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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    • "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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    ABSTRACT: A mechanistic understanding of the pathophysiology underpinning psychiatric disorders is essential for the development of targeted molecular therapies. For fragile X syndrome (FXS), recent mechanistic studies have been focused on the metabotropic glutamate receptor (mGluR) signaling pathway. This line of research has led to the discovery of promising candidate drugs currently undergoing various phases of clinical trial, and represents a model of how biological insights can inform therapeutic strategies in neurodevelopmental disorders. Although mGluR signaling is a key mechanism at which targeted treatments can be directed, it is likely to be one of many mechanisms contributing to FXS. A more complete understanding of the molecular and neural underpinnings of the disorder is expected to inform additional therapeutic strategies. Alterations in the assembly of neural circuits in the neocortex have been recently implicated in genetic studies of autism and schizophrenia, and may also contribute to FXS. In this review, we explore dysregulated nitric oxide signaling in the developing neocortex as a novel candidate mechanism of FXS. This possibility stems from our previous work demonstrating that neuronal nitric oxide synthase 1 (NOS1 or nNOS) is regulated by the FXS protein FMRP in the mid-fetal human neocortex. Remarkably, in the mid-late fetal and early postnatal neocortex of human FXS patients, NOS1 expression is severely diminished. Given the role of nitric oxide in diverse neural processes, including synaptic development and plasticity, the loss of NOS1 in FXS may contribute to the etiology of the disorder. Here, we outline the genetic and neurobiological data that implicate neocortical dysfunction in FXS, review the evidence supporting dysregulated nitric oxide signaling in the developing FXS neocortex and its contribution to the disorder, and discuss the implications for targeting nitric oxide signaling in the treatment of FXS and other psychiatric illnesses.
    Frontiers in Genetics 07/2014; 5:239. DOI:10.3389/fgene.2014.00239
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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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    ABSTRACT: In clinical practice, pharmacological treatment is mostly focused on behavioral symptoms in everyday life. Nevertheless, persistent effort continues to develop medication for causal treatment. Recent changes in diagnostic criteria from Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR) to DSM-5 would affect not only diagnosing approaches, but also therapeutic approaches. Because previous pervasive developmental disorders have been integrated into a single entity, the autism spectrum disorder (ASD), we have to prepare for what medications are valuable for the ASD. In this article, we reviewed the following etiological treatment: acetylcholine and glutamate related medicine; amino acid medicine such as secretin, endogenous opioid, and oxytocin; complementary and alternative medicine such as chelating agents, vitamins, and omega-3; promising drugs related to the scope of pharmacogenetics currently under study.
    Clinical Psychopharmacology and Neuroscience 04/2014; 12(1):19-30. DOI:10.9758/cpn.2014.12.1.19
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    • "To date, only two studies have been completed in patients affected by FXS. A pilot study was conducted to determine pharmacokinetics and side effects of a single dose trial of the mGluR-5 antagonist, fenobam, to 12 male and female FXS patients (Berry-Kravis et al., 2009). Pre/post outcome measures included prepulse inhibition (PPI) and the continuous performance test (CPT) to assess sensory gating, attention and inhibition. "
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    ABSTRACT: Fragile X syndrome (FXS) is caused by the lack of expression of the fragile X mental retardation protein (FMRP), which results in intellectual disability and other debilitating symptoms including impairment of visual-spatial functioning. FXS is the only single-gene disorder that is highly co-morbid with autism spectrum disorder and can therefore provide insight into its pathophysiology. Lack of FMRP results in altered group I metabotropic glutamate receptor (mGluR) signalling, which is a target for putative treatments. The Hebb-Williams (H-W) mazes are a set of increasingly complex spatial navigation problems that depend on intact hippocampal and thus mGluR-5 functioning. In the present investigation, we examined whether an antagonist of mGluR-5 would reverse previously described behavioural deficits in Fmr1 KO mice. Mice were trained on a subset of the H-W mazes and then treated with either 20 mg/kg of an mGluR-5 antagonist, 2-Methyl-6-(phenylethynyl) pyridine (MPEP; n = 11) or an equivalent dose of saline (n = 11) prior to running test mazes. Latency and errors were dependent variables recorded during the test phase. Immediately after completing each test, marble-burying behavior was assessed which confirmed that the drug treatment was pharmacologically active during maze learning. Although latency was not statistically different between the groups, MPEP treated Fmr1 KO mice made significantly fewer errors on mazes deemed more difficult suggesting a reversal of the behavioural deficit. MPEP treated mice were also less perseverative and impulsive when navigating mazes. Furthermore, MPEP treatment reversed PSD-95 protein deficits in Fmr1 KO treated mice, whereas levels of a control protein (β-tubulin) remained unchanged. These data further validate MPEP as a potentially beneficial treatment for FXS. Our findings also suggest that adapted H-W mazes may be a useful tool to document alterations in behavioural functioning following pharmacological intervention in FXS.
    Frontiers in Cellular Neuroscience 03/2014; 8:70. DOI:10.3389/fncel.2014.00070 · 4.29 Impact Factor
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