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J Med Genet 46:266-271 doi:10.1136/jmg.2008.063701
  • Original article

A pilot open label, single dose trial of fenobam in adults with fragile X syndrome

Open Access
  1. E Berry-Kravis1,
  2. D Hessl2,3,
  3. S Coffey3,8,
  4. C Hervey4,
  5. A Schneider2,3,
  6. J Yuhas2,
  7. J Hutchison5,
  8. M Snape5,
  9. M Tranfaglia6,
  10. D V Nguyen7,
  11. R Hagerman3,8
  1. 1
    Departments of Pediatrics, Neurological Sciences, Biochemistry, Rush University Medical Center, Chicago, Illinois, USA
  2. 2
    Department of Psychiatry and Behavioral Sciences, University of California Davis, Davis, California, USA
  3. 3
    MIND Institute, University of California Davis Medical Center, Davis, California, USA
  4. 4
    Department of Pediatrics, Rush University Medical Center, Chicago, Illinois, USA
  5. 5
    Neuropharm Ltd, Leatherhead, Surrey, UK
  6. 6
    FRAXA Research Foundation, Newburyport, Massachusetts, USA
  7. 7
    Department of Public Health Sciences, University of California Davis, Davis, California, USA
  8. 8
    Department of Pediatrics, University of California Davis Medical Center, Davis, California, USA
  1. Dr E Berry-Kravis, Rush University Medical Center, 1725 West Harrison Street, Suite 718, Chicago, IL 60612, USA; elizabeth_m_berry-kravis{at}rush.edu
  • Received 29 October 2008
  • Revised 3 December 2008
  • Accepted 5 December 2008
  • Published Online First 6 January 2009

Abstract

Objective: A pilot open label, single dose trial of fenobam, an mGluR5 antagonist, was conducted to provide an initial evaluation of safety and pharmacokinetics in adult males and females with fragile X syndrome (FXS).

Methods: Twelve subjects, recruited from two fragile X clinics, received a single oral dose of 50–150 mg of fenobam. Blood for pharmacokinetic testing, vital signs and side effect screening was obtained at baseline and numerous time points for 6 h after dosing. Outcome measures included prepulse inhibition (PPI) and a continuous performance test (CPT) obtained before and after dosing to explore the effects of fenobam on core phenotypic measures of sensory gating, attention and inhibition.

Results: There were no significant adverse reactions to fenobam administration. Pharmacokinetic analysis showed that fenobam concentrations were dose dependent but variable, with mean (SEM) peak values of 39.7 (18.4) ng/ml at 180 min after the 150 mg dose. PPI met a response criterion of an improvement of at least 20% over baseline in 6 of 12 individuals (4/6 males and 2/6 females). The CPT did not display improvement with treatment due to ceiling effects.

Conclusions: Clinically significant adverse effects were not identified in this study of single dose fenobam across the range of dosages utilised. The positive effects seen in animal models of FXS treated with fenobam or other mGluR5 antagonists, the apparent lack of clinically significant adverse effects, and the potential beneficial clinical effects seen in this pilot trial support further study of the compound in adults with FXS.

Footnotes

  • Funding: This study was sponsored and supported by Neuropharm Ltd with supplementary support from the FRAXA Research Foundation, Administration of Developmental Disabilities grant 90DD0596 (RJH), and NIH grants UL1DEO19583, RL1AG032119, RL1AG032115, HD036071, UL1RR024146 (DN and RJH) and MH77554 (DH). This publication was also made possible by Grant Number UL1 RR024146 from the National Center for Research for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH.

  • Competing interests: None declared.

  • Patient consent: Obtained.