Clobazam and Its Active Metabolite N-desmethylclobazam Display Significantly Greater Affinities for α2- versus α1-GABAA–Receptor Complexes

Jensen, Henrik Sindal; Nichol, Kathryn; Lee, Dong Hoon; Ebert, Bjarke

doi:10.1371/journal.pone.0088456

Cited by 52 publications

(55 citation statements)

References 29 publications

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“…The smaller sedative effect of CBZ is consistent with a recent report that compared the affinities of CBZ, NDMC, and zolpidem to a1GABA A Rs and a2GABA A Rs. 18 According to this study, CBZ and NDMC have higher affinities to a2GABA A Rs than to a1GABA A Rs, whereas CLN has similar affinities to both subtypes, and zolpidem binds a1GABA A Rs with higher affinity than a2GABA A Rs. Therefore, CBZ seemed to be a suitable tool compound to further study the role of GABA A receptors in human pain pathways.…”

Section: Discussionmentioning

confidence: 58%

“…26 At subsaturating concentrations, NDMC may exert even stronger effects on spinal GABA A Rs than CBZ, as NDMC's affinity to a2GABA A Rs, which predominate in the spinal cord, 31 is higher than that of CBZ. 18 In this study, the duration of secondary hyperalgesia was too short to verify the contribution of NDMC to antihyperalgesia because NDMC plasma levels rose only slowly and reached maximum values only after 23.5 (62.4) hours when ASH was no longer detectable. Future studies should be designed to specifically assess the contribution of NDMC to antihyperalgesic and sedative effects in humans.…”

Section: Discussionmentioning

confidence: 81%

“…It exerted less cognitive and psychomotor side effects compared with CLN and lorazepam in a wide range of pharmacodynamic tests in healthy volunteers and patients. 14,29,38 According to recent work, CBZ displays significantly higher affinity for a2GABA A R than for a1GABA A R. 18 We previously demonstrated its antihyperalgesic effect in mice, 6 and a recent exploratory study in healthy volunteers has suggested an antihyperalgesic effect in capsaicin-induced hyperalgesia. 41 Hence, CBZ seems to be a suitable compound to test the antihyperalgesic effect of GABA A receptor modulators in humans.…”

Section: Introductionmentioning

confidence: 97%

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GABAergic modulation in central sensitization in humans

Besson

Matthey

Daali

et al. 2015

Pain

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Positive allosteric modulators of GABAA receptors (GAMs) acting at specific subtypes of GABAA receptors effectively restore compromised spinal pain control in rodents. Studies addressing a similar antihyperalgesic effect in humans are sparse and are hampered by sedative effects of nonselective GAMs available for use in humans. We present results from a randomized controlled double-blind crossover study in 25 healthy volunteers, which addressed potential antihyperalgesic actions of clobazam (CBZ) and clonazepam (CLN) at mildly sedating equianticonvulsive doses. Clobazam was chosen because of its relatively low sedative properties and CLN because of its use in neuropathic pain. Tolterodine (TLT) was used as an active placebo. The primary outcome parameter was a change in the area of cutaneous UVB irradiation-induced secondary hyperalgesia (ASH), which was monitored for 8 hours after drug application. Sedative effects were assessed in parallel to antihyperalgesia. Compared with TLT, recovery from hyperalgesia was significantly faster in the CBZ and CLN groups (P = 0.009). At the time point of maximum effect, the rate of recovery from hyperalgesia was accelerated by CBZ and CLN, relative to placebo by 15.7% (95% confidence interval [CI] 0.8-30.5), P = 0.040, and 28.6% (95% CI 4.5-52.6), P = 0.022, respectively. Active compounds induced stronger sedation than placebo, but these differences disappeared 8 hours after drug application. We demonstrate here that GAMs effectively reduce central sensitization in healthy volunteers. These results provide proof-of-principle evidence supporting efficacy of GAMs as antihyperalgesic agents in humans and should stimulate further research on compounds with improved subtype specificity.

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 97%

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GABAergic modulation in central sensitization in humans

Besson

Matthey

Daali

et al. 2015

Pain

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“…[34][35][36] Because Na V 1.1 channels are expressed predominantly on GABAergic interneurons, loss-of-function SCN1A mutations found in Dravet syndrome patients impair interneuron function leading to neuronal hyperexcitability. [34][35][36] Because Na V 1.1 channels are expressed predominantly on GABAergic interneurons, loss-of-function SCN1A mutations found in Dravet syndrome patients impair interneuron function leading to neuronal hyperexcitability.…”

Section: Discussionmentioning

confidence: 99%

Coadministered cannabidiol and clobazam: Preclinical evidence for both pharmacodynamic and pharmacokinetic interactions

et al. 2019

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Objective: Cannabidiol (CBD) has been approved by the US Food and DrugAdministration (FDA) to treat intractable childhood epilepsies, such as Dravet syndrome and Lennox-Gastaut syndrome. However, the intrinsic anticonvulsant activity of CBD has been questioned due to a pharmacokinetic interaction between CBD and a first-line medication, clobazam. This recognized interaction has led to speculation that the anticonvulsant efficacy of CBD may simply reflect CBD augmenting clobazam exposure. The present study aimed to address the nature of the interaction between CBD and clobazam. Methods: We examined whether CBD inhibits human CYP3A4 and CYP2C19 mediated metabolism of clobazam and N-desmethylclobazam (N-CLB), respectively, and performed studies assessing the effects of CBD on brain and plasma pharmacokinetics of clobazam in mice. We then used the Scn1a +/− mouse model of Dravet syndrome to examine how CBD and clobazam interact. We compared anticonvulsant effects of CBD-clobazam combination therapy to monotherapy against thermally-induced seizures, spontaneous seizures and mortality in Scn1a +/− mice. In addition, we used Xenopus oocytes expressing γ-aminobutyric acid (GABA) A receptors to investigate the activity of GABA A receptors when treated with CBD and clobazam together. Results: CBD potently inhibited CYP3A4 mediated metabolism of clobazam and CYP2C19 mediated metabolism of N-CLB. Combination CBD-clobazam treatment resulted in greater anticonvulsant efficacy in Scn1a +/− mice, but only when an anticonvulsant dose of CBD was used. It is important to note that a sub-anticonvulsant dose of CBD did not promote greater anticonvulsant effects despite increasing plasma clobazam concentrations. In addition, we delineated a novel pharmacodynamic mechanism where CBD and clobazam together enhanced inhibitory GABA A receptor activation.

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“…This apparent pattern of binding selectivity differentiates this agent from other classic benzodiazepines such as clonazepam. 27 These properties may allow clobazam to retain efficacy as antiepileptic agent while displaying a relatively low risk for the development of tolerance with long-term treatment. 17–19 …”

Section: Discussionmentioning

confidence: 99%

Deconstructing tolerance with clobazam

et al. 2016

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Objective:To evaluate potential development of tolerance to adjunctive clobazam in patients with Lennox-Gastaut syndrome.Methods:Eligible patients enrolled in open-label extension study OV-1004, which continued until clobazam was commercially available in the United States or for a maximum of 2 years outside the United States. Enrolled patients started at 0.5 mg·kg−1·d−1 clobazam, not to exceed 40 mg/d. After 48 hours, dosages could be adjusted up to 2.0 mg·kg−1·d−1 (maximum 80 mg/d) on the basis of efficacy and tolerability. Post hoc analyses evaluated mean dosages and drop-seizure rates for the first 2 years of the open-label extension based on responder categories and baseline seizure quartiles in OV-1012. Individual patient listings were reviewed for dosage increases ≥40% and increasing seizure rates.Results:Data from 200 patients were included. For patients free of drop seizures, there was no notable change in dosage over 24 months. For responder groups still exhibiting drop seizures, dosages were increased. Weekly drop-seizure rates for 100% and ≥75% responders demonstrated a consistent response over time. Few patients had a dosage increase ≥40% associated with an increase in seizure rates.Conclusions:Two-year findings suggest that the majority of patients do not develop tolerance to the antiseizure actions of clobazam. Observed dosage increases may reflect best efforts to achieve seizure freedom. It is possible that the clinical development of tolerance to clobazam has been overstated.ClinicalTrials.gov identifier:NCT00518713 and NCT01160770.Classification of evidence:This study provides Class III evidence that the majority of patients do not develop tolerance to clobazam over 2 years of treatment.

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Clobazam and Its Active Metabolite N-desmethylclobazam Display Significantly Greater Affinities for α2- versus α1-GABAA–Receptor Complexes

Cited by 52 publications

References 29 publications

GABAergic modulation in central sensitization in humans

GABAergic modulation in central sensitization in humans

Coadministered cannabidiol and clobazam: Preclinical evidence for both pharmacodynamic and pharmacokinetic interactions

Deconstructing tolerance with clobazam

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