopharmacology & biological psychiatry Hardan, A. Y., Fung, L. K., Frazier, T., Berquist, S. W., Minshew, N. J., Keshavan, M. S., Stanley, J. A. 2016; 66: 48-53
Pharmacologic Treatment of Severe Irritability and Problem Behaviors in Autism: A Systematic Review and Meta-analysis. Pediatrics Fung, L. K., Mahajan, R., Nozzolillo, A., Bernal, P., Krasner, A., Jo, B., Coury, D., Whitaker, A., Veenstra-VanderWeele, J., Hardan, A. Y. 2016; 137: S124-35
Brief Report: An Open-Label Study of the Neurosteroid Pregnenolone in Adults with Autism Spectrum Disorder JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS Fung, L. K., Libove, R. A., Phillips, J., Haddad, F., Hardan, A. Y. 2014; 44 (11): 2971-2977
A Randomized Controlled Pilot Trial of Oral N-Acetylcysteine in Children with Autism BIOLOGICAL PSYCHIATRY Hardan, A. Y., Fung, L. K., Libove, R. A., Obukhanych, T. V., Nair, S., Herzenberg, L. A., Frazier, T. W., Tirouvanziam, R. 2012; 71 (11): 956-961


This study quantified toe-walking trends and treatment decisions in patients with autism spectrum disorder (ASD) in the United States between 2005 and 2016 using a large national private-payer database.A retrospective database review was performed on paediatric patients with ASD, and for International Classification of Diseases-9/10 diagnosis codes for toe-walking. Patients were filtered based on treatment type by Current Procedural Terminology (CPT) code. Continued toe-walking rates were assessed for each patient population and treatment group. A Pearson's chi-squared test was used to evaluate differences in group characteristics.Of 2 221 009 paediatric patients in the database, 5739 patients had a diagnosis of ASD, and 8.4% of patients with ASD also had a diagnosis of toe-walking (n = 484). For typically developing children in the database, 0.47% of patients had a diagnosis of persistent toe-walking. In all, 59.3% of ASD patients underwent physical therapy, 7.4% serial casting and 3.3% surgical correction, compared with 38.1%, 3.6% and 1.2% of normally developing children, respectively (chi-square 6.4031; p < 0.040699). Without intervention, 63.6% of patients with ASD continued to toe-walk within ten years of their diagnosis, with 19.3% of patients without ASD (chi-square 82.9762; p < 0.0001).This study supports the association between a greater prevalence of toe-walking in children with ASD. We showed that patients with ASD and toe-walking receive surgical correction at nearly triple the rate of children without ASD who toe-walk. The continued rate of toe-walking is comparable between treatment groups as well as between ASD and typically developing children. Typically developing children have higher rates of toe-walking resolution without intervention than children with ASD.Level II.

View details for DOI 10.1302/1863-2548.13.180160

View details for PubMedID 31489038

View details for PubMedCentralID PMC6701446

FAR: End-to-End Vibrotactile Distributed System Designed to Facilitate Affect Regulation in Children Diagnosed with Autism Spectrum Disorder Through Slow Breathing Miri, P., Arora, M., Malhotra, A., Flory, R., Hu, S., Lowber, A., Goyal, I., Nguyen, J., Hegarty, J., Kohn, M., Schneider, D., Culbertson, H., Yamins, D. K., Fung, L., Hardan, A., Gross, J. J., Marzullo, K., ACM ASSOC COMPUTING MACHINERY. 2022
Neurodiversity: From Phenomenology to Neurobiology and Enhancing Technologies edited by Fung, L. K. American Psychiatric Publishing Inc. 2021
Sex Differences in Resting-State Functional Connectivity in High-Functioning Adults With Autism Sun, K., Ayub, R., Lam, V., Saggar, M., Fung, L. SPRINGERNATURE. 2020: 29798
Autism and toe-walking: are they related? Trends and treatment patterns between 2005 and 2016 JOURNAL OF CHILDRENS ORTHOPAEDICS Leyden, J., Fung, L., Frick, S. 2019; 13 (4): 34045
Autism and toe-walking: are they related? Trends and treatment patterns between 2005 and 2016. Journal of children's orthopaedics Leyden, J., Fung, L., Frick, S. 2019; 13 (4): 340-345
Neurodevelopmental Disorders AMERICAN PSYCHIATRIC ASSOCIATION PUBLISHING TEXTBOOK OF PSYCHIATRY, 7TH EDITION Hong, D. S., Fung, L. K., Hardan, A., Roberts, L. W. 2019: 22555
Oxidative Stress in Psychiatric Disorders The Therapeutic use of N-Acetylcysteine (NAC) in Medicine Fung, L., Hardan, A. Springer Nature. 2019: 5372
Socio-Communicative Deficits are Modulated by GABA Concentrations but Not GABA(A) Receptor Densities in Adults With Autism Spectrum Disorder Fung, L., Flores, R., Gu, M., Spielman, D., Chin, F., Hardan, A. NATURE PUBLISHING GROUP. 2018: S317


MRI-guided pulsed focused ultrasound combined with systemic infusion of contrast agent microbubbles induces local neuroinflammation in the rat.

View details for DOI 10.1126/scitranslmed.aal4994

View details for PubMedID 28100836

THE FRAGILE X BRAIN: A PET/MR CASE STUDY Gade, S., Gade, S., Shen, B., Jung, J., Lee, B., Kim, S., Fung, L., Chin, F. OXFORD UNIV PRESS INC. 2018: S713
Comprehensive Examination of the GABAergic System in Adults With Autism by Simultaneous [18F] Flumazenil-Positron Emission Tomography and Magnetic Resonance Spectroscopy Fung, L., Flores, R., Liu, K., Gu, M., Spielman, D., Chin, F., Hardan, A. NATURE PUBLISHING GROUP. 2017: S206S207

View details for PubMedID 27903859

Simultaneous [18F]Flumazenil-Positron Emission Tomography and GABA-Magnetic Resonance Spectroscopy in Adults with Autism and Healthy Volunteers Fung, L., Flores, R., Gu, M., Hjoernevik, T., Hardan, A., Spielman, D., Chin, F. ELSEVIER SCIENCE INC. 2017: S127S128


The availability of GABAA receptor binding sites in the brain can be assessed by positron emission tomography (PET) using the radioligand, [(18)F]flumazenil. However, the brain uptake and binding of this PET radioligand are influenced by anesthetic drugs, which are typically needed in preclinical imaging studies and clinical imaging studies involving patient populations that do not tolerate relatively longer scan times. The objective of this study was to examine the effects of anesthesia on the binding of [(18)F]flumazenil to GABAA receptors in mice.Brain and whole blood radioactivity concentrations were measured ex vivo by scintillation counting or in vivo by PET in four groups of mice following administration of [(18)F]flumazenil: awake mice and mice anesthetized with isoflurane, dexmedetomidine, or ketamine/dexmedetomidine. Dynamic PET recordings were obtained for 60min in mice anesthetized by either isoflurane or ketamine/dexmedetomidine. Static PET recordings were obtained at 25 or 55min after [(18)F]flumazenil injection in awake or dexmedetomidine-treated mice acutely anesthetized with isoflurane. The apparent distribution volume (VT*) was calculated for the hippocampus and frontal cortex from either the full dynamic PET scans using an image-derived input function or from a series of ex vivo experiments using whole blood as the input function.PET images showed persistence of high [(18)F]flumazenil uptake (up to 20 % ID/g) in the brains of mice scanned under isoflurane or ketamine/dexmedetomidine anesthesia, whereas uptake was almost indiscernible in late samples or static scans from awake or dexmedetomidine-treated animals. The steady-state VT* was twofold higher in hippocampus of isoflurane-treated mice and dexmedetomidine-treated mice than in awake mice.Anesthesia has pronounced effects on the binding and blood-brain distribution of [(18)F]flumazenil. Consequently, considerable caution must be exercised in the interpretation of preclinical and clinical PET studies of GABAA receptors involving the use of anesthesia.

View details for DOI 10.1186/s13550-016-0235-2

View details for Web of Science ID 000387828200001

Interrogating the GABAergic system with simultaneous [F-18]-Flumazenilpositron emission tomography and GABA-magnetic resonance spectroscopy in healthy volunteers Fung, L., Flores, R., Gu, M., Leuze, C., Hjoernevik, T., Shen, B., Park, J., Jung, J. H., Lee, B. C., Kim, S. E., McNab, J., Srinivas, S., Spielman, D., Chin, F. SAGE PUBLICATIONS INC. 2017: 214-215
A sterile animal model for neuroinflammation? Science translational medicine Fung, L. K. 2017; 9 (373)
Corpus Callosum and Autism Autism Imaging and Devices Fung, L. K., Hardan, A. Y. CRC Press. 2017: 157169


Pediatric primary care providers (PCPs) caring for patients with autism spectrum disorder (ASD) often encounter irritability (vocal or motoric outbursts expressive of anger, frustration, or distress) and problem behavior (directed acts of aggression toward other people, self, or property). The Autism Intervention Research Network on Physical Health and Autism Speaks Autism Treatment Network charged a multidisciplinary workgroup with developing a practice pathway to assist PCPs in the evaluation and treatment of irritability and problem behavior (I/PB).The workgroup reviewed the literature on the evaluation and treatment of contributory factors for I/PB in ASD. The workgroup then achieved consensus on the content and sequence of each step in the pathway.The practice pathway is designed to help the PCP generate individualized treatment plans based on contributing factors identified in each patient. These factors may include medical conditions, which the PCP is in a key position to address; functional communication challenges that can be addressed at school or at home; psychosocial stressors that may be ameliorated; inadvertent reinforcement of I/PB; and co-occurring psychiatric conditions that can be treated. The pathway provides guidance on psychotropic medication use, when indicated, within an individualized treatment plan. In addition to guidance on assessment, referral, and initial treatment, the pathway includes monitoring of treatment response and periodic reassessment.The pediatric PCP caring for the patient with ASD is in a unique position to help generate an individualized treatment plan that targets factors contributing to I/PB and to implement this plan in collaboration with parents, schools, and other providers.

View details for DOI 10.1542/peds.2015-2851L

View details for Web of Science ID 000371393700011

View details for PubMedID 26908469

Studying GABA Neurophysiology by Simultaneous [18F]Flumazenil-Positron Emission Tomography and Magnetic Resonance Spectroscopy Fung, L., Gu, M., Leuze, C., Hjoernevik, T., Shen, B., Park, J., Flores, R., Reyes, S., Holley, D., Gandhi, H., Jung, J., Lee, B., Kim, S., Khalighi, M., Gulaka, P., Zaharchuk, G., McNab, J., Quon, A., Spielman, D., Chin, F. NATURE PUBLISHING GROUP. 2016: S209
Intranasal Vasopressin Treatment Improves Social Abilities in Children With Autism Parker, K., Oztan, O., Libove, R., Sumiyoshi, R., Summers, J., Hinman, K., Fung, L., Motonaga, K., Carson, D., Phillips, J., Garner, J., Hardan, A. NATURE PUBLISHING GROUP. 2016: S341


Pharmacologic treatments targeting specific molecular mechanisms relevant for autism spectrum disorder (ASD) are beginning to emerge in early drug development. This article reviews the evidence for the disruption of glutamatergic neurotransmission in animal models of social deficits and summarizes key pre-clinical and clinical efforts in developing pharmacologic interventions based on modulation of glutamatergic systems in individuals with ASD. Understanding the pathobiology of the glutamatergic system has led to the development of new investigational treatments for individuals with ASD. Specific examples of medications that modulate the glutamatergic system in pre-clinical and clinical studies are described. Finally, we discuss the limitations of current strategies and future opportunities in developing medications targeting the glutamatergic system for treating individuals with ASD.

View details for DOI 10.1007/s40263-015-0252-0

View details for PubMedID 26104862

Imaging serotonin reuptake in the living brain. Science translational medicine Fung, L. K. 2016; 8 (367): 367ec191-?


Pharmacologic treatments targeting specific molecular mechanisms relevant for autism spectrum disorder (ASD) are beginning to emerge in early drug development. This article reviews the evidence for the disruption of glutamatergic neurotransmission in animal models of social deficits and summarizes key pre-clinical and clinical efforts in developing pharmacologic interventions based on modulation of glutamatergic systems in individuals with ASD. Understanding the pathobiology of the glutamatergic system has led to the development of new investigational treatments for individuals with ASD. Specific examples of medications that modulate the glutamatergic system in pre-clinical and clinical studies are described. Finally, we discuss the limitations of current strategies and future opportunities in developing medications targeting the glutamatergic system for treating individuals with ASD.

View details for DOI 10.1007/s40263-015-0252-0

View details for Web of Science ID 000358443400003

Effects of common anesthetic agents on [F-18] flumazenil binding to the GABA(A) receptor EJNMMI RESEARCH Palner, M., Beinat, C., Banister, S., Zanderigo, F., Park, J. H., Shen, B., Hjoernevik, T., Jung, J. H., Lee, B. C., Kim, S. E., Fung, L., Chin, F. T. 2016; 6


The objective of this study is to assess the attitudes of chairs of psychiatry departments, psychiatrists, and psychiatry trainees toward neuroscience education in residency programs and beyond in order to inform future neuroscience education approaches.This multi-stakeholder survey captured data on demographics, self-assessments of neuroscience knowledge, attitudes toward neuroscience education, preferences in learning modalities, and interests in specific neuroscience topics. In 2012, the authors distributed the surveys: by paper to 133 US psychiatry department chairs and electronically through the American Psychiatric Association to 3,563 of its members (1,000 psychiatrists and 2,563 trainees).The response rates for the chair, psychiatrist, and trainee surveys were 53, 9, and 18%, respectively. A large majority of respondents agreed with the need for more neuroscience education in general and with respect to their own training. Most respondents believed that neuroscience will help destigmatize mental illness and begin producing new treatments or personalized medicines in 5-10years. Only a small proportion of trainees and psychiatrists, however, reported a strong knowledge base in neuroscience. Respondents also reported broad enthusiasm for transdiagnostic topics in neuroscience (such as emotion regulation and attention/cognition) and description at the level of neural circuits.This study demonstrates the opportunity and enthusiasm for teaching more neuroscience in psychiatry among a broad range of stakeholder groups. A high level of interest was also found for transdiagnostic topics and approaches. We suggest that a transdiagnostic framework may be an effective way to deliver neuroscience education to the psychiatric community and illustrate this through a case example, drawing the similarity between this neuroscience approach and problem-based formulations familiar to clinicians.

View details for DOI 10.1007/s40596-014-0183-y

View details for Web of Science ID 000351433800003

View details for PubMedID 25001432



The changes in the diagnostic classification of the pervasive developmental disorders from the 4th edition of the Diagnostic and Statistical Manual for Mental Disorders (DSM-IV) to DSM-5 are expected to affect patients with autism, their families, as well as clinicians and researchers in the field of autism. This article reviews the new DSM-5 diagnostic criteria for Autism Spectrum Disorder (ASD) and Social Communication Disorder (SCD), and discusses potential consequences in the perspectives of major stakeholders.

View details for DOI 10.1016/j.ajp.2014.08.010

View details for PubMedID 25219947



The purpose of this study is to assess the attitudes of psychiatry trainees toward neuroscience education in psychiatry residency and subsequent training in order to inform neuroscience education approaches in the future.This online survey was designed to capture demographic information, self-assessed neuroscience knowledge, attitudes toward neuroscience education, preferences in learning modalities, and interest in specific neuroscience topics. Volunteers were identified through the American Psychiatric Association, which invited 2,563 psychiatry trainees among their members.Four hundred thirty-six trainees completed the survey. Nearly all agreed that there is a need for more neuroscience education in psychiatry residency training (94%) and that neuroscience education could help destigmatize mental illness (91%). Nearly all (94%) expressed interest in attending a 3-day course on neuroscience. Many neuroscience topics and modes of learning were viewed favorably by participants. Residents in their first 2years of training expressed attitudes similar to those of more advanced residents and fellows. Some differences were found based on the level of interest in a future academic role.This web-based study demonstrates that psychiatry residents see neuroscience education as important in their training and worthy of greater attention. Our results suggest potential opportunities for advancing neuroscience education.

View details for DOI 10.1007/s40596-014-0034-x

View details for PubMedID 24493359

Irritability and Problem Behavior in Autism Spectrum Disorder: A Practice Pathway for Pediatric Primary Care PEDIATRICS McGuire, K., Fung, L. K., Hagopian, L., Vasa, R. A., Mahajan, R., Bernal, P., Silberman, A. E., Wolfe, A., Coury, D. L., Hardan, A. Y., Veenstra-VanderWeele, J., Whitaker, A. H. 2016; 137: S136-S148
Genetic disorders associated with the autism spectrum disorder phenotype Primer on Autism Spectrum Disorder Fung, L. K., Reiss, A. L. Oxford University Press. 2016: 117137


Although sensory deficits are frequently observed in autistic individuals, pharmacologic interventions targeting these abnormalities are lacking. The goal of this investigation was to assess the effectiveness of aripiprazole in targeting sensory deficits in children and adolescents with autism. Using an outpatient clinic registry for pervasive developmental disorder, 13 individuals who had received aripiprazole for treating disruptive behaviors and had completed behavioral rating scales (aberrant behavior checklist [ABC] and sensory profile questionnaire [SPQ]) were identified. Mean treatment duration was 24.4 weeks with a mean final aripiprazole dosage of 10.8 mg. Aripiprazole yielded improvements in the total ABC and in several items of the SPQ including registration, inattention/distractibility, auditory processing, and modulation of visual input affecting emotional responses and activity level, suggesting that aripiprazole might be beneficial in targeting sensory abnormalities in autism.

View details for DOI 10.1089/cap.2010.0103

View details for Web of Science ID 000305337300009

View details for PubMedID 22537360

Pregnenolone in the Treatment of Irritability in Autism Spectrum Disorder: A Post-Hoc Metabolomic Analysis Fung, L., Sun, W., Libove, R., Tanaka, S., Kwa, L., Philips, J., Haddad, F., Rajadas, J., Hardan, A. NATURE PUBLISHING GROUP. 2015: S188


The overarching goal of this review is to compare and contrast the cognitive-behavioral features of fragile X syndrome (FraX) and Williams syndrome and to review the putative neural and molecular underpinnings of these features. Information is presented in a framework that provides guiding principles for conceptualizing gene-brain-behavior associations in neurodevelopmental disorders.Abnormalities, in particular cognitive-behavioral domains with similarities in underlying neurodevelopmental correlates, occur in both FraX and Williams syndrome including aberrant frontostriatal pathways leading to executive function deficits, and magnocellular/dorsal visual stream, superior parietal lobe, inferior parietal lobe, and postcentral gyrus abnormalities contributing to deficits in visuospatial function. Compelling cognitive-behavioral and neurodevelopmental contrasts also exist in these two disorders, for example, aberrant amygdala and fusiform cortex structure and function occurring in the context of contrasting social behavioral phenotypes, and temporal cortical and cerebellar abnormalities potentially underlying differences in language function. Abnormal dendritic development is a shared neurodevelopmental morphologic feature between FraX and Williams syndrome. Commonalities in molecular machinery and processes across FraX and Williams syndrome occur as well - microRNAs involved in translational regulation of major synaptic proteins; scaffolding proteins in excitatory synapses; and proteins involved in axonal development.Although the genetic variations leading to FraX and Williams syndrome are different, important similarities and contrasts in the phenotype, neurocircuitry, molecular machinery, and cellular processes in these two disorders allow for a unique approach to conceptualizing gene-brain-behavior links occurring in neurodevelopmental disorders.

View details for DOI 10.1097/WCO.0b013e328351823c

View details for Web of Science ID 000301288000003

View details for PubMedID 22395002

Developing Medications Targeting Glutamatergic Dysfunction in Autism: Progress to Date. CNS drugs Fung, L. K., Hardan, A. Y. 2015


The design, synthesis, and structure-activity relationships of a novel series of pyrazines, acting as corticotropin releasing factor-1 (CRF-1) receptor antagonists, are described. Synthetic methodologies were developed to prepare a number of substituted pyrazine cores utilizing regioselective halogenation and chemoselective derivatization. Noteworthy, an efficient 5-step synthesis was developed for the lead compound 59 (NGD 98-2), which required no chromatography. Compound 59 was characterized as an orally bioavailable, brain penetrant, and highly selective CRF-1 receptor antagonist. Occupancy of rat brain CRF-1 receptors was quantified using ex vivo receptor occupancy assays, using both brain tissue homogenates as well as brain slices receptor autoradiography. Behaviorally, oral administration of 59 significantly antagonized CRF-induced locomotor activity at doses as low as 10 mg/kg and dose-dependently reduced the restraint stress-induced ACTH increases.

View details for DOI 10.1021/jm200365y

View details for Web of Science ID 000291709100016

View details for PubMedID 21618986

Developing Medications Targeting Glutamatergic Dysfunction in Autism: Progress to Date CNS DRUGS Fung, L. K., Hardan, A. Y. 2015; 29 (6): 453-463

View details for DOI 10.1089/cap.2010.0013

View details for Web of Science ID 000283436700013

View details for PubMedID 20973719

Attitudes Toward Neuroscience Education in Psychiatry: a National Multi-stakeholder Survey ACADEMIC PSYCHIATRY Fung, L. K., Akil, M., Widge, A., Roberts, L. W., Etkin, A. 2015; 39 (2): 139-146


Clozapine, a dibenzodiazepine antipsychotic, is the most effective medication for treatment-resistant schizophrenia. However, its use has been limited by the high risk of neutropenia. In children, the rate of neutropenia is higher when compared to adults. We decided to explore the use of lithium to manage neutropenia in childhood-onset schizophrenia (COS) through a systematic audit of COS cases.Medical records were reviewed for patients with COS who had been treated with the combination of clozapine and lithium carbonate.Seven patients were found to have been treated with both clozapine and lithium. After initiation of lithium, ANC increased significantly in six out of seven subjects by 29 to 106% with a mean of 66%. In addition, six out of seven subjects continued using both clozapine and lithium for over 2 years (range: 2.0-7.2 years) and do not have immediate plans for discontinuation of either medications.Our study bolsters support for the use of lithium in the management of neutropenia in children treated with clozapine. Although the coadministration of lithium and clozapine appears effective in the management of neutropenia, it is not without its risks and clinicians must be diligent in their joint use of these medications.

View details for DOI 10.1002/hup.1056

View details for Web of Science ID 000270889900009

View details for PubMedID 19743394

View details for PubMedCentralID PMC2772202

Autism in DSM-5 under the microscope: Implications to patients, families, clinicians, and researchers. Asian journal of psychiatry Fung, L. K., Hardan, A. Y. 2014; 11: 93-97
Attitudes toward neuroscience education among psychiatry residents and fellows. Academic psychiatry Fung, L. K., Akil, M., Widge, A., Roberts, L. W., Etkin, A. 2014; 38 (2): 127-134


A focused SAR exploration of the lead 4-aminoquinazoline TRPV1 antagonist 2 led to the discovery of compound 18. In rats, compound 18 is readily absorbed following oral dosing and demonstrates excellent in vivo potency and efficacy in an acute inflammatory pain model.

View details for DOI 10.1016/j.bmcl.2008.07.036

View details for Web of Science ID 000258769200027

View details for PubMedID 18662872

Investigating the Attitudes Toward Neuroscience Education in Psychiatry -- The Stanford Education in Neuroscience Study (SENS) Fung, L., Akil, M., Widge, A., Roberts, L., Etkin, A. ELSEVIER SCIENCE INC. 2013: 219S


8-Aryl-1,3a,8-triaza-cyclopenta[a]indenes represent a novel series of high binding affinity corticotropin-releasing factor 1 receptor antagonists. Here, we report their synthesis, SAR, and pharmacokinetic properties of compound 8e (K(i) = 23 nM).

View details for DOI 10.1016/j.bmcl.2005.06.028

View details for Web of Science ID 000231493400009

View details for PubMedID 15982881

A Retrospective Review of the Effectiveness of Aripiprazole in the Treatment of Sensory Abnormalities in Autism JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Fung, L. K., Chahal, L., Libove, R. A., Bivas, R., Hardan, A. Y. 2012; 22 (3): 245-248


7-Aryl-6,7-dihydroimidazoimidazoles represent a novel series of high-affinity corticotropin-releasing factor 1 receptor antagonists. Here, we report their synthesis and SAR as well as behavioral activity of two exemplary compounds, 7b and 7k, in a mouse canopy model of anxiety.

View details for DOI 10.1016/j.bmcl.2005.05.117

View details for Web of Science ID 000231186000012

View details for PubMedID 15990298

Conceptualizing neurodevelopmental disorders through a mechanistic understanding of fragile X syndrome and Williams syndrome CURRENT OPINION IN NEUROLOGY Fung, L. K., Quintin, E., Haas, B. W., Reiss, A. L. 2012; 25 (2): 112-124


2-arylamino-4-trifluoromethyl-5-aminomethylthiazoles represent a novel series of high-affinity corticotropin releasing factor-1 receptor (CRF(1)R) antagonists that are prepared in three steps in good overall yields. Herein, we report binding SAR as well as anxiolytic activity of an exemplary compound (7a, K(i)=8.6 nM) in a mouse canopy model.

View details for DOI 10.1016/j.bmcl.2003.08.055

View details for Web of Science ID 000186486400024

View details for PubMedID 14592493

Autism spectrum and neurodevelopmental disorders: clinical update for psychiatrists PSYCHIATRIC TIMES Froehlich, W., Fung, L. K. 2012; 29 (11)


The pH of ex vivo plasma, bile and urine was monitored at different times and temperatures of storage, and following different sample processing methods such as ultrafiltration, centrifugation, precipitation and evaporation. The results showed that the pH of ex vivo plasma, bile and urine increased upon storage, and following sample processing and could lead to significant degradation of pH-labile compounds. Several compounds were used to illustrate the impact of pH shifts on drug stability and interpretation of results obtained from in vivo studies. For example, after 1 h of incubation (37 degrees C) in rat plasma (pH 8.3), about 60%, of I was lost. However, in phosphate buffer, losses were about 12% at pH 7.4 and 40% at pH 8.0. Plasma pH also increased during ultrafiltration, centrifugation and extraction. After methanol precipitation of plasma proteins, and evaporation of the supernatant and redissolution of the residue, the resulting solution had a pH of 9.5. Under these conditions, II was degraded by 60% but was stable when phosphate buffer was used to maintain the pH at 7.4. The shift in plasma pH can yield misleading results from in vivo studies if the pH is not controlled. For example, the major circulating metabolite of II was also formed in plasma ex-vivo. This ex vivo degradation was prevented when blood samples were collected into tubes containing 0.1 volume of phosphate buffer (0.3 M, pH 5). The pH of ex vivo plasma can best be stabilized at physiological conditions using 10% CO2 atmosphere in a CO2 incubator. Changes in pH of ex vivo urine and bile samples can have similar adverse effect on pH-labile samples. Thus, processing of plasma samples under a 10% CO2 atmosphere is a method of choice for stability or protein binding studies in plasma, whereas citrate or phosphate buffers are suitable for stabilizing pH in bile and urine and for plasma samples requiring extensive preparations or long term storage.

View details for DOI 10.1016/S0731-7085(03)00159-6

View details for Web of Science ID 000184301900014

View details for PubMedID 14565556

Discovery of N-(1-Ethylpropyl)-(3-methoxy-5-(2-methoxy-4-trifluoromethoxyphenyl)-6-methyl-pyrazin-2-yl)amine 59 (NGD 98-2): An Orally Active Corticotropin Releasing Factor-1 (CRF-1) Receptor Antagonist JOURNAL OF MEDICINAL CHEMISTRY Hodgetts, K. J., Ge, P., Yoon, T., De Lombaert, S., Brodbeck, R., Gulianello, M., Kieltyka, A., Horvath, R. F., Kehne, J. H., Krause, J. E., Maynard, G. D., Hoffman, D., Lee, Y., Fung, L., Doller, D. 2011; 54 (12): 4187-4206


Polymeric interstitial chemotherapy increases survival of humans with recurrent gliomas and animals with transplanted tumors in the brain, but the relationship between rates of drug release from polymer implants and drug concentration in brain tissue is unknown. This work presents a pharmacokinetic framework for application of this new modality of chemotherapy delivery in primates. Either [3H]carmustine, 4-hydroperoxycyclophosphamide (4-HC), or paclitaxel was encapsulated in a polyanhydride pellet (28-41 microCi/animal, 40 mg/animal), which was implanted intracranially in cynomolgus monkeys (Macaca fascicularis); (n = 17) for up to 30 days. Drug concentrations in the brain, blood, and cerebrospinal fluid were measured by quantitative autoradiography, TLC, and scintillation counting. High drug concentrations (0.5-3.5 mM for carmustine, 0.3-0.4 mM for 4-HC, and 0.2-1.0 mM for paclitaxel) were measured within the first 3 mm from the polymer implant; significant (0.4 microM for carmustine, 3 microM for 4-HC, and 0.6 microM for paclitaxel) concentrations were measured up to approximately 5 cm from the implant as long as 30 days after implantation. Pharmacokinetic analysis indicated that tissue exposure to carmustine area under concentration-time curve achieved by polymeric delivery was 4-1200 times higher than that produced by i.v. administration of a higher dose.

View details for Web of Science ID 000072025300021

View details for PubMedID 9485020

Risperidone: Switching from Brand Name to Generic JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Hardan, A. Y., Fung, L. K., Amin, H. 2010; 20 (5): 457-458


Cancer chemotherapy is not always effective. Difficulties in drug delivery to the tumor, drug toxicity to normal tissues, and drug stability in the body contribute to this problem. Polymeric materials provide an alternate means for delivering chemotherapeutic agents. When anticancer drugs are encapsulated in polymers, they can be protected from degradation. Implanted polymeric pellets or injected microspheres localize therapy to specific anatomic sites, providing a continuous sustained release of anticancer drugs while minimizing systemic exposure. In certain cases, polymeric microspheres delivered intravascularly can be targeted to specific organs or tumors. This article reviews the principles of chemotherapy using polymer implants and injectable microspheres, and summarizes recent preclinical and clinical studies of this new technology for treating cancer.

View details for PubMedID 10837544

Adjunctive use of lithium carbonate for the management of neutropenia in clozapine-treated children HUMAN PSYCHOPHARMACOLOGY-CLINICAL AND EXPERIMENTAL Mattai, A., Fung, L., Bakalar, J., Overman, G., Tossell, J., Miller, R., Rapoport, J., Gogtay, N. 2009; 24 (7): 584-589


The distribution of [(3)H]BCNU following release from polymer implants in the rat brain was measured and evaluated by using mathematical models.[(3)H]BCNU was loaded into p(CPP:SA) pellets, which were subsequently implanted intracerebrally in rats; [(3)H]BCNU was also directly injected into the brains of normal rats and rats with intracranially transplanted 9L gliomas. Concentrations of [(3)H]BCNU on coronal sections of the brain were measured by autoradiography and image processing. For comparison, the kinetics of [(3)H]BCNU release from the p(CPP:SA) polymer discs into phosphate-buffered saline were also measured.High concentrations of BCNU (corresponding to 1 mM) were measured near the polymer for the entire 30-day experiment. The penetration distance, defined as the distance from the polymer surface to the point where the concentration of [(3)H]BCNU in the tissue had dropped to 10 percent of the maximum value, was determined: penetration distance was 5 mm at day 1 and 1 mm at days 3 through 14. Local concentration profiles were compared with a mathematical model for estimation of the modulus phi (2), an indicator of the relative rate of elimination to diffusion in the brain. From day 3 to 14, phi(2) was 7, indicating that BCNU elimination was rapid compared to the rate of diffusive penetration into tissue. The enhanced penetration observed on day 1 appears to be due to convection of extracellular fluid caused by transient, vasogenic edema, which disappears by day 3.Polymer implants produce very high levels of BCNU in the brain, but BCNU penetration into brain tissue is limited due to rapid elimination.

View details for Web of Science ID A1996UJ92000003

View details for PubMedID 8860421

Use of Lithium Carbonate in the Management of Clozapine-Induced Neutropenia in Childhood-Onset Schizophrenia Mattai, A., Fung, L., Bakalar, J., Tossell, J., Miller, R., Rapoport, J., Gogtay, N. ELSEVIER SCIENCE INC. 2009: 212S


Intracranial tumors, such as glioblastoma multiforme and astrocytomas, are among the most aggressive and difficult to cure. In the present study, we evaluated the intracranial distribution of released agents during the first 3 days after implantation. Polymer implants containing [3H]-1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), [3H]dextran (MW 70,000) or [14C]iodoantipyrene (IAP) were implanted into the brains of rabbits; autoradiography was used to measure the distribution of radiolabels within the brain at 6, 24 and 72 hr after implantation. For all of the agents studied, the majority of the radioactivity was found within the region 1 to 2 mm from the surface of the polymer. Dextran, however, penetrated farther into the brain than either IAP or BCNU. The distribution of radiolabel on an anteroposterior axis was determined by examining serial coronal images: after 72 hr, significant radioactivity (< 2 S.D. above background) extended > 17 mm in animals with [3H]dextran implants and approximately mm in animals receiving [3H]BCNU or [14C]IAP. Concentration profiles were also measured on coronal images obtained at the implant site: radioactivity dropped to a 10% maximum value 1.7 mm from the surface of the pellet in [3H]dextran-treated animals and < 1.2 mm in [3H]BCNU or [14C]IAP-treated animals. Measured concentration profiles near the polymer were compared to mathematical models of drug diffusion and elimination. These results demonstrate that the majority of agents delivered into the brain by intracranially implanted polymers accumulates in the tissue within 1 to 2 mm of the implant, but that the size of the treated region depends on physicochemical properties of the agents.(ABSTRACT TRUNCATED AT 250 WORDS)

View details for Web of Science ID A1995TL75700075

View details for PubMedID 8531140

Aminoquinazolines as TRPV1 antagonists: Modulation of drug-like properties through the exploration of 2-position substitution BIOORGANIC & MEDICINAL CHEMISTRY LETTERS Blum, C. A., Zheng, X., Brielmann, H., Hodgetts, K. J., Bakthavatchalam, R., Chandrasekhar, J., Krause, J. E., Cortright, D., Matson, D., Crandall, M., Ngo, C. K., Fung, L., Day, M., Kershaw, M., De Lombaert, S., Chenard, B. L. 2008; 18 (16): 4573-4577


Intracranial controlled release polymers have been used for drug delivery to the brain, bypassing the blood brain barrier (BBB). By understanding the rates and patterns of transport in the local tissues, it is possible to design delivery systems that provide the optimal spatial and temporal pattern of chemotherapy within the intracranial space. This paper reviews the kinetics of drug release from polymeric controlled release implants, and describes the fate of drug molecules following release into the brain interstitium. Potential improvements in drug delivery based on the understanding of the mechanisms of drug release, transport and elimination are discussed.

View details for Web of Science ID A1995TM53400003

View details for PubMedID 8787851

Synthesis and structure-activity relationship of imidazo[1,2-a]benzimidazoles as corticotropin-releasing factor 1 receptor antagonists BIOORGANIC & MEDICINAL CHEMISTRY LETTERS Han, X. J., Pin, S. S., Burris, K., Fung, L. K., Huang, S., Taber, M. T., Zhang, J., Dubowchik, G. M. 2005; 15 (18): 4029-4032
Synthesis, structure-activity relationships, and anxiolytic activity of 7-aryl-6,7-dihydroimidazoimidazole corticotropin-releasing factor 1 receptor antagonists BIOORGANIC & MEDICINAL CHEMISTRY LETTERS Han, X. J., Michne, J. A., Pin, S. S., Burris, K. D., Balanda, L. A., Fung, L. K., Fiedler, T., Browman, K. E., Taber, M. T., Zhang, J., Dubowchik, G. M. 2005; 15 (17): 3870-3873
2-arylaminothiazoles as high-affinity corticotropin-releasing factor 1 receptor (CRF1R) antagonists: Synthesis, binding studies and behavioral efficacy BIOORGANIC & MEDICINAL CHEMISTRY LETTERS Dubowchik, G. M., Michne, J. A., Zuev, D., Schwartz, W., Scola, P. M., James, C. A., Ruediger, E. H., Pin, S. S., Burris, K. D., Balanda, L. A., Gao, Q., Wu, D. D., Fung, L., Fiedler, T., Browman, K. E., Taber, M. T., Zhang, J. 2003; 13 (22): 3997-4000
Shift in pH of biological fluids during storage and processing: effect on bioanalysis JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS Fura, A., Harper, T. W., Zhang, H. J., Fung, L., Shyu, W. C. 2003; 32 (3): 513-522
Pharmacokinetics of interstitial delivery of carmustine, 4-hydroperoxycyclophosphamide, and paclitaxel from a biodegradable polymer implant in the monkey brain CANCER RESEARCH Fung, L. K., Ewend, M. G., Sills, A., Sipos, E. P., Thompson, R., Watts, M., Colvin, O. M., Brem, H., Saltzman, W. M. 1998; 58 (4): 672-684
Polymeric implants for cancer chemotherapy. Advanced drug delivery reviews Saltzman, W. M., Fung, L. K. 1997; 26 (2-3): 209-230
Chemotherapeutic drugs released from polymers: Distribution of 1,3-bis(2-chloroethyl)-1-nitrosourea in the rat brain PHARMACEUTICAL RESEARCH Fung, L. K., Shin, M., Tyler, B., Brem, H., Saltzman, W. M. 1996; 13 (5): 671-682
Distribution of 1,3-bis(2-chloroethyl)-1-nitrosourea and tracers in the rabbit brain after interstitial delivery by biodegradable polymer implants JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Strasser, J. F., Fung, L. K., Eller, S., Grossman, S. A., Saltzman, W. M. 1995; 275 (3): 1647-1655
Distribution of drugs following controlled delivery to the brain interstitium JOURNAL OF NEURO-ONCOLOGY Mak, M., Fung, L., Strasser, J. F., Saltzman, W. M. 1995; 26 (2): 91-102