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Cited by 511Epilepsy research and treatmentPharmacological Effects and Toxicity StudiesNeuroscience and Neuropharmacology Research

Benzodiazepines in epilepsy: Pharmacology and pharmacokinetics

Open access
Riss, J., Cloyd, J., Gates, J., Collins, S.·2008·Acta Neurologica Scandinavica
DOI 10.1111/j.1600-0404.2008.01004.x
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Abstract

Benzodiazepines (BZDs) remain important agents in the management of epilepsy. They are drugs of first choice for status epilepticus and seizures associated with post-anoxic insult and are also frequently used in the treatment of febrile, acute repetitive and alcohol withdrawal seizures. Clinical advantages of these drugs include rapid onset of action, high efficacy rates and minimal toxicity. Benzodiazepines are used in a variety of clinical situations because they have a broad spectrum of clinical activity and can be administered via several routes. Potential shortcomings of BZDs include tolerance, withdrawal symptoms, adverse events, such as cognitive impairment and sedation, and drug interactions. Benzodiazepines differ in their pharmacologic effects and pharmacokinetic profiles, which dictate how the drugs are used. Among the approximately 35 BZDs available, a select few are used for the management of seizures and epilepsy: clobazam, clonazepam, clorazepate, diazepam, lorazepam and midazolam. Among these BZDs, clorazepate has a unique profile that includes a long half-life of its active metabolite and slow onset of tolerance. Additionally, the pharmacokinetic characteristics of clorazepate (particularly the sustained-release formulation) could theoretically help minimize adverse events. However, larger, controlled studies of clorazepate are needed to further examine its role in the treatment of patients with epilepsy.

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Crossref · 10.1111/j.1600-0404.2008.01004.x

Cites

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Claims the paper makes

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  • Findingown data
    § Special formulations of BZDs

    Despite DMD's long half-life, missing a day's clorazepate dose can alter peak-to-trough concentration ratios.

    “Despite the long half-life of DMD, a missed dayÕs dosing can result in altered peak-to-trough concentration ratios.”
    Quote in the paperSubstantial claim
  • Findingown data
    § Special formulations of BZDs

    After a missed daily clorazepate dose, peak-to-trough plasma DMD differences increased more with the immediate-release formulation than with the sustained-release formulation.

    “Overall, the differences between peak and trough plasma DMD concentrations after a missed daily dose of clorazepate increased more with the immediate-release formulation than with the sustained-release formulation (Table 4).”
    Quote in the paperSubstantial claim
  • Findingown data
    § Special formulations of BZDs

    The sustained-release clorazepate tablet maintained higher trough concentrations after a missed daily dose and replacement of the missed dose.

    “Although the effect was modest, the sustained-release tablet maintained higher trough concentrations after a missed daily dose and replacement of the missed dose.”
    Quote in the paperSubstantial claim
  • Findingown data
    § Special formulations of BZDs

    There was little difference between immediate-release and sustained-release clorazepate in peak and trough concentrations after a missed day's dose.

    “There was little difference between the two formulations in peak and trough concentrations following a missed dayÕs dose.”
    Quote in the paperSubstantial claim
  • Findingcitation
    § Conclusions

    After missed doses without replacement, the peak-to-trough difference in simulated plasma N-desmethyldiazepam concentration is 0.18 μg/ml for both sustained-release and immediate-release clorazepate.

    “Peak ⁄ trough difference b after missed dose(s) (lg ⁄ ml) | NA | 0.18 | 0.41 | NA | 0.18 | 0.42”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] Riss

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  • Classified as probably not a substantial claim. 28
  • The quote only partly states this claim. 4

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    Findingown data
    § Special formulations of BZDs

    In simulations, a missed day's dose of sustained-release clorazepate increased peak-to-trough differences by 0.01 μg/ml (5.9%) without replacement and by 0.24 μg/ml (141.2%) with replacement.

    “However, when a missed dayÕs dose of the sustainedrelease formulation was simulated, peak-to-trough differences increased by 0.01 lg ⁄ ml (5.9%) with no dose replacement and increased by 0.24 lg ⁄ ml (141.2%) with replacement of the missed dose (Table 4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Special formulations of BZDs

    In simulations, time to maximum concentration was 2.43 hours for immediate-release clorazepate and 9.20 hours for sustained-release clorazepate.

    “The time to maximum concentration was 2.43 and 9.20 h for the immediate-release and sustained-release formulations respectively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Special formulations of BZDs

    In simulations, a missed day's dose of immediate-release clorazepate increased peak-to-trough differences by 0.05 μg/ml (38.5%) without replacement and by 0.29 μg/ml (223.1%) with replacement.

    “When a missed dayÕs dose of the immediate-release formulation was simulated, peak-to-trough differences (compared with steady state) increased by 0.05 lg ⁄ ml (38.5%) with no dose replacement and increased by 0.29 lg ⁄ ml (223.1%) with replacement of the missed doses (Table 4).”
    Quote in the paperSubstantial claim

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    Findingown data
    § Special formulations of BZDs

    In simulations, mean steady-state plasma DMD concentration was about 0.71 μg/ml for immediate-release clorazepate and about 0.73 μg/ml for sustained-release clorazepate.

    “The mean steady-state plasma DMD concentration was approximately 0.71 lg ⁄ ml for the immediaterelease formulation and 0.73 lg ⁄ ml for the sustained-release”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation
    § Conclusions

    Missed daily doses with replacement decrease trough plasma N-desmethyldiazepam concentrations by 41.9% for sustained-release clorazepate and by 48.8% for immediate-release clorazepate.

    “Change in trough plasma DMD concentrations (%) | NA | )44.1 | )41.9 | NA | )48.8 | )48.8”
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    • cites [71] Riss

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    Findingcitation
    § Conclusions

    At steady state, the peak-to-trough difference in simulated plasma N-desmethyldiazepam concentration is 0.17 μg/ml for sustained-release clorazepate and 0.13 μg/ml for immediate-release clorazepate.

    “Peak ⁄ trough difference b at steady state (lg ⁄ ml) | 0.17 | NA | NA | 0.13 | NA | NA”
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    • cites [71] Riss

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    Findingcitation
    § Conclusions

    Missed daily doses without replacement decrease peak plasma N-desmethyldiazepam concentrations by 29.6% for sustained-release clorazepate and by 27.1% for immediate-release clorazepate.

    “Change in peak plasma DMD concentrations (%) | NA | )29.6 | 6.0 | NA | )27.1 | 9.6”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] Riss

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    Findingcitation
    § Conclusions

    After missed doses with replacement, the peak-to-trough difference in simulated plasma N-desmethyldiazepam concentration is 0.41 μg/ml for sustained-release clorazepate and 0.42 μg/ml for immediate-release clorazepate.

    “Peak ⁄ trough difference b after missed dose(s) (lg ⁄ ml) | NA | 0.18 | 0.41 | NA | 0.18 | 0.42”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] Riss

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  • May combine two claims.

    Findingcitation
    § Conclusions

    Missed daily doses with replacement increase peak plasma N-desmethyldiazepam concentrations by 6.0% for sustained-release clorazepate and by 9.6% for immediate-release clorazepate.

    “Change in peak plasma DMD concentrations (%) | NA | )29.6 | 6.0 | NA | )27.1 | 9.6”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] Riss

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  • May combine two claims.

    Findingcitation
    § Conclusions

    Missed daily doses without replacement decrease trough plasma N-desmethyldiazepam concentrations by 44.1% for sustained-release clorazepate and by 48.8% for immediate-release clorazepate.

    “Change in trough plasma DMD concentrations (%) | NA | )44.1 | )41.9 | NA | )48.8 | )48.8”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] Riss

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    Premisecitation
    § Abstract

    Benzodiazepines are frequently used for febrile seizures, acute repetitive seizures, and alcohol withdrawal seizures.

    “are also frequently used in the treatment of febrile, acute repetitive and alcohol withdrawal seizures”
    • Also stated in: § Introduction · plain
      “Benzodiazepines also continue to play major roles in treating other conditions such as febrile seizures, acute repetitive seizures and alcohol withdrawal seizures.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] Ko, 1997

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    Premisecitation
    § Abstract

    Benzodiazepines are used in many clinical situations because they have broad clinical activity and can be given by several routes.

    “Benzodiazepines are used in a variety of clinical situations because they have a broad spectrum of clinical activity and can be administered via several routes.”
    • Also stated in: § Efficacy · plain
      “Benzodiazepines are versatile drugs that can be employed in a variety of clinical settings because of their broad spectrum of activity and multiple formulations and because they can be administered by several routes”
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    • cites [81] Ko, 1997

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    Premisenone given
    § Abstract

    The main clinical advantages of benzodiazepines are rapid onset, high efficacy, and minimal toxicity.

    “Clinical advantages of these drugs include rapid onset of action, high efficacy rates and minimal toxicity.”
    • Also stated in: § Introduction · plain
      “The major clinical advantages of BZDs are high efficacy rates, rapid onset of action and minimal toxicity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Abstract

    Benzodiazepines remain important in epilepsy management and are first-choice drugs for status epilepticus and seizures after anoxic injury.

    “Benzodiazepines (BZDs) remain important agents in the management of epilepsy.They are drugs of first choice for status epilepticus and seizures associated with post-anoxic insult”
    • Also stated in: § Introduction · plain
      “Nonetheless, benzodiazepines (BZDs), which have been used since the 1960s, remain important in epilepsy management and are the drugs of first choice for status epilepticus and seizures associated with postanoxic insult.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [77] Alldredge, 2001, A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus, N Engl J Med source

      Not checked in the free run.

    • cites [78] Shaner, 1988, Treatment of status epilepticus: a prospective comparison of diazepam and phenytoin versus phenobarbital and optional phenytoin, Neurology source

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    • cites [79] Treiman, 1998, A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group, N Engl J Med source

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    Premisereasoning
    § Abstract

    Benzodiazepines differ in pharmacologic effects and pharmacokinetic profiles, and these differences determine how the drugs are used.

    “Benzodiazepines differ in their pharmacologic effects and pharmacokinetic profiles, which dictate how the drugs are used.”
    • Also stated in: § Introduction · hedged
      “Thus, pharmacokinetic differences often dictate the use of specific BZDs, route(s) of administration and formulation(s).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given
    § Abstract

    Benzodiazepine shortcomings include tolerance, withdrawal symptoms, adverse events such as cognitive impairment and sedation, and drug interactions.

    “Potential shortcomings of BZDs include tolerance, withdrawal symptoms, adverse events, such as cognitive impairment and sedation, and drug interactions.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Benzodiazepine pharmacology

    Clobazam is an exception because it has a 1-5-benzodiazepine structure.

    “Clobazam is an exception with its 1-5-BZD structure (17).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Shorvon, 1995

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    Premisecitation
    § Absorption and distribution

    Most orally administered benzodiazepines are extensively and rapidly absorbed, with bioavailability from 80% to 100% and times to peak concentration from minutes to several hours.

    “When orally administered, most BZDs are extensively and rapidly absorbed, with bioavailabilities varying from 80% to 100% and times to peak concentration ranging from minutes to several hours (Table 1).”
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    • cites [24] Anderson, 2002

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    Premisecitation
    § Benzodiazepine pharmacology

    GABA C receptors are transmitter-gated chloride channels activated by certain conformationally restricted GABA analogs and are not modulated by steroids, benzodiazepines, or barbiturates.

    “Transmitter-gated chloride channels, GABA C receptors, are selectively activated by certain conformationally restricted GABA analogs and are not modulated by steroids, BZDs or barbiturates (3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Chebib, 1999, The ABC of GABA receptors: a brief review, Clin Exp Pharmacol Physiol source

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    Premisecitation
    § Absorption and distribution

    Benzodiazepines have large volumes of distribution, are highly bound to plasma proteins, and cross into the placenta and breast milk.

    “Benzodiazepines also have large volumes of distribution, are highly bound to plasma proteins (Table 1) and readily cross into the placenta and breast milk (25).”
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    • cites [25] Hobbs, 1996

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    Interpretationreasoning
    § Abstract

    The pharmacokinetic properties of clorazepate, especially the sustained-release form, could theoretically reduce adverse events.

    “Additionally, the pharmacokinetic characteristics of clorazepate (particularly the sustained-release formulation) could theoretically help minimize adverse events.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning
    § Introduction

    Diazepam and lorazepam are mainly used for seizure emergencies, while clobazam, clonazepam, and clorazepate are commonly used for chronic epilepsy.

    “Diazepam and lorazepam are primarily used for management of seizure emergencies, whereas clobazam, clonazepam and clorazepate are commonly used in chronic epilepsy management.”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § Benzodiazepine pharmacology

    GABA binds to its receptor, opens chloride ion gates, and produces an inhibitory current.

    “The inhibitory neurotransmitter GABA binds to the receptor to open the chloride ion gates and produce an inhibitory current (6,8).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [6] Macdonald, 1994, GABAA receptor channels, Annu Rev Neurosci source

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    • cites [8] Barker, 1978, Amino acid pharmacology of mammalian central neurones grown in tissue culture, J Physiol source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Benzodiazepine pharmacology

    GABA A receptors are ligand-activated ion channels that bicuculline blocks and that steroids, benzodiazepines, and barbiturates modulate.

    “Ligand-activated ion channels that are selectively blocked by bicuculline and modulated by steroids, BZDs, and barbiturates are known as GABA A receptors (3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Chebib, 1999, The ABC of GABA receptors: a brief review, Clin Exp Pharmacol Physiol source

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  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given
    § Abstract

    Clorazepate has a distinctive profile, including a long half-life of its active metabolite and slow development of tolerance.

    “Among these BZDs, clorazepate has a unique profile that includes a long half-life of its active metabolite and slow onset of tolerance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given
    § Metabolism and elimination

    Benzodiazepines differ in elimination rates and in whether they form pharmacologically active metabolites.

    “Benzodiazepines differ in their rates of elimination and the formation of pharmacologically active metabolites (Table 2).”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § Benzodiazepine pharmacology

    The basic benzodiazepine chemical structure is a benzene ring fused to a seven-membered diazepine ring.

    “The basic chemical structure of BZDs is formed from the fusion of a benzene ring and a sevenmembered diazepine ring (16) (Fig. 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Feldman, 1997

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    Premisecitation
    § Benzodiazepine pharmacology

    Benzodiazepines bind allosterically at a site different from GABA and increase the frequency of chloride channel opening.

    “Benzodiazepines allosterically bind to the receptor at a different location than GABA does and enhance the chloride channelÕs conductance by increasing the frequency of gated channel opening (6,7,(10)(11)(12).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [6] Macdonald, 1994, GABAA receptor channels, Annu Rev Neurosci source

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    • cites [7] McKernan, 1996, Which GABAA-receptor subtypes really occur in the brain?, Trends Neurosci source

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    • cites [10] Atack, 2006, Rat pharmacokinetics and pharmacodynamics of a sustained release formulation of the GABAA5-selective compound L-655,708, Drug Metab Dispos source

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    Premisecitation
    § Benzodiazepine pharmacology

    Three principal GABA receptor subtypes exist.

    “There are three principal c-aminobutyric acid (GABA) receptor subtypes.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Chebib, 1999, The ABC of GABA receptors: a brief review, Clin Exp Pharmacol Physiol source

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    Premisenone given
    § Benzodiazepine pharmacology

    The GABA A receptor is a pentamer with multiple subunits needed for normal physiologic function.

    “The GABA A receptor consists of a pentameric structure with multiple subunits that are necessary for normal physiologic function.”
    Quote in the paperNot a substantial claim

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    Premisenone given
    § Introduction

    Midazolam is often used as an alternative to diazepam and lorazepam in seizure emergencies and for refractory status epilepticus.

    “Midazolam often is used as an alternative to diazepam and lorazepam in seizure emergencies and for treating refractory status epilepticus.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Absorption and distribution

    After rapid uptake, benzodiazepines redistribute into less well-perfused tissues, and the rate of redistribution is fastest for the most lipid-soluble drugs.

    “Following rapid uptake, BZDs redistribute into less well-perfused tissues; the rate of redistribution is the fastest for the most lipid-soluble drugs (25).”
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    • cites [25] Hobbs, 1996

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    Premisecitation
    § Benzodiazepine pharmacology

    In vivo point mutations indicate that a-1-GABA A receptors mediate sedation and anterograde amnesia and partially mediate anticonvulsant activity, while a-2-GABA A receptors mediate anxiolysis.

    “Based on in vivo point mutations, a-1-GABA A receptors have been found to mediate sedation and anterograde amnesia and to partially mediate anticonvulsant activity, whereas a-2-GABA A receptors mediate anxiolysis (14,15).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] Lw, 2000, Molecular and neuronal substrate for the selective attenuation of anxiety, Science source

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    • cites [15] Rudolph, 1999, Benzodiazepine actions mediated by specific -aminobutyric acidA receptor subtypes, Nature source

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    Premisecitation
    § Benzodiazepine pharmacology

    GABA B receptors are G-protein-coupled seven-transmembrane receptors activated by baclofen and 3-aminopropylphosphinic acid and blocked by phaclofen.

    “The second receptor subtype, GABA B , consists of G-protein-coupled, seven-transmembrane receptors, which are selectively activated by (R)-())baclofen and 3-aminopropylphosphinic acid and are blocked by phaclofen (3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Chebib, 1999, The ABC of GABA receptors: a brief review, Clin Exp Pharmacol Physiol source

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    Premisenone given
    § Introduction

    Benzodiazepines differ in their affinity for receptor subtypes, which may lead to different pharmacologic effects.

    “There are, however, differences among BZDs in affinity for receptor subtypes, which may produce different pharmacologic effects.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Benzodiazepine pharmacology

    Benzodiazepines are classified as low, medium (clorazepate and diazepam), or high (clonazepam and lorazepam) potency.

    “Benzodiazepines are classified as low, medium (e.g.clorazepate and diazepam) or high (e.g.clonazepam and lorazepam) potency (18,19).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [18] Nelson, 1999, Guidelines for the clinical use of benzodiazepines: pharmacokinetics, dependency, rebound and withdrawal, Can J Clin Pharmacol

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    • cites [19] Chouinard, 2004, Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound, J Clin Psychiatry

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    Premisecitation
    § Benzodiazepine pharmacology

    GABA A receptor subunits are assembled from combinations of 19 polypeptides, and different subunit combinations determine the receptor's pharmacologic properties.

    “The receptor subunits are assembled from combinations of 19 polypeptides (i.e.a1-6, b1-3, c1-3, d, e, p, h and q1-3) (4); different subunit combinations determine the pharmacologic properties of the receptor (5,6).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [4] Simon, 2004, Analysis of the set of GABAA receptor genes in the human genome, J Biol Chem source

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    • cites [5] Sieghart, 1999, Structure and subunit composition of GABAA receptors, Neurochem Int source

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    • cites [6] Macdonald, 1994, GABAA receptor channels, Annu Rev Neurosci source

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    Premisecitation
    § Absorption and distribution

    Benzodiazepines cross the blood-brain barrier rapidly, and the diffusion rate into the brain varies by drug and is largely determined by lipophilicity.

    “Benzodiazepines cross the blood-brain barrier rapidly, although the diffusion rate into the brain varies by drug and is largely determined by lipophilicity (21).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Rey, 1999, Pharmacokinetic optimization of benzodiazepine therapy for acute seizures. Focus on delivery routes, Clin Pharmacokinet source

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    Premisecitation
    § Special populations

    In neonates, clorazepate has a prolonged half-life and decreased clearance.

    “In neonates, the t 1 ⁄ 2 of clorazepate is prolonged and clearance is decreased (67).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] Rey, 1979, Pharmacokinetics of the placental transfer and distribution of clorazepate and its metabolite nordiazepam in the feto-placental unit and in the neonate, Eur J Clin Pharmacol source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given
    § Special populations

    Many elderly individuals take multiple medications, increasing their risk of drug-drug interactions.

    “Additionally, many elderly individuals take multiple medications, which increase their risk of drug-drug interactions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Special populations

    Increased sensitivity of older patients to benzodiazepines is partly due to reduced drug metabolism, which can cause drug accumulation.

    “Increased sensitivity of older patients to BZDs is partly due to reduced drug metabolism (when compared with younger adults), which can result in drug accumulation (62).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [62] Demaagd, 1995, High-risk drugs in the elderly population, Geriatr Nurs source

      Not checked in the free run.

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    Premisecitation
    § Metabolism and elimination

    Clonazepam and lorazepam undergo extensive metabolism but do not form active metabolites.

    “Clonazepam and lorazepam undergo extensive metabolism, but no active metabolites are formed (18,24).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [18] Nelson, 1999, Guidelines for the clinical use of benzodiazepines: pharmacokinetics, dependency, rebound and withdrawal, Can J Clin Pharmacol

      Not checked in the free run.

    • cites [24] Anderson, 2002

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Metabolism and elimination

    Clorazepate is rapidly and completely converted to DMD in the gastrointestinal tract, and its pharmacologic effects are largely due to DMD.

    “By contrast, clorazepate undergoes rapid and complete chemical conversion to DMD in the gastrointestinal tract; its pharmacologic effects are largely due to DMD (24,56).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24] Anderson, 2002

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    • cites [56] Breimer, 1980, Pharmacokinetics of benzodiazepines. Short-acting versus long-acting, Arzneimittelforschung

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Special populations

    Benzodiazepine pharmacologic effects appear greater in elderly patients than in younger patients even at similar plasma concentrations, possibly because of age-related changes in drug-receptor interactions, post-receptor mechanisms, and organ function.

    “Furthermore, BZD pharmacologic effects appear to be greater in elderly patients than in younger patients even at similar plasma BZD concentrations (63,64), possibly because of age-related changes in drug-receptor interactions, post-receptor mechanisms and organ function.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [63] Castleden, 1977, Increased sensitivity to nitrazepam in old age, Br Med J source

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    • cites [64] Kraemer, 1999, Managing alcohol withdrawal in the elderly, Drugs Aging source

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    Premisereasoning
    § Drug-drug interactions

    Benzodiazepine metabolism is complex and largely catalyzed by CYP isoenzymes, creating potential interactions with drugs that induce or inhibit those enzymes.

    “As discussed earlier, BZD metabolism is complex and largely catalyzed by CYP isoenzymes.Consequently, there is potential for interactions between BZDs and drugs that induce or inhibit CYP isoenzymes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Drug-drug interactions

    Oral contraceptive steroids may inhibit the metabolism of some oxidatively metabolized or nitroreduced benzodiazepines and accelerate the metabolism of some conjugated benzodiazepines.

    “Oral contraceptive steroids may inhibit the metabolism of some BZDs that undergo oxidative metabolism or nitroreduction and accelerate the metabolism of some BZDs that are conjugated.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Back, 1990, Pharmacokinetic drug interactions with oral contraceptives, Clin Pharmacokinet source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given
    § Special formulations of BZDs

    Some benzodiazepines are available as oral liquids, disintegrating tablets, or rectal gel.

    “Some BZDs are also available as oral liquids [diazepam (Diazepam Intensol; 5 mg ⁄ ml), lorazepam (Lorazepam Intensol; 2 mg ⁄ ml) and midazolam (generic only; 2 mg ⁄ ml)], disintegrating tablets [clonazepam (Klonopin Ò Wafer; Roche Pharmaceuticals, Nutley, NJ, USA; 0.125-, 0.25-, 0.5-, 1-and 2-mg tablets)] or a rectal gel [diazepam (Diastat Ò AcuDial; Valeant Pharmaceuticals International, Costa M”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning
    § Drug-drug interactions

    Inhibiting a minor metabolic pathway may have little effect on drug concentration, whereas inhibiting a major pathway may increase clinical effect or toxicity.

    “For example, inhibition of a minor pathway may have little impact on drug concentration, whereas inhibition of a major pathway may result in enhanced clinical effect or toxicity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Special populations

    CYP-catalyzed metabolism is low at birth, exceeds adult values by age 2-3 years, and then decreases to adult levels around puberty.

    “Cytochrome P-450-catalyzed metabolism tends to be low at birth, but exceeds adult values by age 2-3 years; thereafter, CYP-catalyzed metabolism decreases, reaching adult levels around puberty (66).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Anderson, 2002, Children versus adults: pharmacokinetic and adverse-effect differences, Epilepsia source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Metabolism and elimination

    Midazolam is rapidly converted by CYP3A4 and CYP3A5 to 1-hydroxymidazolam, which contributes about 10% of the parent drug's biologic activity.

    “Midazolam is rapidly converted by CYP 3A4 and CYP 3A5 to 1-hydroxymidazolam, which contributes approximately 10% to the biologic activity of its parent drug (24,41).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24] Anderson, 2002

      Not checked in the free run.

    • cites [41] Gorski, 1994, Regioselective biotransformation of midazolam by members of the human cytochrome P450 3A (CYP3A) subfamily, Biochem Pharmacol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Special populations

    Elderly patients often have variable drug absorption, decreased plasma protein binding due to lower albumin, and reduced hepatic and renal clearance.

    “Elderly individuals often have variable drug absorption, decreased plasma protein-drug binding due to lower albumin concentrations, and reduced hepatic and renal clearance (61).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] Patsalos, 2002, The importance of drug interactions in epilepsy therapy, Epilepsia source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Special formulations of BZDs

    Extended-release formulations can help epilepsy patients control seizures while reducing side effects by minimizing drug concentration fluctuations and improving compliance.

    “Extended-release drug formulations can help patients with epilepsy achieve their primary treatment goals of controlling seizures while reducing side effects by minimizing fluctuations in drug concentration and by improving compliance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Efficacy

    In the Veterans Affairs cooperative study, lorazepam terminated seizures in 64.9% of patients and was significantly more effective than phenytoin (P = 0.002).

    “In the Veterans Affairs cooperative study of status epilepticus, lorazepam terminated seizures in 64.9% of patients and was significantly more effective than phenytoin (P = 0.002) (79).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [79] Treiman, 1998, A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group, N Engl J Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given
    § Efficacy

    Fewer studies have evaluated the clinical efficacy of benzodiazepines in chronic epilepsy.

    “Fewer studies have evaluated the clinical efficacy of BZDs in chronic epilepsy.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Efficacy

    Results from four comparative studies suggest that lorazepam is superior to phenytoin and as effective as clonazepam, diazepam, or diazepam plus phenytoin in the initial treatment of status epilepticus.

    “Results from four comparative studies (three of blinded design) have suggested that lorazepam is superior to phenytoin and as effective as clonazepam, diazepam or the combination of diazepam and phenytoin in the initial treatment of status epilepticus (77,79,80,96).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [77] Alldredge, 2001, A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus, N Engl J Med source

      Not checked in the free run.

    • cites [79] Treiman, 1998, A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group, N Engl J Med source

      Not checked in the free run.

    • cites [80] Leppik, 1983, Double-blind study of lorazepam and diazepam in status epilepticus, JAMA source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Efficacy

    Benzodiazepines were used in epilepsy management as early as 1965, when Gastaut et al. gave intravenous diazepam for status epilepticus.

    “Benzodiazepines were used in epilepsy management as early as 1965, when Gastaut et al. (73,74) administered i.v.diazepam to treat status epilepticus.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [73] Gastaut, 1965, Treatment of status epilepticus with diazepam (Valium), Epilepsia source

      Not checked in the free run.

    • cites [74] Gastaut, 1965, Laction du diazepam (Valium) dans le traitement des formes non-convulsive de lepilepsie generalisee [in French], Rev Neurol (Paris)

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Efficacy

    Benzodiazepines are among the most useful antiepileptic drugs for status epilepticus, acute repetitive seizures, and febrile seizure prophylaxis.

    “Benzodiazepines are among the most useful AEDs available for treating status epilepticus and acute repetitive seizures and for febrile seizure prophylaxis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data
    § Special formulations of BZDs

    When a missed daily clorazepate dose is replaced, the sustained-release formulation produces a smaller change in peak concentrations, which may reduce the risk of drug toxicity.

    “Additionally, when a missed daily dose was replaced, the sustainedrelease formulation resulted in a smaller change in peak concentrations, which may reduce the risk of drug toxicity.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Changes in simulated plasma DMD peak-to-trough concentrations correspond to clinical risks of breakthrough seizures and drug toxicity.

  • May combine two claims.

    Premisecitation
    § Efficacy

    Multiple injections or continuous infusion of diazepam may be required, which can lead to drug accumulation and possibly acute respiratory depression, sedation, and hypotension.

    “Therefore, multiple injections or continuous infusion may be required, which can lead to drug accumulation and possibly to acute respiratory depression, sedation and hypotension (76).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [76] Schmidt, 2002

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Efficacy

    Diazepam is a first-choice drug for early status epilepticus, acute repetitive seizures, and febrile seizure prophylaxis.

    “Diazepam is a drug of first choice for treatment of early status epilepticus and acute repetitive seizures and for febrile seizure prophylaxis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Efficacy

    In one study, 70% of children with absence seizures treated with clonazepam (7 of 10) had at least 75% reduction in seizure frequency after 8 weeks, and an additional 10% (1 of 10) had a 30% reduction.

    “In one study, 70% of children with absence seizures treated with clonazepam (seven of 10) had a ‡ 75% reduction in seizure frequency after 8 weeks of treatment, and an additional 10% of children (one of 10) had a 30% reduction in seizure frequency (105).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [105] Dreifuss, 1975, Serum clonazepam concentrations in children with absence seizures, Neurology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Efficacy

    In a randomized trial comparing buccal midazolam with rectal diazepam in children, the drugs had similar efficacy and onset of action.

    “In a randomized trial comparing buccal midazolam with rectal diazepam in children, the drugs showed similar efficacy and onset of action (125).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Scott, 1999, Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial, Lancet source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given
    § Efficacy

    Midazolam does not have an FDA-approved indication for seizures.

    “Although it is used for many seizure types, midazolam does not have an FDA-approved indication for seizures.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Efficacy

    In that trial, therapeutic success occurred in 56% of midazolam-treated patients (61 of 109) and 27% of diazepam-treated patients (30 of 110), a 29% difference (95% CI 16-41).

    “Therapeutic success (defined as cessation of visible signs of seizure activity within 10 min of drug administration, lack of respiratory depression and no further seizures within 1 h) was noted in 56% of midazolam-treated patients (61 of 109) and 27% of diazepam-treated patients (30 of 110), a 29% difference between groups; (95% confidence interval, 16-41%).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [134] McIntyre, 2005, Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomised controlled trial, Lancet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Efficacy

    In that trial, seizure cessation occurred in 75% of midazolam cases (30 of 40) and 59% of diazepam cases (23 of 39), with P = 0.16.

    “In that study, seizure cessation was achieved in 75% of cases ( 30 of 40)with midazolam and in 59% of cases (23 of 39) with diazepam treatment (P = 0.16).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [125] Scott, 1999, Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial, Lancet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Efficacy

    Clobazam is not approved in the USA but is commonly used elsewhere as adjunctive therapy for refractory epilepsy.

    “Although not currently approved in the USA, clobazam is commonly used elsewhere as adjunctive therapy for patients with refractory epilepsy (103).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] Trimble, 2002, On the use of tranquillisers in epilepsy, Epilepsia source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Efficacy

    Midazolam is the only available water-soluble benzodiazepine; its solubility is achieved when the injectable solution is buffered to pH 2.9-3.7.

    “Midazolam is the only available water-soluble BZD; solubility is achieved when the injectable solution is buffered to a pH of 2.9-3.7 (123).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [123] 123.Midazolam HCl injection [package insert]. Weston, FL: Apotex Corp, 2000.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Efficacy

    Clobazam was studied in a large double-blind trial as first-line monotherapy in children with partial, partial with secondary generalization, or primary generalized tonic-clonic seizures and was reported to have efficacy and tolerability similar to phenytoin or carbamazepine monotherapy.

    “Clobazam was studied in a large double-blind trial as first-line monotherapy in children with partial, partial with secondary generalization or primary generalized tonic-clonic seizures and was reported to have efficacy and tolerability similar to that of monotherapy with phenytoin or carbamazepine (153, 154).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [153] Canadian Study Group for Childhood Epilepsy, 1998, Clobazam has equivalent efficacy to carbamazepine and phenytoin as monotherapy for childhood epilepsy, Epilepsia source

      Not checked in the free run.

    • cites [154] Bawden, 1999, The cognitive and behavioural effects of clobazam and standard monotherapy are comparable, Epilepsy Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Efficacy

    Open-label studies suggest that intranasal midazolam is safe and effective for acute seizure management in children.

    “Open-label studies have suggested that intranasal midazolam is safe and effective for acute seizure management in children (124, 127, 128, 135, 136).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [124] Lahat, 2000, Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study, BMJ source

      Not checked in the free run.

    • cites [127] Fisgin, 2002, Effects of intranasal midazolam and rectal diazepam on acute convulsions in children: prospective randomized study, J Child Neurol source

      Not checked in the free run.

    • cites [128] Mahmoudian, 2004, Comparison of intranasal midazolam with intravenous diazepam for treating acute seizures in children, Epilepsy Behav source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Efficacy

    Initial treatment response occurred in 23 of 26 seizures (88%) with intranasal midazolam and 24 of 26 (92%) with intravenous diazepam.

    “with 88% of seizures (23 of 26) responding to initial treatment with midazolam and 92% (24 of 26) responding to diazepam (124).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [124] Lahat, 2000, Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study, BMJ source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Efficacy

    Clobazam is highly effective as adjunctive therapy for partial and generalized seizures, for intermittent therapy, and for controlling nonconvulsive status epilepticus.

    “It is highly effective as adjunctive therapy for partial and generalized seizures, for intermittent therapy and for controlling nonconvulsive status epilepticus”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [140] Shorvon, 1998, The use of clobazam, midazolam, and nitrazepam in epilepsy, Epilepsia source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Efficacy

    For children with acute seizures, intranasal midazolam is both safe and effective.

    “studies have suggested that intranasal midazolam is safe and effective for acute seizure management in children (124, 127, 128, 135, 136).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [124] Lahat, 2000, Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study, BMJ source

      Not checked in the free run.

    • cites [127] Fisgin, 2002, Effects of intranasal midazolam and rectal diazepam on acute convulsions in children: prospective randomized study, J Child Neurol source

      Not checked in the free run.

    • cites [128] Mahmoudian, 2004, Comparison of intranasal midazolam with intravenous diazepam for treating acute seizures in children, Epilepsy Behav source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Efficacy

    Pain is common with intranasal midazolam and may reflect nasal mucosal irritation from the formulation's low pH of 3-4.3.

    “Additionally, pain is common with intranasal midazolam administration, which may indicate irritation of the nasal mucosa due to the low pH (3-4.3) of the formulation (137-139).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [137] Scott, 2001, Intranasal midazolam for treating febrile seizures in children. Buccal midazolam should be preferred to nasal midazolam [letter], BMJ source

      Not checked in the free run.

    • cites [138] Loftsson, 2001, Cyclodextrin solubilization of benzodiazepines: formulation of midazolam nasal spray, Int J Pharm source

      Not checked in the free run.

    • cites [139] Gudmundsdttir, 2001, Intranasal administration of midazolam in a cyclodextrin based formulation: bioavailability and clinical evaluation in humans, Pharmazie

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Efficacy

    A large volume is needed to deliver a therapeutic intranasal midazolam dose, which makes administration difficult because much of the solution may leak out or be swallowed.

    “A large volume is required to deliver a therapeutic dose, making administration difficult because much of the solution may leak out of the nose or be swallowed (137).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [137] Scott, 2001, Intranasal midazolam for treating febrile seizures in children. Buccal midazolam should be preferred to nasal midazolam [letter], BMJ source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Adverse effects

    Paradoxical excitement is sometimes associated with benzodiazepine use and may include exacerbation of seizures in patients with epilepsy.

    “Paradoxical excitement is sometimes associated with BZD use and may include exacerbation of seizures in patients with epilepsy (171).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [171] Gayatri, 2006, Aggravation of epilepsy by anti-epileptic drugs, Dev Med Child Neurol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Adverse effects

    Diazepam impairs explicit memory, but results regarding impairment of implicit memory by diazepam are mixed.

    “and although diazepam impairs explicit memory, results regarding impairment of implicit memory by diazepam are mixed (176-179).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [176] Legrand, 1995, Time course of the effects of diazepam and lorazepam on perceptual priming and explicit memory, Psychopharmacology source

      Not checked in the free run.

    • cites [177] Wagemans, 1998, Lorazepam but not diazepam impairs identification of pictures on the basis of specific contour fragments, Psychopharmacology source

      Not checked in the free run.

    • cites [178] Vidailhet, 1994, Lorazepam and diazepam effects on memory acquisition in priming tasks, Psychopharmacology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Adverse effects

    Benzodiazepine use is associated with falls, possibly due to over-sedation in elderly patients.

    “Benzodiazepine use is also associated with falls, a possible result of over-sedation in elderly patients (167).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [167] Souchet, 2005, Drug related falls: a study in the French pharmacovigilance database, Pharmacoepidemiol Drug Saf source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Adverse effects

    Over-sedation is more problematic in elderly than younger patients and may occur at lower doses in the elderly.

    “Over-sedation is more problematic in the elderly than in younger patients, and it may occur at lower doses in the elderly (165, 166).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [165] Greenblatt, 1982, Drug therapy: drug disposition in old age, N Engl J Med source

      Not checked in the free run.

    • cites [166] Montamat, 1989, Management of drug therapy in the elderly, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Adverse effects

    High benzodiazepine dosage and potency, short duration of action, long duration of therapy, and premorbid dependent personality traits are risk factors for development of benzodiazepine dependence.

    “High BZD dosage and potency, short duration of BZD action, long duration of therapy and premorbid dependent personality traits are risk factors for the development of BZD dependence (173).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [173] Marriott, 1993, Benzodiazepine dependence. Avoidance and withdrawal, Drug Saf source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Adverse effects

    Lorazepam appears to impair both explicit and implicit memory.

    “Lorazepam appears to impair both explicit memory and implicit memory”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [176] Legrand, 1995, Time course of the effects of diazepam and lorazepam on perceptual priming and explicit memory, Psychopharmacology source

      Not checked in the free run.

    • cites [177] Wagemans, 1998, Lorazepam but not diazepam impairs identification of pictures on the basis of specific contour fragments, Psychopharmacology source

      Not checked in the free run.

    • cites [178] Vidailhet, 1994, Lorazepam and diazepam effects on memory acquisition in priming tasks, Psychopharmacology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Adverse effects

    For long-term benzodiazepine users, the possible degree of recovery and the extent of residual impairment after withdrawal are unclear.

    “For individuals who use BZDs long term, the possible degree of recovery and the extent of residual impairment that may remain after the drugs are withdrawn are unclear (170).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [170] Barker, 2004, Persistence of cognitive effects after withdrawal from long-term benzodiazepine use: a meta-analysis, Arch Clin Neuropsychol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Adverse effects

    This amnesic effect is sometimes deliberately utilized in presurgical medication.

    “This effect is sometimes deliberately utilized in presurgical medication (169).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [169] Ranta, 2002, Patients conscious recollections from cardiac anesthesia, J Cardiothorac Vasc Anesth source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Adverse effects

    Although benzodiazepines generally affect memory, some studies show that effects differ depending on the benzodiazepine used.

    “Additionally, although BZDs are generally known to affect memory, some studies have shown that effects differ depending on the BZD used.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [176] Legrand, 1995, Time course of the effects of diazepam and lorazepam on perceptual priming and explicit memory, Psychopharmacology source

      Not checked in the free run.

    • cites [177] Wagemans, 1998, Lorazepam but not diazepam impairs identification of pictures on the basis of specific contour fragments, Psychopharmacology source

      Not checked in the free run.

    • cites [178] Vidailhet, 1994, Lorazepam and diazepam effects on memory acquisition in priming tasks, Psychopharmacology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Efficacy

    In that study, excellent response was observed for 19% of patients with major generalized seizures (3/16), 39% with absence seizures (7/18), 33% with akinetic seizures (3/9), and 57% with myoclonic seizures (4/7).

    “In that study, an excellent response (defined as complete seizure control or seizure control that produced a notable improvement in social, educational or vocational assessment) was observed for 19% of patients with major generalized seizures (three of 16), 39% of patients with absence seizures (seven of 18), 33% of patients with akinetic seizures (three of nine) and 57% of patients with myoclonic”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [155] Booker, 1974, Clorazepate dipotassium in the treatment of intractable epilepsy, JAMA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Adverse effects

    Elderly patients treated with benzodiazepines can experience confusion, amnesia, ataxia, and hangover effects.

    “Elderly patients treated with BZDs can experience confusion, amnesia, ataxia and hangover effects (62).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Demaagd, 1995, High-risk drugs in the elderly population, Geriatr Nurs source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Tolerance

    Young et al. found that tolerance to clobazam developed within 3 days of initial drug exposure, whereas tolerance to clonazepam developed gradually over a 19-day study.

    “Young et al. (185) found that tolerance to clobazam developed within 3 days of initial drug exposure, whereas tolerance to clonazepam developed gradually over the course of a 19-day study.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [185] Young, 1988, Differences in the development of tolerance to two anticonvulsant benzodiazepines in the amygdaloid kindled rat, J Pharm Pharmacol source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisenone given
    § Conclusions

    Other shortcomings of benzodiazepines include adverse events such as cognitive impairment and sedation, and drug interactions.

    “Other shortcomings include adverse events, such as cognitive impairment and sedation, and drug interactions.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationcitation
    § Tolerance

    The authors suggested that differences in tolerance and cross-tolerance could result from differential regulation of receptor subunit expression by each drug and from differences between drugs in receptor interactions at the time of testing.

    “The authors suggested that differences in tolerance and crosstolerance could result from differential regulation of receptor subunit expression by each drug and from differences between the drugs in their interactions with receptors at the time of testing.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [187] Ramsey-Williams, 1994, Comparison of anticonvulsant tolerance, crosstolerance, and benzodiazepine receptor binding following chronic treatment with diazepam or midazolam, Pharmacol Biochem Behav source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given
    § Conclusions

    Benzodiazepines have the clinical advantages of being highly effective, having a rapid onset of action, and having relatively low toxicity.

    “They have the clinical advantages of being highly effective, with a rapid onset of action and relatively low toxicity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Tolerance

    Rats treated with midazolam for 3 weeks developed cross-tolerance to diazepam but not to clobazam or clonazepam.

    “Rats treated with midazolam for 3 weeks developed cross-tolerance to diazepam but not to clobazam or clonazepam.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [187] Ramsey-Williams, 1994, Comparison of anticonvulsant tolerance, crosstolerance, and benzodiazepine receptor binding following chronic treatment with diazepam or midazolam, Pharmacol Biochem Behav source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given
    § Conclusions

    Benzodiazepines can be used in a variety of clinical situations because they can be administered by several routes and in different formulations.

    “Benzodiazepines can be used in a variety of clinical situations because they can be administered by several routes and in different formulations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Tolerance

    When benzodiazepines are used as anticonvulsants, the time to onset of tolerance varies, and the potential of a benzodiazepine to induce anticonvulsant tolerance does not appear related to its chemical or pharmacokinetic properties.

    “When BZDs are used as anticonvulsants, the time to onset of tolerance varies, and the potential of a BZD to induce anticonvulsant tolerance does not appear to have any relationship with its chemical or pharmacokinetic properties (188).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [188] Garratt, 1988, Can benzodiazepines be classified by characterising their anticonvulsant tolerance-inducing potential?, Eur J Pharmacol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Tolerance

    Cross-tolerance between benzodiazepines occurs and appears to be drug specific.

    “Cross-tolerance between BZDs occurs and appears to be drug specific.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [187] Ramsey-Williams, 1994, Comparison of anticonvulsant tolerance, crosstolerance, and benzodiazepine receptor binding following chronic treatment with diazepam or midazolam, Pharmacol Biochem Behav source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Conclusions

    Clobazam parent drug elimination half-life is 10-30 h and its active metabolite half-life is 36-46 h.

    “Clobazam | Demethylation (26) | N-desmethylclobazam (27) | 10-30 (28) | 36-46 (28)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Rupp, 1979, Pharmacokinetics of single and multiple doses of clobazam in humans, Br J Clin Pharmacol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Conclusions

    Clonazepam is metabolized by nitroreduction (CYP 3A4), acetylation (NAT), and hydroxylation; it has no active metabolites; and its parent drug elimination half-life is 19-60 h.

    “Clonazepam | Nitroreduction (CYP 3A4), | NA | 19-60 (32) | NA”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [29] Seree, 1993, Fundam Clin Pharmacol source

      Not checked in the free run.

    • cites [30] Miller, 1981, Clonazepam acetylation in fast and slow acetylators, Clin Pharmacol Ther source

      Not checked in the free run.

    • cites [31] Peng, 1984, Polymorphic acetylation of 7-amino-clonazepam in human liver cytosol, Pediatr Pharmacol (New York)

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning
    § Conclusions

    Clorazepate is unique among benzodiazepines in being associated with slow onset of tolerance, having an active metabolite with a long half-life, and being available as a sustained-release formulation.

    “Clorazepate is unique among BZDs in that it is associated with slow onset of tolerance, its active metabolite has a long t 1 ⁄ 2 , and it is available as a sustained-release formulation”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given
    § Conclusions

    Benzodiazepines are indicated for the treatment of seizure emergencies and epilepsy.

    “Benzodiazepines are indicated for the treatment of seizure emergencies and epilepsy.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given
    § Conclusions

    Studies of clorazepate in patients with epilepsy have mainly been small, open-label investigations.

    “Studies of clorazepate in patients with epilepsy have mainly been small, open-label investigations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Tolerance

    Gobbi et al. demonstrated that diazepam and N-desmethyldiazepam have the same affinity for central-type benzodiazepine receptors, but N-desmethyldiazepam proved to be a partial agonist with intrinsic activity approximately 43% that of diazepam.

    “Gobbi et al. (199) demonstrated that diazepam and DMD have the same affinity for the central type of BZD receptors, but when the intrinsic activity of DMD was calculated, it proved to be a partial agonist, with intrinsic activity approximately 43% that of diazepam.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [199] Gobbi, 1987, Diazepam and desmethyldiazepam differ in their affinities and efficacies at central and peripheral benzodiazepine receptors, J Pharm Pharmacol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Tolerance

    One putative mechanism for the development of tolerance is simple down-regulation of GABA receptors in response to prolonged benzodiazepine exposure; however, studies testing this hypothesis have reported mixed results.

    “One putative mechanism for the development of tolerance is simple down-regulation of GABA receptors in response to prolonged BZD exposure; however, studies testing this hypothesis have reported mixed results (197).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [197] Bateson, 2002, Basic pharmacologic mechanisms involved in benzodiazepine tolerance and withdrawal, Curr Pharm Des source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Tolerance

    Several other mechanisms for benzodiazepine tolerance have been proposed based on animal and cell culture models, including uncoupling of allosteric linkage between GABA and benzodiazepine sites, changes in turnover of receptor subunits, and changes in receptor gene expression.

    “Several other mechanisms for BZD tolerance have been proposed on the basis of animal and cell culture models.These processes include uncoupling of allosteric linkage between GABA and BZD sites, changes in the turnover of receptor subunits and changes in receptor gene expression (197).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [197] Bateson, 2002, Basic pharmacologic mechanisms involved in benzodiazepine tolerance and withdrawal, Curr Pharm Des source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning
    § Conclusions

    These clorazepate properties may theoretically help minimize adverse effects and withdrawal symptoms.

    “all of which may, theoretically, help minimize adverse effects and withdrawal symptoms.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Tolerance

    Li et al. suggested that down-regulation of benzodiazepine receptor binding sites could not fully explain the development of tolerance because tolerance to some benzodiazepines has been observed even when no changes in benzodiazepine-receptor binding were noted.

    “Li et al. (198) suggested that down-regulation of BZD receptor binding sites could not fully explain the development of tolerance because tolerance to some BZDs has been observed even when no changes in BZDreceptor binding were noted (187).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [198] Li, 2000, Down-regulation of benzodiazepine binding to alpha-5 subunit-containing gamma-aminobutyric acidA receptors in tolerant rat brain indicates particular involvement of the hippocampal CA1 region, J Pharmacol Exp Ther

      Not checked in the free run.

    • cites [187] Ramsey-Williams, 1994, Comparison of anticonvulsant tolerance, crosstolerance, and benzodiazepine receptor binding following chronic treatment with diazepam or midazolam, Pharmacol Biochem Behav source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Withdrawal

    Other studies have suggested that compared with long-half-life benzodiazepines, short-half-life benzodiazepines are associated with faster onset or more severe withdrawal symptoms when benzodiazepine therapy is stopped abruptly.

    “However, results from other studies have suggested that, compared with long-t 1 ⁄ 2 BZDs, BZDs with short t 1 ⁄ 2 are associated with faster onset of withdrawal symptoms or more severe withdrawal symptoms when BZD therapy is stopped abruptly (211, 212).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [211] Rickels, 1990, Long-term therapeutic use of benzodiazepines. I. Effects of abrupt discontinuation [erratum in Arch Gen Psychiatry 1991;48:51], Arch Gen Psychiatry source

      Not checked in the free run.

    • cites [212] Busto, 1986, Withdrawal reaction after long-term therapeutic use of benzodiazepines, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Conclusions

    Clobazam is metabolized primarily by demethylation and has the active metabolite N-desmethylclobazam.

    “Clobazam | Demethylation (26) | N-desmethylclobazam (27) | 10-30 (28) | 36-46 (28)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [26] Volz, 1979, Kinetics and metabolism of clobazam in animals and man, Br J Clin Pharmacol source

      Not checked in the free run.

    • cites [27] Hanks, 1979, Clobazam: pharmacological and therapeutic profile, Br J Clin Pharmacol source

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Premisecitation
    § Conclusions

    Clorazepate is metabolized by decarboxylation, glucuronidation, and hydroxylation (CYP 2C19 and 3A4); its active metabolites include N-desmethyldiazepam (major) and oxazepam (minor); N-desmethyldiazepam half-life is 20-160 h and oxazepam half-life is 6-24 h.

    “Clorazepate | Decarboxylation, glucuronidation, | DMD (major), oxazepam (minor) (24) | NA | 20-160 (24, 33, 34)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [24] Anderson, 2002

      Not checked in the free run.

    • cites [33] Greenblatt, 1988, Desmethyldiazepam pharmacokinetics: studies following intravenous and oral desmethyldiazepam, oral clorazepate, and intravenous diazepam, J Clin Pharmacol source

      Not checked in the free run.

    • cites [34] Bertler, 1980, Pharmacokinetics of dipotassium chlorazepate in patients after repeated 50mg oral doses, Psychopharmacology (Berl) source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Tolerance

    Tolerance may recur at a higher dose, and adverse effects may persist or worsen.

    “However, tolerance may recur at the higher dose, and adverse effects may persist or worsen.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § Conclusions

    Tolerance may develop over time, making benzodiazepines unsuitable for long-term epilepsy management.

    “Tolerance may develop over time, making BZDs unsuitable for use in long-term epilepsy management.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Tolerance

    Rosenberg et al. compared the anticonvulsant activity of clonazepam, clobazam, and diazepam in rats and found that tolerance developed most rapidly to clobazam and most slowly to clonazepam.

    “Rosenberg et al. (189) compared the anticonvulsant activity of clonazepam, clobazam and diazepam in rats and found that tolerance developed most rapidly to clobazam and most slowly to clonazepam.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [189] Rosenberg, 1989, Tolerance to anticonvulsant effects of diazepam, clonazepam, and clobazam in amygdala-kindled rats, Epilepsia source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given
    § Conclusions

    Withdrawal symptoms, some severe, may develop after cessation of benzodiazepine therapy.

    “Additionally, withdrawal symptoms, some severe, may develop after cessation of BZD therapy.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Tolerance

    Bateson proposed that multiple mechanisms mediate tolerance and dependence and described a unified model of molecular mechanisms underlying tolerance.

    “Considering the evidence that tolerance to the various behavioral effects of BZDs develops at different rates and that behavioral effects of BZDs are mediated by different GABA A receptor subtypes, Bateson (197) proposed that multiple mechanisms mediate tolerance and dependence.He described a unified model of molecular mechanisms underlying tolerance that incorporates the molecular processes”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [197] Bateson, 2002, Basic pharmacologic mechanisms involved in benzodiazepine tolerance and withdrawal, Curr Pharm Des source

      Not checked in the free run.

    • The authors state this as an assumption: In Bateson's unified model, initial potentiation of the GABA response leads to desensitization, and prolonged desensitization could result in uncoupling as either a signal for or a consequence of receptor internalization.
    • The authors state this as an assumption: After receptor internalization, degradation of certain receptor subunits could provide a signal for changes in GABA A receptor gene transcription.

  • May combine two claims.

    Premisecitation
    § Tolerance

    In a study comparing clorazepate and clobazam, tolerance occurred in 48% of patients treated with clorazepate for at least 4 weeks, but in only 24% of patients treated with clobazam for at least 3 months.

    “Tolerance occurred in 48% of patients treated with clorazepate for ‡4 weeks, but in only 24% of patients treated with clobazam for ‡3 months (193).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [193] Sugai, 2004, Clobazam as a new antiepileptic drug and clorazepate dipotassium as an alternative antiepileptic drug in Japan, Epilepsia source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Withdrawal

    Some reports have suggested that benzodiazepine half-life does not influence withdrawal symptoms.

    “Some reports have suggested that BZD t 1 ⁄ 2 does not influence withdrawal symptoms (208, 210).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [208] Schweizer, 1990, Long-term therapeutic use of benzodiazepines. II. Effects of gradual taper, Arch Gen Psychiatry source

      Not checked in the free run.

    • cites [210] Murphy, 1991, A double-blind comparison of the effects of gradual withdrawal of lorazepam, diazepam and bromazepam in benzodiazepine dependence, Br J Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Withdrawal

    Numerous reports have identified predictors of the occurrence or increased severity of withdrawal symptoms: higher benzodiazepine dose, longer duration of use, immediate cessation or rapid tapering, history of drug abuse, dependence on other drugs, personality pathology, and a diagnosis of panic disorder.

    “Numerous reports have identified certain predictors of the occurrence or increased severity of withdrawal symptoms: higher BZD dose (200-204), longer duration of BZD use (202, 203, 205, 206), immediate cessation or rapid tapering of the BZD dose (200, 203, 204, 207-209), history of drug abuse (202, 203), dependence on other drugs (209), personality pathology (e.g.neuroticism and dependency) (203)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [200] Martnez-Cano, 1995, Benzodiazepine withdrawal syndrome seizures, Pharmacopsychiatry source

      Not checked in the free run.

    • cites [202] Uhlenhuth, 1999, International study of expert judgment on therapeutic use of benzodiazepines and other psychotherapeutic medications. IV. Therapeutic dose dependence and abuse liability of benzodiazepines in the long-term treatment of anxiety disorders, J Clin Psychopharmacol source

      Not checked in the free run.

    • cites [203] Schweizer, 1998, Benzodiazepine dependence and withdrawal: a review of the syndrome and its clinical management, Acta Psychiatr Scand Suppl source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Conclusions

    Clorazepate product-labeled uses include anxiety, alcohol withdrawal, and adjunctive treatment of partial seizures; its common use in epilepsy is adjunctive treatment of partial seizures.

    “Clorazepate | Tranxene T-Tab | Yes | Anxiety, alcohol withdrawal, | Adjunctive treatment of partial seizures (75)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [75] Lacy, 2004

      Not checked in the free run.

    • cites [76] Schmidt, 2002

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Conclusions

    Clobazam is not FDA approved; its common uses in epilepsy include first-line adjunctive treatment for treatment-resistant partial and generalized seizures, intermittent therapy, and non-convulsive status epilepticus.

    “Clobazam | Frisium | NA | Not FDA approved | First-line adjunctive treatment for treatment-resistant”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [75] Lacy, 2004

      Not checked in the free run.

    • cites [76] Schmidt, 2002

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Conclusions

    Lorazepam is metabolized by glucuronidation, has no active metabolites, and its parent drug elimination half-life is 7-26 h.

    “Lorazepam | Glucuronidation (24) | NA | 7-26 (39, 40) | NA”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [24] Anderson, 2002

      Not checked in the free run.

    • cites [39] Greenblatt, 1979, Pharmacokinetics and bioavailability of intravenous, intramuscular, and oral lorazepam in humans, J Pharm Sci source

      Not checked in the free run.

    • cites [40] Greenblatt, 1982, Pharmacokinetic comparison of sublingual lorazepam with intravenous, intramuscular, and oral lorazepam, J Pharm Sci source

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Premisecitation
    § Conclusions

    Diazepam is metabolized by demethylation (CYP 2C9, 2C19, 2B6, 3A4, and 3A5), hydroxylation (CYP 3A4 and 2C19), and glucuronidation; its active metabolites include N-desmethyldiazepam (major), oxazepam (minor), and temazepam (minor); parent half-life is 21-70 h; N-desmethyldiazepam half-life is 49-179 h; oxazepam half-life is 6-24 h; and temazepam half-life is 8-24 h.

    “Diazepam | Demethylation (CYP 2C9, 2C19, 2B6, 3A4, | DMD (major), oxazepam (minor), | 21-70 (23, 38) | DMD: 49-179 (33, 38)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [23] Cloyd, 1998, A single-blind, crossover comparison of the pharmacokinetics and cognitive effects of a new diazepam rectal gel with intravenous diazepam, Epilepsia source

      Not checked in the free run.

    • cites [38] Kaplan, 1973, Pharmacokinetic profile of diazepam in man following single intravenous and oral and chronic oral administrations, J Pharm Sci source

      Not checked in the free run.

    • cites [24] Anderson, 2002

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Conclusions

    Midazolam product-labeled uses include anesthesia and preoperative and procedural sedation; its common use in epilepsy is second-line therapy for early status epilepticus.

    “Midazolam | Versed | Yes | Anesthesia, preoperative and procedural | Second-line therapy for early status epilepticus”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [75] Lacy, 2004

      Not checked in the free run.

    • cites [76] Schmidt, 2002

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Conclusions

    Clonazepam product-labeled uses include panic disorder and epileptic seizures (alone or adjunct); common uses in epilepsy include second-line adjunctive treatment for partial and generalized seizures, early status epilepticus, Lennox-Gastaut syndrome, and second-line treatment of status epilepticus.

    “Clonazepam | Klonopin | Yes | Panic disorder, epileptic | Second-line adjunctive treatment for partial and”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [75] Lacy, 2004

      Not checked in the free run.

    • cites [76] Schmidt, 2002

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Conclusions

    Midazolam is metabolized by hydroxylation (CYP 3A4 and 3A5), has the minor active metabolite 1-hydroxymidazolam, parent half-life is 1-4 h, and active metabolite half-life is 1 h.

    “Midazolam | Hydroxylation (CYP 3A4 and 3A5) (25, 41, 42) | 1-hydroxymidazolam (minor) (24) | 1-4 (24) | 1 (24)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [25] Hobbs, 1996

      Not checked in the free run.

    • cites [41] Gorski, 1994, Regioselective biotransformation of midazolam by members of the human cytochrome P450 3A (CYP3A) subfamily, Biochem Pharmacol source

      Not checked in the free run.

    • cites [42] Kronbach, 1989, Oxidation of midazolam and triazolam by human liver cytochrome P450IIIA4, Mol Pharmacol

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Premisecitation
    § Conclusions

    Diazepam product-labeled uses include anxiety, alcohol withdrawal, muscle relaxation, and epileptic seizures; common uses in epilepsy include first-line treatment for early status epilepticus, second-line therapy for established status epilepticus, treatment of non-convulsive status epilepticus, intermittent prophylactic therapy for febrile seizures, and at-home treatment of acute repetitive seizu

    “Diazepam | Valium | Yes | Anxiety, alcohol withdrawal, | First-line treatment for early status epilepticus;”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [75] Lacy, 2004

      Not checked in the free run.

    • cites [76] Schmidt, 2002

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Premisecitation
    § Conclusions

    Lorazepam product-labeled uses include anxiety, pre-anesthetic amnesia induction, antiemetic adjunct, and status epilepticus; common uses in epilepsy include first-line treatment for early status epilepticus and out-of-hospital status epilepticus.

    “Lorazepam | Ativan | Yes | Anxiety, pre-anesthetic to induce amnesia, | First-line treatment for early status epilepticus”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [75] Lacy, 2004

      Not checked in the free run.

    • cites [76] Schmidt, 2002

      Not checked in the free run.

123 of 123

  • The paper relies on this without support.

    Changes in simulated plasma DMD peak-to-trough concentrations correspond to clinical risks of breakthrough seizures and drug toxicity.

    “This effect may prevent breakthrough seizures in some patients.”
    “which may reduce the risk of drug toxicity.”

  • The paper relies on this without support.

    Tolerance to antiepileptic drugs is associated with a progressive increase in the number and severity of seizures and an increased risk of withdrawal seizures when the maintenance dose is constant.

    “Tolerance to AEDs is associated with a progressive increase in the number and severity of seizures and an increased risk of withdrawal seizures in the presence of a constant maintenance dose.”

  • The authors state this as an assumption.

    In Bateson's unified model, initial potentiation of the GABA response leads to desensitization, and prolonged desensitization could result in uncoupling as either a signal for or a consequence of receptor internalization.

    “This model assumes that initial potentiation of the GABA response leads to desensitization and that prolonged desensitization could result in uncoupling (as either a signal for or a consequence of receptor internalization, i.e. endocytosis).”

  • The authors state this as an assumption.

    After receptor internalization, degradation of certain receptor subunits could provide a signal for changes in GABA A receptor gene transcription.

    “Subsequent to receptor internalization, degradation of certain receptor subunits could provide a signal for changes in GABA A receptor gene transcription.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Concomitant use of B. monnieri with clinically prescribed drugs that are substrates of CYP3A4, CYP2C9, and CYP2C19, particularly those with poor bioavailability due to extensive metabolism such as clozapine and midazolam, could cause potential herb-drug interactions.

    “Therefore, the concomitant use of B. monnieri with clinically prescribed drugs that are substrates of CYP3A4, CYP2C9, and CYP2C19 isoforms, particularly those exhibiting poor bioavailability due to extensive metabolism such as clozapine [31] and midazolam [32] could cause potential herb-drug interactions.”

    From Inhibition of Human Cytochrome P450 Enzymes by Bacopa monnieri Standardized Extract and Constituents (2014) · cites this paper as [32]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • The Kaplan and DuPont citation number does not match the bibliography

    Minor

    The text attributes a description of the simulations to Kaplan and DuPont at reference 72, but the bibliography lists their work as reference 71.

  • Lorazepam's listed half-life exceeds its short-acting category

    Minor

    The paper defines short-acting benzodiazepines as having a half-life below 10 hours and includes lorazepam, but Table 2 gives lorazepam a range extending to 26 hours.

  • Clonazepam's listed half-life exceeds its intermediate-acting category

    Minor

    The paper places clonazepam in the 10-24-hour intermediate-acting category, while Table 2 reports a parent-drug half-life of up to 60 hours and no active metabolite.

3 of 3

Cites

Flagged first, then by citations

3 of the 205 references couldn’t be matched to a known paper.

Research works printed but not linked: 26

  1. International Narcotics Control Board, Psychotropic Substances 2006
  2. Shorvon, 1995, Antiepileptic drugs, 763
  3. Anderson, 2002, Antiepileptic drugs, 187
  4. Hobbs, 1996, Goodman & Gilmans. The pharmacological basis of therapeutics, 361
  5. United Nations, 1997, Recommended methods for the detection and assay of barbiturates and benzodiazepines in biological specimens. Manual for use by national laboratories
  6. Flockhart, Drug interaction table (cytochrome P450 system)
  7. 47.Trileptal [package insert]. East Hanover, NJ: Novartis, 2007.
  8. Lacy, Anticonvulsants and antimicrobial cytochrome P-450 effects
  9. Goshman, 1999, Clinically significant P450 drug interactions, J Pharm Soc Wisconsin, 23
  10. Riss, The simulation of desmethyldiazepam (DMD) concentrations following missed daily doses of Tranxene-SD and Tranxene T-Tab
  11. Gastaut, 1965, Laction du diazepam (Valium) dans le traitement des formes non-convulsive de lepilepsie generalisee [in French], Rev Neurol (Paris), 112, 99
  12. Schmidt, 2002, Antiepileptic drugs, 206
  13. Schmidt, 1995, Antiepileptic drugs, 705
  14. Sato, 1995, Antiepileptic drugs, 725
  15. Sato, 1977, Clonazepam in the treatment of absence seizures: a double-blind clinical trial [abstract], Neurology, 27, 371
  16. Beck, 1973, Traitement des etats de mal epileptiques par le clonazepam [in French], Sem Hop Paris, 49, 21
  17. Bergamini, 1970, Elektroenzephalographische und klinische Bewertung des neuen Benzodiazepin Ro 54023 [in German], EEG EMG, 1, 182
  18. Bergamini, 1972, LAction du Ro 54023 dans le traitement des differentes formes depilepsie [in French]
  19. Gastaut, 1970, Properties anti-epileptiques exceptionneles dune benzodiazepine nouvelle le Ro 05-4023 [in French], La Vie Medicale, 51, 5175
  20. Gimenez-Roldan, 1972, Un nuevo medicamento eficaz en el trataimento del status epilepticus - Ro 5-4023 [in Spanish], Med Clin (Barc), 58, 133
  21. Tridon, 1973, Conduite du traitement des etats de mal epileptiques par le Ro 05-4023 (clonazepam) [in French], Sem Hop Paris, 49, 29
  22. 123.Midazolam HCl injection [package insert]. Weston, FL: Apotex Corp, 2000.
  23. Wolf, 1985, Clobazam. Human psychopharmacology and clinical application, 167
  24. Critchley, 1981, Clobazam, 159
  25. Wilson, 1985, Clobazam. Human psychopharmacology and clinical application, 172
  26. Graf, 1987, Clorazepate therapy in children with refractory seizures [abstract], Epilepsia, 28, 606

Cited by

Sorted by citations

Related

Authors
Riss, J., Cloyd, J., Gates, J., & Collins, S.
Affiliations
  • University of Minnesota (US)
  • Minnesota Epilepsy Group (US)
Corresponding author
Cloyd, J.
ORCID
Cloyd, J.
Venue
Acta Neurologica Scandinavica
Publisher
Wiley
Published
2008-08
Volume
118
Issue
2
Pages
69-86
ISSN
  • 0001-6314 (ISSN-L)
  • 1600-0404
DOI
10.1111/j.1600-0404.2008.01004.x
OpenAlex
W2047978949
Cited by
511
References
205
Citations by year
2026: 10 · 2025: 19 · 2024: 30 · 2023: 26 · 2022: 25 · 2021: 26 · 2020: 40 · 2019: 36 · 2018: 33 · 2017: 25 · 2016: 37 · 2015: 30 · 2014: 39 · 2013: 23 · 2012: 38
FWCI
3.16
Type
journal article
Language
en
Open access
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 2587 d)
Locations
  • Acta Neurologica Scandinavica (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
benzodiazepines, epilepsy, pharmacokinetics, pharmacology, clorazepate, clonazepam, diazepam, lorazepam, midazolam, clobazam, drug tolerance, drug interactions, sedation, cognitive impairment, status epilepticus, febrile seizures, alcohol withdrawal seizures
MeSH terms
Benzodiazepines, Epilepsy, Humans

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.

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