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

Departments of Pediatrics, Rush University Medical Center, 1725 West Harrison Street, Suite 718, Chicago, IL 60612, USA.
Journal of Medical Genetics (Impact Factor: 6.34). 02/2009; 46(4):266-71. DOI: 10.1136/jmg.2008.063701
Source: PubMed


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).
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.
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.
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.

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Available from: Andrea Schneider
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    • "Both MTEP and MPEP are rapidly metabolized after administration (Keck et al., 2013). Other highly potent and selective mGluR5 NAMs, such as fenobam (Pecknold et al., 1982;Porter et al., 2005;Berry-Kravis et al., 2009), mavoglurant (Kumar et al., 2013;Stocchi et al., 2013;Reilmann et al., 2015), ADX10059, AZD2066 (Keywood et al., 2009;Zerbib et al., 2010;Zerbib et al., 2011;Rohof et al., 2012), and AZD9272 (Kalliomaki et al., 2013), have been investigated in humans for different indications and could find application in the treatment of addiction if their pharmacokinetics and side effect profile prove favourable. Moreover, the industry continuously develops new compounds (Felts et al., 2009;Emmitte, 2011;Kaae et al., 2012;Keck et al., 2012;Molck et al., 2012;Molck et al., 2014;Anighoro et al., 2015;Jaeschke et al., 2015;Lindemann et al., 2015) and new mGluR5-specific PET tracers (Yu, 2007;Mu et al., 2010;Sobrio, 2013), such as[18F]PSS232 (Sephton et al., 2015) and[18F]FPEB (Lim et al., 2014). "
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    • "Since the proposal of the mGluR theory (Bear et al., 2004; Pop et al., 2014), a number of therapies targeting molecules up or downstream of mGluR signaling have been developed and reached various phases of clinical trial. For example, an open label trial of fenobam (NPL-2009), an mGluR5 antagonist, ameliorated anxiety, hyperarousal, and deficits in prepulse inhibition, and improved continuous performance task outcomes (Berry-Kravis et al., 2009). Arbaclofen (STX209), a GABA receptor agonist acting upstream of mGluR signaling, showed mixed promise in correcting behavioral problems, which was strengthened when adjusted for baseline severity of social withdrawal (Berry-Kravis et al., 2012; Erickson et al., 2014; Jacquemont et al., 2014). "
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    • "The first mGluR antagonist to go into human trials was fenobam, which was studied in 12 patients with FXS in a pilot open-label study.32) About half of the patients showed improved eye contact and 25% showed improvements in social interaction with a single dose of the drug. "
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