Lawrence Fung

All Publications

• 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

  Abstract

  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

• 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

  Abstract

  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

• 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

  Abstract

  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

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

  Abstract

  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

• 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

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

  View details for Web of Science ID 000343724000027

• 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

  Abstract

  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 sterile animal model for neuroinflammation? Science translational medicine Fung, L. K. 2017; 9 (373)

  Abstract

  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

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

  View details for PubMedID 27903859

• 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

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

  View details for Web of Science ID 000387828200001

• 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

  Abstract

  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

• 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

  Abstract

  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 5-10 years. 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

• 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

  Abstract

  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

• 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

  Abstract

  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 2 years 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

• 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

  Abstract

  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

• 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

  Abstract

  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

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

  Abstract

  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

• 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

  View details for DOI 10.1089/cap.2010.0013

  View details for Web of Science ID 000283436700013

  View details for PubMedID 20973719

• 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

  Abstract

  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

• 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

  Abstract

  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

• 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

  Abstract

  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

• 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

  Abstract

  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

• 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

  Abstract

  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

• 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

  Abstract

  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

• 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

  Abstract

  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

• Polymeric implants for cancer chemotherapy. Advanced drug delivery reviews Saltzman, W. M., Fung, L. K. 1997; 26 (2-3): 209–30

  Abstract

  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

• 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

  Abstract

  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

• 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

  Abstract

  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

• 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

  Abstract

  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