Cited by 511Epilepsy research and treatmentPharmacological Effects and Toxicity StudiesNeuroscience and Neuropharmacology Research
The DOI matches its Crossref record; 202 of the 205 references it cites were found in a registry or an index; 2 of the 287 sources its claims cite were checked for support.
Benzodiazepines in epilepsy: pharmacology and pharmacokinetics
Open accessAbstract
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.
Overview
Integrity signals
Registry
Crossref · 10.1111/j.1600-0404.2008.01004.x
Cites
202 of 202 references verified0 citation errors · 0 not checkable
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Claims the paper makes
191 Not checked yet · 37 No basis given · 8 Own interpretation · 8 Own result · 2 Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“they suggested that longer than 6 months may be needed for recovery from some deficits.”
What the sources say
- Supportedcites [170] Barker, 2004, Persistence of cognitive effects after withdrawal from long-term benzodiazepine use: a meta-analysis, Arch Clin Neuropsychol source
The Discussion states that the data do not support full cognitive recovery in the first 6 months after cessation and suggests that some deficits may take longer than 6 months to recover. This directly supports the citing sentence’s hedged wording. (LLM, conf=0.95)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Despite the long half-life of DMD, a missed dayÕs dosing can result in altered peak-to-trough concentration ratios.”
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although the effect was modest, the sustained-release tablet maintained higher trough concentrations after a missed daily dose and replacement of the missed dose.”
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There was little difference between the two formulations in peak and trough concentrations following a missed dayÕs dose.”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Peak ⁄ trough difference b after missed dose(s) (lg ⁄ ml) | NA | 0.18 | 0.41 | NA | 0.18 | 0.42”
What the sources say
- Not checked yetcites [71] Riss
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
- Also stated in: § Introduction · plain
“few of the approximately 35 BZDs available worldwide (2) are used for managing epilepsy.”
What the sources say
- Not checked yetcites [2] International Narcotics Control Board
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- Also stated in: § Introduction · plain
In the paper
“Midazolam is an exception, with low oral bioavailability due to metabolism by cytochrome P-450 (CYP) enzyme 3A5 in intestinal epithelial tissue, which can reduce by up to 50% the fraction of the dose reaching the bloodstream (24).”
What the sources say
- Not checked yetcites [24] Anderson, 2002
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Benzodiazepines have differences in their physiochemical properties, most notably lipid solubility, which influence their rate of absorption and diffusion into tissue compartments and their pharmacokinetics.”
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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None of the sources cited for this claim have been checked yet.
In the paper
“The CYP isoenzymes catalyzing these reactions include 3A4, 3A5, 2B6, 2C9 and 2C19 (Tables 2 and 3).”
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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None of the sources cited for this claim have been checked yet.
In the paper
“Benzodiazepine metabolism is primarily catalyzed by CYP-dependent hydroxylation, demethylation and nitroreduction (26,44,45).”
What the sources say
- Not checked yetcites [26] Volz, 1979, Kinetics and metabolism of clobazam in animals and man, Br J Clin Pharmacol source
- Not checked yetcites [44] Tanaka, 1999, Clinically significant pharmacokinetic drug interactions with benzodiazepines, J Clin Pharm Ther source
- Not checked yetcites [45] Kosaki, 2004, A major influence of CYP2C19 genotype on the steady-state concentration of N-desmethylclobazam, Brain Dev source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“The elimination half-life (t 1 ⁄ 2 ) of a BZD or of its active metabolite is used to categorize BZD duration of effect: short acting (<10 h; lorazepam, midazolam), intermediate acting (10-24 h; clonazepam) or long acting (>24 h; clobazam, clorazepate and diazepam) (43).”
What the sources say
- Not checked yetcites [43] United Nations, 1997
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“The number and types of subunits vary depending on the location of the receptor in the CNS (7).”
What the sources say
- Not checked yetcites [7] McKernan, 1996, Which GABAA-receptor subtypes really occur in the brain?, Trends Neurosci source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The faster the diffusion rate, the earlier is the onset of pharmacodynamic effects.”
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“With multiple doses, the pharmacologic and toxic effects of diazepam are attributable to the parent drug, DMD, and other minor active metabolites (i.e.temazepam and oxazepam) (24).”
What the sources say
- Not checked yetcites [24] Anderson, 2002
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Uridine diphosphate glucuronosyltransferase is also involved in the conjugation of some BZDs (Table 3).”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Thus, some BZDs are more effective than others as anticonvulsants”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“In the search for BZD site ligands with higher therapeutic selectivity and a more favorable safety profile, GABA A receptor subtypes have long been considered promising targets (13).”
What the sources say
- Not checked yetcites [13] Mhler, 2002, A new benzodiazepine pharmacology, J Pharmacol Exp Ther source
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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None of the sources cited for this claim have been checked yet.
In the paper
“Rapid entry of BZDs into the CNS and highly perfused tissues is consistent with their short distribution half-lives (21,25).”
What the sources say
- Not checked yetcites [21] Rey, 1999, Pharmacokinetic optimization of benzodiazepine therapy for acute seizures. Focus on delivery routes, Clin Pharmacokinet source
- Not checked yetcites [25] Hobbs, 1996
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Benzodiazepines do not substitute for GABA, but instead enhance the inhibitory effects of GABA.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“All BZDs share similar neuropharmacologic properties including anxiety reduction, sedation, sleep induction, anticonvulsant effects and muscle relaxation (1).”
What the sources say
- Not checked yetcites [1] Shader, 1979, Benzodiazepines: some aspects of their clinical pharmacology, Ciba Found Symp
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The BZDs also have widely varying pharmacokinetic profiles, with differences in absorption, onset and duration of action and formation of active metabolites.”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Benzodiazepines bind to GABA A receptors, ionotropic transmembrane proteins located in the neuronal membranes of the central nervous system (CNS) (3).”
What the sources say
- Not checked yetcites [3] Chebib, 1999, The ABC of GABA receptors: a brief review, Clin Exp Pharmacol Physiol source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“After an intravenous (i.v.) BZD administration, BZD pharmacokinetics can be characterized by a multicompartmental mathematical model, with the first phase being distribution, followed by a longer elimination phase.”
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Binding of BZDs to the c subunit of the receptor is important in the potentiation of GABAergic inhibition (9).”
What the sources say
- Not checked yetcites [9] Mihic, 1994, A single amino acid of the human gamma-aminobutyric acid type A receptor gamma 2 subunit determines benzodiazepine efficacy, J Biol Chem source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Diazepam and clorazepate are metabolized into the long-acting metabolite DMD (56).”
What the sources say
- Not checked yetcites [56] Breimer, 1980, Pharmacokinetics of benzodiazepines. Short-acting versus long-acting, Arzneimittelforschung
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Approximately 5-9% of DMD is excreted unchanged in the urine (24).”
What the sources say
- Not checked yetcites [24] Anderson, 2002
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“By contrast, addition of an enzymeinducing drug that affects even a relatively minor pathway may lead to a clinically important reduction in plasma BZD concentration.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“For BZDs with active metabolites, the addition of an inhibitor or inducer may affect only the parent drug, only the metabolite, or both.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“N-Desmethyldiazepam undergoes glucuronidation to form a glucuronide conjugate (25%) and is hydroxylated (50%) by CYP 2C19 and CYP 3A4 to form oxazepam (24,37).”
What the sources say
- Not checked yetcites [24] Anderson, 2002
- Not checked yetcites [37] Andersson, 1994, Diazepam metabolism by human liver microsomes is mediated by both S-mephenytoin hydroxylase and CYP3A isoforms, Br J Clin Pharmacol source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“Equivalent doses of BZDs differ as much as 20-fold because of differences in potency (57).”
What the sources say
- Not checked yetcites [57] Ashton, 1994, Guidelines for the rational use of benzodiazepines. When and what to use, Drugs source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“The intensity of single-dose effects may vary, even if equipotent doses are used, because of varying oral absorption rates (58).”
What the sources say
- Not checked yetcites [58] Shader, 1984, Plasma concentrations and clinical effects after single oral doses of prazepam, clorazepate, and diazepam, J Clin Psychiatry
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“Infants have reduced hydroxylation metabolism, which results in a decreased clearance of diazepam (68).”
What the sources say
- Not checked yetcites [68] Morselli, 1973, Diazepam elimination in premature and full term infants, and children, J Perinat Med source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Metabolism via glucuronidation tends to be low in neonates, reaching adult levels by age 3-4 years (66).”
What the sources say
- Not checked yetcites [66] Anderson, 2002, Children versus adults: pharmacokinetic and adverse-effect differences, Epilepsia source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Benzodiazepines interact with other drugs such as certain antidepressants, AEDs (e.g.phenobarbital, phenytoin and carbamazepine), sedative antihistamines, opiates, antipsychotics and alcohol (44,57,59), which may result in additive sedative effects.”
What the sources say
- Not checked yetcites [44] Tanaka, 1999, Clinically significant pharmacokinetic drug interactions with benzodiazepines, J Clin Pharm Ther source
- Not checked yetcites [57] Ashton, 1994, Guidelines for the rational use of benzodiazepines. When and what to use, Drugs source
- Not checked yetcites [59] Lader, 1987, Clinical pharmacology of benzodiazepines, Ann Rev Med source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“Clobazam is demethylated into an active metabolite (N-desmethylclobazam) (27).”
What the sources say
- Not checked yetcites [27] Hanks, 1979, Clobazam: pharmacological and therapeutic profile, Br J Clin Pharmacol source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“Extended-release formulations may also improve quality of life and patient satisfaction with treatment, in part by simplifying dosage regimens (70).”
What the sources say
- Not checked yetcites [70] Pellock, 2004, Extended-release formulations: simplifying strategies in the management of antiepileptic drug therapy, Epilepsy Behav source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Currently, clorazepate is the only BZD available in both a sustained-release, single-dose (Tranxene Ò -SD, Ovation Pharmaceuticals, Deerfield, IL, USA) formulation (11.25-and 22.5-mg tablets) and an immediate-release formulation that requires multiple doses per day (Tranxene Ò T-Tab; 3.75-, 7.5-and 15-mg tablets) that is approved in the USA for the treatment of seizures.”
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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None of the sources cited for this claim have been checked yet.
In the paper
“The t 1 ⁄ 2 of DMD ranges widely from 20 to 179 h (24,33,34,38).”
What the sources say
- Not checked yetcites [24] Anderson, 2002
- Not checked yetcites [33] Greenblatt, 1988, Desmethyldiazepam pharmacokinetics: studies following intravenous and oral desmethyldiazepam, oral clorazepate, and intravenous diazepam, J Clin Pharmacol source
- Not checked yetcites [34] Bertler, 1980, Pharmacokinetics of dipotassium chlorazepate in patients after repeated 50mg oral doses, Psychopharmacology (Berl) source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Conversely, potent enzyme inducers (e.g.phenytoin, phenobarbital and carbamazepine) substantially increase clearance and reduce the t 1 ⁄ 2 of certain BZDs (44).”
What the sources say
- Not checked yetcites [44] Tanaka, 1999, Clinically significant pharmacokinetic drug interactions with benzodiazepines, J Clin Pharm Ther source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“The t 1 ⁄ 2 of midazolam is shorter in children than in adults: 0.79-2.83h in children (69) vs 1.36-4 h in adults (24).”
What the sources say
- Not checked yetcites [69] Salonen, 1987, Midazolam as an induction agent in children: a pharmacokinetic and clinical study, Anesth Analg source
- Not checked yetcites [24] Anderson, 2002
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The clinical importance of these interactions depends on the net effect of inhibition or induction on the metabolic pathway of a particular BZD.”
plainconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Clinicians should exercise particular caution when using BZDs with selective serotonin reuptake inhibitors, cimetidine, macrolide antibiotics and antimycotics; these drugs may inhibit reactions catalyzed by certain CYP isoenzymes and, therefore, inhibit the metabolism of many BZDs, which results in increased plasma BZD concentrations (44).”
What the sources say
- Not checked yetcites [44] Tanaka, 1999, Clinically significant pharmacokinetic drug interactions with benzodiazepines, J Clin Pharm Ther source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Intermittent use of BZDs is especially suitable for patients with clusters of repetitive seizures (81).”
What the sources say
- Not checked yetcites [81] Ko, 1997
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“In a short-term, placebo-controlled trial, adjunctive oral lorazepam therapy was effective (i.e.reduced seizure frequency significantly more than placebo did, P < 0.01) for treating partial seizures that were unresponsive to standard AEDs (101).”
What the sources say
- Not checked yetcites [101] Walker, 1984, Lorazepam: a controlled trial in patients with intractable partial complex seizures, Epilepsia source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Shaner et al. (78) reported that seizures were aborted in <10 min in 55.6% of patients (10 of 18) treated with diazepam (2 mg ⁄ min) and phenytoin (40 mg ⁄ min).”
What the sources say
- Not checked yetcites [78] Shaner, 1988, Treatment of status epilepticus: a prospective comparison of diazepam and phenytoin versus phenobarbital and optional phenytoin, Neurology source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Nevertheless, BZDs are useful as adjunctive agents in treating certain patients with both partial and primary generalized seizures (81).”
What the sources say
- Not checked yetcites [81] Ko, 1997
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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In the paper
“Uncontrolled studies of clonazepam in patients with partial and generalized epilepsy have generally shown modest effects (76).”
What the sources say
- Not checked yetcites [76] Schmidt, 2002
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The development of tolerance has also been reported for infusions lasting >24 h (85).”
What the sources say
- Not checked yetcites [85] Parsonage, 1967, Use of diazepam in the treatment of severe convulsive status epilepticus, Br Med J source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Leppik et al. (80) found that 76% of status epilepticus episodes (25 of 33) were terminated by one or two diazepam doses (5 mg ⁄ min).”
What the sources say
- Not checked yetcites [80] Leppik, 1983, Double-blind study of lorazepam and diazepam in status epilepticus, JAMA source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Clonazepam also can be useful in treating patients with myoclonic seizures (107).”
What the sources say
- Not checked yetcites [107] Pinder, 1976, Clonazepam: a review of its pharmacological properties and therapeutic efficacy in epilepsy, Drugs source
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“As reviewed by Browne (102), clonazepam has been shown to be efficacious in treating patients with both partial and generalized seizures.”
What the sources say
- Not checked yetcites [102] Browne, 1978, Clonazepam, N Engl J Med source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This effect may prevent breakthrough seizures in some patients.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Changes in simulated plasma DMD peak-to-trough concentrations correspond to clinical risks of breakthrough seizures and drug toxicity.
In the paper
“Similarly, Leppik et al. (80) found that one or two lorazepam doses (4 mg each) terminated seizures in 89% of status epilepticus episodes.”
What the sources say
- Not checked yetcites [80] Leppik, 1983, Double-blind study of lorazepam and diazepam in status epilepticus, JAMA source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Rectally administered diazepam may also be effective for short-term prophylaxis (at doses of 5-10 mg or 0.3-0.6 mg ⁄ kg in patients weighing <10 kg) in children prone to febrile seizures (91-93)”
What the sources say
- Not checked yetcites [91] Daugbjerg, 1990, Intermittent prophylaxis in febrile convulsions: diazepam or valproic acid?, Acta Neurol Scand source
- Not checked yetcites [92] Knudsen, 1985, Effective short-term diazepam prophylaxis in febrile convulsions, J Pediatr source
- Not checked yetcites [93] Ventura, 1982, Home treatment of seizures as a strategy for the long-term management of febrile convulsions in children, Helv Paediatr Acta
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Four randomized controlled trials support diazepam as a drug of first choice for managing status epilepticus (77)(78)(79)(80).”
What the sources say
- Not checked yetcites [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 yetcites [78] Shaner, 1988, Treatment of status epilepticus: a prospective comparison of diazepam and phenytoin versus phenobarbital and optional phenytoin, Neurology source
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Clinical results were comparable between groups, with 67.9% of lorazepam-treated patients and 69.0% of clonazepam-treated patients having ‡75% improvement.”
What the sources say
- Not checked yetcites [96] Sorel, 1981, Comparative trial of intravenous lorazepam and clonazepam in status epilepticus, Clin Ther
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Large lorazepam doses (0.3-9 mg ⁄ h) have been used as an alternative to pentobarbital for treating refractory status epilepticus; for all nine cases in an open-label study, lorazepam terminated status epilepticus (97).”
What the sources say
- Not checked yetcites [97] Labar, 1994, High-dose intravenous lorazepam for the treatment of refractory status epilepticus, Neurology source
plaindirectn = 9- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Several randomized controlled trials support the use of BZDs (particularly diazepam and loraze- Missed dose Replaced dose Missed doses Replaced doses 0 100 200 1.0 0.8 0.6 0.4 0.2 0.0 300 Time (h) Predicted DMD concentration (µg/ml) 400 500 50 150 250 350 450 Figure 4. Simulated plasma N-desmethyldiazepam (DMD) concentration over time for immediate-release clorazepate (solid line, 7.5 mg given”
What the sources say
- Not checked yetcites [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 yetcites [78] Shaner, 1988, Treatment of status epilepticus: a prospective comparison of diazepam and phenytoin versus phenobarbital and optional phenytoin, Neurology source
- Not checked yetcites [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
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“In generalized epilepsies, clonazepam is effective for treating patients with absence seizures (105, 106).”
What the sources say
- Not checked yetcites [105] Dreifuss, 1975, Serum clonazepam concentrations in children with absence seizures, Neurology source
- Not checked yetcites [106] Sato, 1977, Clonazepam in the treatment of absence seizures: a double-blind clinical trial [abstract], Neurology
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“In placebo-controlled trials, rectal diazepam gel (doses of 0.2-0.5 mg ⁄ kg) reduced seizure recurrence in children, adolescents and adults who had clusters of repetitive seizures in a non-medical or home setting (87)(88)(89)(90).”
What the sources say
- Not checked yetcites [87] Cereghino, 1998, Treating repetitive seizures with a rectal diazepam formulation: a randomized study. The North American Diastat Study Group, Neurology source
- Not checked yetcites [88] Dreifuss, 1998, A comparison of rectal diazepam gel and placebo for acute repetitive seizures, N Engl J Med source
- Not checked yetcites [89] Kriel, 1999, Rectal diazepam gel for treatment of acute repetitive seizures. The North American Diastat Study Group, Pediatr Neurol source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“In lorazepam-treated patients, 53.0% had ‡75% improvement, as did 39.6% of clonazepam-treated patients, as measured by electroencephalograms.”
What the sources say
- Not checked yetcites [96] Sorel, 1981, Comparative trial of intravenous lorazepam and clonazepam in status epilepticus, Clin Ther
plainn = 61- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“and higher doses of rectal diazepam (20-30 mg) have been used in adult patients with drug-resistant epilepsy who are prone to serial seizures (94,95).”
What the sources say
- Not checked yetcites [94] Milligan, 1984, A clinical trial of single dose rectal and oral administration of diazepam for the prevention of serial seizures in adult epileptic patients, J Neurol Neurosurg Psychiatry source
- Not checked yetcites [95] Remy, 1992, Intrarectal diazepam in epileptic adults, Epilepsia source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Clonazepam is used primarily as an adjunctive therapy to treat patients with a wide range of treatment-resistant primary and secondarily generalized seizures (103).”
What the sources say
- Not checked yetcites [103] Trimble, 2002, On the use of tranquillisers in epilepsy, Epilepsia source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“In the previously mentioned study by Alldredge et al. (77), i.v.lorazepam (2 mg, one to two doses) administered to 66 adults with repetitive or ongoing generalized seizures lasting >5 min terminated convulsions by the time of arrival at the emergency department in 59.1% of patients.”
What the sources say
- Not checked yetcites [77] Alldredge, 2001, A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus, N Engl J Med source
plaindirectn = 66- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Results from another randomized controlled trial that compared buccal midazolam with rectal diazepam for emergency treatment of seizures in children suggested that midazolam was more effective than diazepam (134).”
What the sources say
- Not checked yetcites [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
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“In three controlled clinical trials, the efficacy of intranasal midazolam was similar to or better than that of i.v. or rectal diazepam (124, 127, 128).”
What the sources say
- Not checked yetcites [124] Lahat, 2000, Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study, BMJ source
- Not checked yetcites [127] Fisgin, 2002, Effects of intranasal midazolam and rectal diazepam on acute convulsions in children: prospective randomized study, J Child Neurol source
- Not checked yetcites [128] Mahmoudian, 2004, Comparison of intranasal midazolam with intravenous diazepam for treating acute seizures in children, Epilepsy Behav source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“In a prospective, randomized, open-label study, intranasal midazolam was as safe and effective as i.v.diazepam was for managing febrile seizures”
What the sources say
- Not checked yetcites [124] Lahat, 2000, Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study, BMJ source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Seizure freedom was maintained for the entire 12 months of the study for 23%, 25% and 11% of patients randomly assigned to receive clobazam, carbamazepine and phenytoin respectively.”
What the sources say
- Not checked yetcites [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 yetcites [154] Bawden, 1999, The cognitive and behavioural effects of clobazam and standard monotherapy are comparable, Epilepsy Res source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Its use is limited by the potential for the development of tolerance.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“In several double-blind, placebo-controlled, add-on trials in patients with refractory epilepsy, adjunctive clobazam was shown to be effective (17,(145)(146)(147)(148)(149)(150)(151)(152).”
What the sources say
- Not checked yetcites [17] Shorvon, 1995
- Not checked yetcites [145] Keene, 1990, Clobazam as an add-on drug in the treatment of refractory epilepsy of childhood, Can J Neurol Sci source
- Not checked yetcites [146] Schmidt, 1986, Clobazam for refractory focal epilepsy. A controlled trial, Arch Neurol source
plaindirectn = 21- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“In a crossover study of 21 patients, a >50% reduction in seizure frequency was seen in 52% of patients receiving clobazam (145).”
What the sources say
- Not checked yetcites [145] Keene, 1990, Clobazam as an add-on drug in the treatment of refractory epilepsy of childhood, Can J Neurol Sci source
plaindirectn = 21- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The Canadian Clobazam Cooperative Group reported that, on the basis of results from a retrospective study, 40-50% of patients could be maintained on clobazam for 4 years or longer (141).”
What the sources say
- Not checked yetcites [141] Canadian Clobazam Cooperative Group, 1991, Clobazam in treatment of refractory epilepsy: the Canadian experience. A retrospective study, Epilepsia source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“It is considered the drug of choice in certain rare childhood epilepsy syndromes (108).”
What the sources say
- Not checked yetcites [108] Hirvasniemi, 1995, Northern epilepsy syndrome: clinical course and the effect of medication on seizures, Epilepsia source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Finally, the short t 1 ⁄ 2 of midazolam (24) may put patients at risk of seizure recurrence as plasma concentrations rapidly decline.”
What the sources say
- Not checked yetcites [24] Anderson, 2002
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These findings compare favorably with adjunctive therapy results for many AEDs currently available in the USA.”
plainn = 21- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Clinical experience with midazolam for treating status epilepticus (as initial treatment or for refractory status epilepticus) is limited (76).”
What the sources say
- Not checked yetcites [76] Schmidt, 2002
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“In another crossover study, Schmidt et al. (146) reported a seizure frequency reduction of ‡75% in 40% of patients receiving adjunctive clobazam.”
What the sources say
- Not checked yetcites [146] Schmidt, 1986, Clobazam for refractory focal epilepsy. A controlled trial, Arch Neurol source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Midazolam has also been found to be safe and effective when administered as a continuous infusion to treat refractory generalized convulsive status epilepticus (129-133).”
What the sources say
- Not checked yetcites [129] Koul, 2002, Eight-year study of childhood status epilepticus: midazolam infusion in management and outcome, J Child Neurol source
- Not checked yetcites [130] Kumar, 1992, Intravenous midazolam for the treatment of refractory status epilepticus, Crit Care Med source
- Not checked yetcites [131] Parent, 1994, Treatment of refractory generalized status epilepticus with continuous infusion of midazolam, Neurology source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“and it produces less sedation than other BZDs do (140).”
What the sources say
- Not checked yetcites [140] Shorvon, 1998, The use of clobazam, midazolam, and nitrazepam in epilepsy, Epilepsia source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“It is also effective in controlling status epilepticus; a review of several studies (109-120) of i.v.clonazepam use in status epilepticus found the drug to be effective in approximately 80-90% of patients (107).”
What the sources say
- Not checked yetcites [107] Pinder, 1976, Clonazepam: a review of its pharmacological properties and therapeutic efficacy in epilepsy, Drugs source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“However, a portion of patients (up to 25%) may remain seizure free while taking adjunctive clobazam for long periods (141-144).”
What the sources say
- Not checked yetcites [141] Canadian Clobazam Cooperative Group, 1991, Clobazam in treatment of refractory epilepsy: the Canadian experience. A retrospective study, Epilepsia source
- Not checked yetcites [142] Guberman, 1990, Add-on trial of clobazam in intractable adult epilepsy with plasma level correlations, Can J Neurol Sci source
- Not checked yetcites [143] Heller, 1988, Factors relating to dramatic response to clobazam therapy in refractory epilepsy, Epilepsy Res source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Clonazepam has been shown to be effective as adjunctive therapy for complex partial seizures, absence seizures, tonic-clonic seizures and myoclonic seizures (121, 122).”
What the sources say
- Not checked yetcites [121] Nanda, 1977, Treatment of epilepsy with clonazepam and its effect on other anticonvulsants, J Neurol Neurosurg Psychiatry source
- Not checked yetcites [122] Bensch, 1977, A double-blind study of clonazepam in the treatment of therapy-resistant epilepsy in children, Dev Med Child Neurol source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“In another open-label study, clorazepate was added to standard AEDs in 29 children with various seizure disorders; 72% of patients experienced improved seizure control (162).”
What the sources say
- Not checked yetcites [162] Mimaki, 1984, Antiepileptic effect and serum levels of clorazepate on children with refractory seizures, Brain Dev source
plaindirectn = 29- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Other studies have found good results with clorazepate in the treatment of refractory childhood epilepsies.”
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Benzodiazepines may cause amnesia, particularly anterograde amnesia (168).”
What the sources say
- Not checked yetcites [168] Buffett-Jerrott, 2002, Cognitive and sedative effects of benzodiazepine use, Curr Pharm Des source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“In a metaanalysis, Barker et al. (170) concluded that longterm BZD users show recovery of function in visuospatial skills, attention ⁄ concentration, general intelligence, psychomotor speed and nonverbal memory assessments after withdrawal.”
What the sources say
- Not checked yetcites [170] Barker, 2004, Persistence of cognitive effects after withdrawal from long-term benzodiazepine use: a meta-analysis, Arch Clin Neuropsychol source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Dependence develops in almost onethird of patients who are treated with BZDs for ‡4 weeks (173).”
What the sources say
- Not checked yetcites [173] Marriott, 1993, Benzodiazepine dependence. Avoidance and withdrawal, Drug Saf source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The authors reported that the study data did not demonstrate complete restoration of function within the first 6 months following discontinuation of BZD use”
What the sources say
- Not checked yetcites [170] Barker, 2004, Persistence of cognitive effects after withdrawal from long-term benzodiazepine use: a meta-analysis, Arch Clin Neuropsychol source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“A withdrawal syndrome upon BZD discontinuation (see Tolerance and withdrawal section) is a common manifestation of BZD dependence (173).”
What the sources say
- Not checked yetcites [173] Marriott, 1993, Benzodiazepine dependence. Avoidance and withdrawal, Drug Saf source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“In an open-label, add-on study, 22% of patients with Lennox-Gastaut syndrome (two of nine) had a partial response (<75% reduction in seizure frequency) to clorazepate (158).”
What the sources say
- Not checked yetcites [158] Fujii, 1987, Clorazepate therapy for intractable epilepsy, Brain Dev source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Other doubleblind (156) and open-label (157-159) studies have demonstrated the efficacy of adjunctive clorazepate for both partial (simple and complex) and generalized seizures.”
What the sources say
- Not checked yetcites [156] Wilensky, 1981, Clorazepate and phenobarbital as antiepileptic drugs: a double-blind study, Neurology source
- Not checked yetcites [157] Berchou, 1981, Clorazepate therapy for refractory seizures, Neurology source
- Not checked yetcites [158] Fujii, 1987, Clorazepate therapy for intractable epilepsy, Brain Dev source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The authors found, however, that significant cognitive impairment was more persistent in long-term users than in control groups or in normative data.”
What the sources say
- Not checked yetcites [170] Barker, 2004, Persistence of cognitive effects after withdrawal from long-term benzodiazepine use: a meta-analysis, Arch Clin Neuropsychol source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“In an uncontrolled, open-label study of 18 children with Lennox-Gastaut syndrome or other conditions with atypical absence seizures, the authors stated that five patients (28%) had an excellent response and eight patients (44%) had a good response to adjunctive clorazepate therapy, although the terms ÔexcellentÕ and ÔgoodÕ were not clearly defined (160).”
What the sources say
- Not checked yetcites [160] Graf, 1987, Clorazepate therapy in children with refractory seizures [abstract], Epilepsia
plaindirectn = 18- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The effectiveness of adjunctive clorazepate for various treatment-resistant seizures has been demonstrated; however, the clinical experience and data available are less extensive for clorazepate than for other BZDs ( 103).”
- Also stated in: § Conclusions · plain
“However, it is important to note that the clinical experience and available data are less extensive for clorazepate than for other BZDs.”
What the sources say
- Not checked yetcites [103] Trimble, 2002, On the use of tranquillisers in epilepsy, Epilepsia source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Conclusions · plain
None of the sources cited for this claim have been checked yet.
In the paper
“Some study results have suggested that diazepam may have greater effects on respiratory depression than are observed with other BZDs such as lorazepam and midazolam (174, 175).”
What the sources say
- Not checked yetcites [174] Appleton, 2002, Drug management for acute tonicclonic convulsions including convulsive status epilepticus in children, Cochrane Database Syst Rev source
- Not checked yetcites [175] Bhattacharyya, 2006, Intranasal midazolam vs rectal diazepam in acute childhood seizures, Pediatr Neurol source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Drowsiness and confusion may be indicative of over-sedation, a doserelated extension of the sedative ⁄ hypnotic effects of BZDs (62,163,164).”
What the sources say
- Not checked yetcites [62] Demaagd, 1995, High-risk drugs in the elderly population, Geriatr Nurs source
- Not checked yetcites [163] Salzman, 1999, An 87-year-old woman taking a benzodiazepine, JAMA source
- Not checked yetcites [164] Shader, 1993, Use of benzodiazepines in anxiety disorders, N Engl J Med source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“However, memory impairment may also be associated with clinical doses of orally administered BZDs (168).”
What the sources say
- Not checked yetcites [168] Buffett-Jerrott, 2002, Cognitive and sedative effects of benzodiazepine use, Curr Pharm Des source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“An openlabel clinical study of clorazepate therapy suggested that the drug might be useful as an add-on treatment for generalized major and minor seizures (e.g.absence, akinetic and myoclonic) (155).”
What the sources say
- Not checked yetcites [155] Booker, 1974, Clorazepate dipotassium in the treatment of intractable epilepsy, JAMA source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Substantial differences in adverse event occurrences associated with the BZDs profiled here have not been reported in large randomized, controlled trials comparing BZDs.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Clorazepate also appears to be useful in childhood epilepsy.”
What the sources say
- Not checked yetcites [158] Fujii, 1987, Clorazepate therapy for intractable epilepsy, Brain Dev source
- Not checked yetcites [160] Graf, 1987, Clorazepate therapy in children with refractory seizures [abstract], Epilepsia
- Not checked yetcites [161] Naidu, 1986, Excellent results with clorazepate in recalcitrant childhood epilepsies, Pediatr Neurol source
hedgedconditionaln = 18- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The effectiveness of adjunctive clorazepate for various treatment-resistant seizures has been demonstrated; however, the clinical experience and data available are less extensive for clorazepate than for other BZDs ( 103).”
What the sources say
- Not checked yetcites [103] Trimble, 2002, On the use of tranquillisers in epilepsy, Epilepsia source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“In an open-label study by Naidu et al. (161), 11 children with generalized seizures (absence and atonic) who received clorazepate as monotherapy (n = 4) or as adjunctive therapy with valproate (n = 7) had a reduction in the number of clinically observed seizures.”
What the sources say
- Not checked yetcites [161] Naidu, 1986, Excellent results with clorazepate in recalcitrant childhood epilepsies, Pediatr Neurol source
plaindirectn = 11- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Potent BZDs with relatively short t 1 ⁄ 2 (e.g.triazolam, alprazolam and lorazepam) appear to carry the highest risk of dependence (173).”
What the sources say
- Not checked yetcites [173] Marriott, 1993, Benzodiazepine dependence. Avoidance and withdrawal, Drug Saf source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Additionally, BZDs can cause or aggravate depression (57).”
What the sources say
- Not checked yetcites [57] Ashton, 1994, Guidelines for the rational use of benzodiazepines. When and what to use, Drugs source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Children and elderly patients, patients with a history of alcohol abuse and individuals with a history of aggressive behavior ⁄ anger may be more likely to experience paradoxical excitement effects than are other patients (172).”
What the sources say
- Not checked yetcites [172] Mancuso, 2004, Paradoxical reactions to benzodiazepines: literature review and treatment options, Pharmacotherapy source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“However, when the dosage was maintained or increased, clorazepate once again became effective in 50% of patients who had previously developed tolerance.”
What the sources say
- Not checked yetcites [193] Sugai, 2004, Clobazam as a new antiepileptic drug and clorazepate dipotassium as an alternative antiepileptic drug in Japan, Epilepsia source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Additionally, rebound anxiety was noted to develop more rapidly in patients treated with short-t 1 ⁄ 2 BZDs than in patients treated with long-t 1 ⁄ 2 BZDs.”
What the sources say
- Not checked yetcites [213] Hallfors, 1993, The dependence potential of short half-life benzodiazepines: a meta-analysis, Am J Public Health source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Because of the development of anticonvulsant tolerance, BZDs are generally considered unsuitable for longterm control of epilepsy (57,186).”
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although tolerance may develop more rapidly to some BZDs than to others, it is important to note that tolerance generally renders BZDs unsuitable for long-term control of epilepsy.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“The onset of tolerance to the sedative effects of BZDs usually occurs within 1-2 weeks (194,195).”
What the sources say
- Not checked yetcites [194] Kroboth, 1990, Alprazolam in the elderly: pharmacokinetics and pharmacodynamics during multiple dosing, Psychopharmacology (Berl) source
- Not checked yetcites [195] Smith, 1987, Influence of dosing regimen on alprazolam and metabolite serum concentrations and tolerance to sedative and psychomotor effects, Psychopharmacology (Berl) source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Increasing the BZD dose may overcome anticonvulsant tolerance.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“They are among the most useful AEDs available for treating patients with status epilepticus or acute repetitive seizures.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“In a meta-analysis of seven studies, Hallfors and Saxe (213) found that patients treated with short-t 1 ⁄ 2 BZDs were more likely to experience rebound anxiety than were patients treated with long-t 1 ⁄ 2 BZDs.”
What the sources say
- Not checked yetcites [213] Hallfors, 1993, The dependence potential of short half-life benzodiazepines: a meta-analysis, Am J Public Health source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Memory and cognition, however, often remain impaired in patients on long-term BZD therapy without full recovery (57,196).”
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Tolerance to some side effects of BZDs can also develop.”
What the sources say
- Not checked yetcites [194] Kroboth, 1990, Alprazolam in the elderly: pharmacokinetics and pharmacodynamics during multiple dosing, Psychopharmacology (Berl) source
- Not checked yetcites [195] Smith, 1987, Influence of dosing regimen on alprazolam and metabolite serum concentrations and tolerance to sedative and psychomotor effects, Psychopharmacology (Berl) source
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Likewise, in 70% of patients who had developed tolerance to clobazam, the drug once again became effective with an increased dosage or at the same dosage.”
What the sources say
- Not checked yetcites [193] Sugai, 2004, Clobazam as a new antiepileptic drug and clorazepate dipotassium as an alternative antiepileptic drug in Japan, Epilepsia source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Differences in the development of anticonvulsant tolerance have been reported for various BZDs in an amygdala-kindling rat model.”
What the sources say
- Not checked yetcites [185] Young, 1988, Differences in the development of tolerance to two anticonvulsant benzodiazepines in the amygdaloid kindled rat, J Pharm Pharmacol source
- Not checked yetcites [189] Rosenberg, 1989, Tolerance to anticonvulsant effects of diazepam, clonazepam, and clobazam in amygdala-kindled rats, Epilepsia source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Ramsey-Williams et al. (187) demonstrated that after 3 weeks of diazepam treatment, rats developed cross-tolerance to the anticonvulsant effects of clobazam, clonazepam and midazolam.”
What the sources say
- Not checked yetcites [187] Ramsey-Williams, 1994, Comparison of anticonvulsant tolerance, crosstolerance, and benzodiazepine receptor binding following chronic treatment with diazepam or midazolam, Pharmacol Biochem Behav source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“In studies investigating anticonvulsant tolerance, animals treated with clorazepate exhibited a later onset or a lesser degree of tolerance than did those treated with either diazepam (190)(191)(192) or clonazepam (184, 192).”
What the sources say
- Not checked yetcites [190] Amano, 2001, Differences between the tolerance characteristics of two anticonvulsant benzodiazepines in the amygdaloid-kindled rat, Life Sci source
- Not checked yetcites [191] Plotnikoff, 1974, Comparison of anticonvulsant effects of clorazepate dipotassium and diazepam: four week anticonvulsant study in rhesus monkeys, Dis Nerv Syst
- Not checked yetcites [192] Scherkl, 1989, Clorazepate in dogs: tolerance to the anticonvulsant effect and signs of physical dependence, Epilepsy Res source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The slow onset of tolerance to the anticonvulsant effect of clorazepate could be due to a low degree of intrinsic activity of DMD at the BZD receptor.”
What the sources say
- Not checked yetcites [199] Gobbi, 1987, Diazepam and desmethyldiazepam differ in their affinities and efficacies at central and peripheral benzodiazepine receptors, J Pharm Pharmacol source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The differences in time to onset of tolerance to the various pharmacologic effects of BZDs suggest that different mechanisms may be involved (197).”
What the sources say
- Not checked yetcites [197] Bateson, 2002, Basic pharmacologic mechanisms involved in benzodiazepine tolerance and withdrawal, Curr Pharm Des source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Tolerance to several BZDs has been demonstrated in experimental epilepsy models (180-185).”
What the sources say
- Not checked yetcites [180] File, 1983, Tolerance to the anti-pentylenetetrazole effects of diazepam in the mouse, Psychopharmacology source
- Not checked yetcites [181] Frey, 1984, Development of tolerance to the anticonvulsant effect of diazepam in dogs, Eur J Pharmacol source
- Not checked yetcites [182] Gent, 1985, Differences between the tolerance characteristics of two anticonvulsant benzodiazepines, Life Sci source
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 106
- Probably not a substantial claim. 28
- The quote only partly states this claim. 4
Every source the paper cites for this claim was checked and supports it.
In the paper
“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).”
What the sources say
- Supportedcites [170] Barker, 2004, Persistence of cognitive effects after withdrawal from long-term benzodiazepine use: a meta-analysis, Arch Clin Neuropsychol source
The Abstract explicitly says that the degree of recovery after withdrawal and the level of residual impairment in long-term benzodiazepine users are unclear. It also reports improvement in many cognitive areas but not full recovery within the first six months, consistent with uncertainty about the eventual extent of impairment. (LLM, conf=0.95)
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The time to maximum concentration was 2.43 and 9.20 h for the immediate-release and sustained-release formulations respectively.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Change in trough plasma DMD concentrations (%) | NA | )44.1 | )41.9 | NA | )48.8 | )48.8”
What the sources say
- Not checked yetcites [71] Riss
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Peak ⁄ trough difference b at steady state (lg ⁄ ml) | 0.17 | NA | NA | 0.13 | NA | NA”
What the sources say
- Not checked yetcites [71] Riss
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Change in peak plasma DMD concentrations (%) | NA | )29.6 | 6.0 | NA | )27.1 | 9.6”
What the sources say
- Not checked yetcites [71] Riss
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Peak ⁄ trough difference b after missed dose(s) (lg ⁄ ml) | NA | 0.18 | 0.41 | NA | 0.18 | 0.42”
What the sources say
- Not checked yetcites [71] Riss
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Change in peak plasma DMD concentrations (%) | NA | )29.6 | 6.0 | NA | )27.1 | 9.6”
What the sources say
- Not checked yetcites [71] Riss
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Change in trough plasma DMD concentrations (%) | NA | )44.1 | )41.9 | NA | )48.8 | )48.8”
What the sources say
- Not checked yetcites [71] Riss
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
What the sources say
- Not checked yetcites [81] Ko, 1997
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Also stated in: § Introduction · plain
In the paper
“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”
What the sources say
- Not checked yetcites [81] Ko, 1997
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Also stated in: § Efficacy · plain
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
- Also stated in: § Introduction · plain
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
What the sources say
- Not checked yetcites [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 yetcites [78] Shaner, 1988, Treatment of status epilepticus: a prospective comparison of diazepam and phenytoin versus phenobarbital and optional phenytoin, Neurology source
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Also stated in: § Introduction · plain
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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).”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Also stated in: § Introduction · hedged
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Potential shortcomings of BZDs include tolerance, withdrawal symptoms, adverse events, such as cognitive impairment and sedation, and drug interactions.”
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“Clobazam is an exception with its 1-5-BZD structure (17).”
What the sources say
- Not checked yetcites [17] Shorvon, 1995
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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).”
What the sources say
- Not checked yetcites [24] Anderson, 2002
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
What the sources say
- Not checked yetcites [3] Chebib, 1999, The ABC of GABA receptors: a brief review, Clin Exp Pharmacol Physiol source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“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).”
What the sources say
- Not checked yetcites [25] Hobbs, 1996
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Additionally, the pharmacokinetic characteristics of clorazepate (particularly the sustained-release formulation) could theoretically help minimize adverse events.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Diazepam and lorazepam are primarily used for management of seizure emergencies, whereas clobazam, clonazepam and clorazepate are commonly used in chronic epilepsy management.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The inhibitory neurotransmitter GABA binds to the receptor to open the chloride ion gates and produce an inhibitory current (6,8).”
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Ligand-activated ion channels that are selectively blocked by bicuculline and modulated by steroids, BZDs, and barbiturates are known as GABA A receptors (3).”
What the sources say
- Not checked yetcites [3] Chebib, 1999, The ABC of GABA receptors: a brief review, Clin Exp Pharmacol Physiol source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Among these BZDs, clorazepate has a unique profile that includes a long half-life of its active metabolite and slow onset of tolerance.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Benzodiazepines differ in their rates of elimination and the formation of pharmacologically active metabolites (Table 2).”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The basic chemical structure of BZDs is formed from the fusion of a benzene ring and a sevenmembered diazepine ring (16) (Fig. 1).”
What the sources say
- Not checked yetcites [16] Feldman, 1997
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
What the sources say
- Not checked yetcites [6] Macdonald, 1994, GABAA receptor channels, Annu Rev Neurosci source
- Not checked yetcites [7] McKernan, 1996, Which GABAA-receptor subtypes really occur in the brain?, Trends Neurosci source
- Not checked yetcites [10] Atack, 2006, Rat pharmacokinetics and pharmacodynamics of a sustained release formulation of the GABAA5-selective compound L-655,708, Drug Metab Dispos source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“There are three principal c-aminobutyric acid (GABA) receptor subtypes.”
What the sources say
- Not checked yetcites [3] Chebib, 1999, The ABC of GABA receptors: a brief review, Clin Exp Pharmacol Physiol source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The GABA A receptor consists of a pentameric structure with multiple subunits that are necessary for normal physiologic function.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Midazolam often is used as an alternative to diazepam and lorazepam in seizure emergencies and for treating refractory status epilepticus.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Following rapid uptake, BZDs redistribute into less well-perfused tissues; the rate of redistribution is the fastest for the most lipid-soluble drugs (25).”
What the sources say
- Not checked yetcites [25] Hobbs, 1996
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
What the sources say
- Not checked yetcites [3] Chebib, 1999, The ABC of GABA receptors: a brief review, Clin Exp Pharmacol Physiol source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“There are, however, differences among BZDs in affinity for receptor subtypes, which may produce different pharmacologic effects.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Benzodiazepines are classified as low, medium (e.g.clorazepate and diazepam) or high (e.g.clonazepam and lorazepam) potency (18,19).”
What the sources say
- Not checked yetcites [18] Nelson, 1999, Guidelines for the clinical use of benzodiazepines: pharmacokinetics, dependency, rebound and withdrawal, Can J Clin Pharmacol
- Not checked yetcites [19] Chouinard, 2004, Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound, J Clin Psychiatry
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
What the sources say
- Not checked yetcites [4] Simon, 2004, Analysis of the set of GABAA receptor genes in the human genome, J Biol Chem source
- Not checked yetcites [5] Sieghart, 1999, Structure and subunit composition of GABAA receptors, Neurochem Int source
- Not checked yetcites [6] Macdonald, 1994, GABAA receptor channels, Annu Rev Neurosci source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Benzodiazepines cross the blood-brain barrier rapidly, although the diffusion rate into the brain varies by drug and is largely determined by lipophilicity (21).”
What the sources say
- Not checked yetcites [21] Rey, 1999, Pharmacokinetic optimization of benzodiazepine therapy for acute seizures. Focus on delivery routes, Clin Pharmacokinet source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In neonates, the t 1 ⁄ 2 of clorazepate is prolonged and clearance is decreased (67).”
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Additionally, many elderly individuals take multiple medications, which increase their risk of drug-drug interactions.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“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).”
What the sources say
- Not checked yetcites [62] Demaagd, 1995, High-risk drugs in the elderly population, Geriatr Nurs source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Clonazepam and lorazepam undergo extensive metabolism, but no active metabolites are formed (18,24).”
What the sources say
- Not checked yetcites [18] Nelson, 1999, Guidelines for the clinical use of benzodiazepines: pharmacokinetics, dependency, rebound and withdrawal, Can J Clin Pharmacol
- Not checked yetcites [24] Anderson, 2002
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
What the sources say
- Not checked yetcites [24] Anderson, 2002
- Not checked yetcites [56] Breimer, 1980, Pharmacokinetics of benzodiazepines. Short-acting versus long-acting, Arzneimittelforschung
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
What the sources say
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
What the sources say
- Not checked yetcites [60] Back, 1990, Pharmacokinetic drug interactions with oral contraceptives, Clin Pharmacokinet source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
What the sources say
- Not checked yetcites [66] Anderson, 2002, Children versus adults: pharmacokinetic and adverse-effect differences, Epilepsia source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
What the sources say
- Not checked yetcites [24] Anderson, 2002
- Not checked yetcites [41] Gorski, 1994, Regioselective biotransformation of midazolam by members of the human cytochrome P450 3A (CYP3A) subfamily, Biochem Pharmacol source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Elderly individuals often have variable drug absorption, decreased plasma protein-drug binding due to lower albumin concentrations, and reduced hepatic and renal clearance (61).”
What the sources say
- Not checked yetcites [61] Patsalos, 2002, The importance of drug interactions in epilepsy therapy, Epilepsia source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Fewer studies have evaluated the clinical efficacy of BZDs in chronic epilepsy.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [80] Leppik, 1983, Double-blind study of lorazepam and diazepam in status epilepticus, JAMA source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Benzodiazepines were used in epilepsy management as early as 1965, when Gastaut et al. (73,74) administered i.v.diazepam to treat status epilepticus.”
What the sources say
- Not checked yetcites [73] Gastaut, 1965, Treatment of status epilepticus with diazepam (Valium), Epilepsia source
- Not checked yetcites [74] Gastaut, 1965, Laction du diazepam (Valium) dans le traitement des formes non-convulsive de lepilepsie generalisee [in French], Rev Neurol (Paris)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Benzodiazepines are among the most useful AEDs available for treating status epilepticus and acute repetitive seizures and for febrile seizure prophylaxis.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Changes in simulated plasma DMD peak-to-trough concentrations correspond to clinical risks of breakthrough seizures and drug toxicity.
In the paper
“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).”
What the sources say
- Not checked yetcites [76] Schmidt, 2002
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Diazepam is a drug of first choice for treatment of early status epilepticus and acute repetitive seizures and for febrile seizure prophylaxis.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
What the sources say
- Not checked yetcites [105] Dreifuss, 1975, Serum clonazepam concentrations in children with absence seizures, Neurology source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In a randomized trial comparing buccal midazolam with rectal diazepam in children, the drugs showed similar efficacy and onset of action (125).”
What the sources say
- Not checked yetcites [125] Scott, 1999, Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial, Lancet source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Although it is used for many seizure types, midazolam does not have an FDA-approved indication for seizures.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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%).”
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
What the sources say
- Not checked yetcites [125] Scott, 1999, Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial, Lancet source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Although not currently approved in the USA, clobazam is commonly used elsewhere as adjunctive therapy for patients with refractory epilepsy (103).”
What the sources say
- Not checked yetcites [103] Trimble, 2002, On the use of tranquillisers in epilepsy, Epilepsia source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
What the sources say
- Not checked yetcites [123] 123.Midazolam HCl injection [package insert]. Weston, FL: Apotex Corp, 2000.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
What the sources say
- Not checked yetcites [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 yetcites [154] Bawden, 1999, The cognitive and behavioural effects of clobazam and standard monotherapy are comparable, Epilepsy Res source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Open-label studies have suggested that intranasal midazolam is safe and effective for acute seizure management in children (124, 127, 128, 135, 136).”
What the sources say
- Not checked yetcites [124] Lahat, 2000, Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study, BMJ source
- Not checked yetcites [127] Fisgin, 2002, Effects of intranasal midazolam and rectal diazepam on acute convulsions in children: prospective randomized study, J Child Neurol source
- Not checked yetcites [128] Mahmoudian, 2004, Comparison of intranasal midazolam with intravenous diazepam for treating acute seizures in children, Epilepsy Behav source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“with 88% of seizures (23 of 26) responding to initial treatment with midazolam and 92% (24 of 26) responding to diazepam (124).”
What the sources say
- Not checked yetcites [124] Lahat, 2000, Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study, BMJ source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“It is highly effective as adjunctive therapy for partial and generalized seizures, for intermittent therapy and for controlling nonconvulsive status epilepticus”
What the sources say
- Not checked yetcites [140] Shorvon, 1998, The use of clobazam, midazolam, and nitrazepam in epilepsy, Epilepsia source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“studies have suggested that intranasal midazolam is safe and effective for acute seizure management in children (124, 127, 128, 135, 136).”
What the sources say
- Not checked yetcites [124] Lahat, 2000, Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study, BMJ source
- Not checked yetcites [127] Fisgin, 2002, Effects of intranasal midazolam and rectal diazepam on acute convulsions in children: prospective randomized study, J Child Neurol source
- Not checked yetcites [128] Mahmoudian, 2004, Comparison of intranasal midazolam with intravenous diazepam for treating acute seizures in children, Epilepsy Behav source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
What the sources say
- Not checked yetcites [137] Scott, 2001, Intranasal midazolam for treating febrile seizures in children. Buccal midazolam should be preferred to nasal midazolam [letter], BMJ source
- Not checked yetcites [138] Loftsson, 2001, Cyclodextrin solubilization of benzodiazepines: formulation of midazolam nasal spray, Int J Pharm source
- Not checked yetcites [139] Gudmundsdttir, 2001, Intranasal administration of midazolam in a cyclodextrin based formulation: bioavailability and clinical evaluation in humans, Pharmazie
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
What the sources say
- Not checked yetcites [137] Scott, 2001, Intranasal midazolam for treating febrile seizures in children. Buccal midazolam should be preferred to nasal midazolam [letter], BMJ source
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Paradoxical excitement is sometimes associated with BZD use and may include exacerbation of seizures in patients with epilepsy (171).”
What the sources say
- Not checked yetcites [171] Gayatri, 2006, Aggravation of epilepsy by anti-epileptic drugs, Dev Med Child Neurol source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“and although diazepam impairs explicit memory, results regarding impairment of implicit memory by diazepam are mixed (176-179).”
What the sources say
- Not checked yetcites [176] Legrand, 1995, Time course of the effects of diazepam and lorazepam on perceptual priming and explicit memory, Psychopharmacology source
- Not checked yetcites [177] Wagemans, 1998, Lorazepam but not diazepam impairs identification of pictures on the basis of specific contour fragments, Psychopharmacology source
- Not checked yetcites [178] Vidailhet, 1994, Lorazepam and diazepam effects on memory acquisition in priming tasks, Psychopharmacology source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Benzodiazepine use is also associated with falls, a possible result of over-sedation in elderly patients (167).”
What the sources say
- Not checked yetcites [167] Souchet, 2005, Drug related falls: a study in the French pharmacovigilance database, Pharmacoepidemiol Drug Saf source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Over-sedation is more problematic in the elderly than in younger patients, and it may occur at lower doses in the elderly (165, 166).”
What the sources say
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
What the sources say
- Not checked yetcites [173] Marriott, 1993, Benzodiazepine dependence. Avoidance and withdrawal, Drug Saf source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Lorazepam appears to impair both explicit memory and implicit memory”
What the sources say
- Not checked yetcites [176] Legrand, 1995, Time course of the effects of diazepam and lorazepam on perceptual priming and explicit memory, Psychopharmacology source
- Not checked yetcites [177] Wagemans, 1998, Lorazepam but not diazepam impairs identification of pictures on the basis of specific contour fragments, Psychopharmacology source
- Not checked yetcites [178] Vidailhet, 1994, Lorazepam and diazepam effects on memory acquisition in priming tasks, Psychopharmacology source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“This effect is sometimes deliberately utilized in presurgical medication (169).”
What the sources say
- Not checked yetcites [169] Ranta, 2002, Patients conscious recollections from cardiac anesthesia, J Cardiothorac Vasc Anesth source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Additionally, although BZDs are generally known to affect memory, some studies have shown that effects differ depending on the BZD used.”
What the sources say
- Not checked yetcites [176] Legrand, 1995, Time course of the effects of diazepam and lorazepam on perceptual priming and explicit memory, Psychopharmacology source
- Not checked yetcites [177] Wagemans, 1998, Lorazepam but not diazepam impairs identification of pictures on the basis of specific contour fragments, Psychopharmacology source
- Not checked yetcites [178] Vidailhet, 1994, Lorazepam and diazepam effects on memory acquisition in priming tasks, Psychopharmacology source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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”
What the sources say
- Not checked yetcites [155] Booker, 1974, Clorazepate dipotassium in the treatment of intractable epilepsy, JAMA source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Elderly patients treated with BZDs can experience confusion, amnesia, ataxia and hangover effects (62).”
What the sources say
- Not checked yetcites [62] Demaagd, 1995, High-risk drugs in the elderly population, Geriatr Nurs source
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
What the sources say
- Not checked yetcites [185] Young, 1988, Differences in the development of tolerance to two anticonvulsant benzodiazepines in the amygdaloid kindled rat, J Pharm Pharmacol source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Other shortcomings include adverse events, such as cognitive impairment and sedation, and drug interactions.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
In the paper
“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.”
What the sources say
- Not checked yetcites [187] Ramsey-Williams, 1994, Comparison of anticonvulsant tolerance, crosstolerance, and benzodiazepine receptor binding following chronic treatment with diazepam or midazolam, Pharmacol Biochem Behav source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“They have the clinical advantages of being highly effective, with a rapid onset of action and relatively low toxicity.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“Rats treated with midazolam for 3 weeks developed cross-tolerance to diazepam but not to clobazam or clonazepam.”
What the sources say
- Not checked yetcites [187] Ramsey-Williams, 1994, Comparison of anticonvulsant tolerance, crosstolerance, and benzodiazepine receptor binding following chronic treatment with diazepam or midazolam, Pharmacol Biochem Behav source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Benzodiazepines can be used in a variety of clinical situations because they can be administered by several routes and in different formulations.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
In the paper
“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).”
What the sources say
- Not checked yetcites [188] Garratt, 1988, Can benzodiazepines be classified by characterising their anticonvulsant tolerance-inducing potential?, Eur J Pharmacol source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Cross-tolerance between BZDs occurs and appears to be drug specific.”
What the sources say
- Not checked yetcites [187] Ramsey-Williams, 1994, Comparison of anticonvulsant tolerance, crosstolerance, and benzodiazepine receptor binding following chronic treatment with diazepam or midazolam, Pharmacol Biochem Behav source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Clobazam | Demethylation (26) | N-desmethylclobazam (27) | 10-30 (28) | 36-46 (28)”
What the sources say
- Not checked yetcites [28] Rupp, 1979, Pharmacokinetics of single and multiple doses of clobazam in humans, Br J Clin Pharmacol source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Clonazepam | Nitroreduction (CYP 3A4), | NA | 19-60 (32) | NA”
What the sources say
- Not checked yetcites [29] Seree, 1993, Fundam Clin Pharmacol source
- Not checked yetcites [30] Miller, 1981, Clonazepam acetylation in fast and slow acetylators, Clin Pharmacol Ther source
- Not checked yetcites [31] Peng, 1984, Polymorphic acetylation of 7-amino-clonazepam in human liver cytosol, Pediatr Pharmacol (New York)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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”
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Benzodiazepines are indicated for the treatment of seizure emergencies and epilepsy.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Studies of clorazepate in patients with epilepsy have mainly been small, open-label investigations.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
In the paper
“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.”
What the sources say
- Not checked yetcites [199] Gobbi, 1987, Diazepam and desmethyldiazepam differ in their affinities and efficacies at central and peripheral benzodiazepine receptors, J Pharm Pharmacol source
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
What the sources say
- Not checked yetcites [197] Bateson, 2002, Basic pharmacologic mechanisms involved in benzodiazepine tolerance and withdrawal, Curr Pharm Des source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
What the sources say
- Not checked yetcites [197] Bateson, 2002, Basic pharmacologic mechanisms involved in benzodiazepine tolerance and withdrawal, Curr Pharm Des source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“all of which may, theoretically, help minimize adverse effects and withdrawal symptoms.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
What the sources say
- Not checked yetcites [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 yetcites [187] Ramsey-Williams, 1994, Comparison of anticonvulsant tolerance, crosstolerance, and benzodiazepine receptor binding following chronic treatment with diazepam or midazolam, Pharmacol Biochem Behav source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
What the sources say
- Not checked yetcites [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 yetcites [212] Busto, 1986, Withdrawal reaction after long-term therapeutic use of benzodiazepines, N Engl J Med source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Clobazam | Demethylation (26) | N-desmethylclobazam (27) | 10-30 (28) | 36-46 (28)”
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Clorazepate | Decarboxylation, glucuronidation, | DMD (major), oxazepam (minor) (24) | NA | 20-160 (24, 33, 34)”
What the sources say
- Not checked yetcites [24] Anderson, 2002
- Not checked yetcites [33] Greenblatt, 1988, Desmethyldiazepam pharmacokinetics: studies following intravenous and oral desmethyldiazepam, oral clorazepate, and intravenous diazepam, J Clin Pharmacol source
- Not checked yetcites [34] Bertler, 1980, Pharmacokinetics of dipotassium chlorazepate in patients after repeated 50mg oral doses, Psychopharmacology (Berl) source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one. The quote only partly states this claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, tolerance may recur at the higher dose, and adverse effects may persist or worsen.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Tolerance may develop over time, making BZDs unsuitable for use in long-term epilepsy management.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
What the sources say
- Not checked yetcites [189] Rosenberg, 1989, Tolerance to anticonvulsant effects of diazepam, clonazepam, and clobazam in amygdala-kindled rats, Epilepsia source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Additionally, withdrawal symptoms, some severe, may develop after cessation of BZD therapy.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
In the paper
“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”
What the sources say
- Not checked yetcites [197] Bateson, 2002, Basic pharmacologic mechanisms involved in benzodiazepine tolerance and withdrawal, Curr Pharm Des source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- 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.
In the paper
“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).”
What the sources say
- Not checked yetcites [193] Sugai, 2004, Clobazam as a new antiepileptic drug and clorazepate dipotassium as an alternative antiepileptic drug in Japan, Epilepsia source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Some reports have suggested that BZD t 1 ⁄ 2 does not influence withdrawal symptoms (208, 210).”
What the sources say
- Not checked yetcites [208] Schweizer, 1990, Long-term therapeutic use of benzodiazepines. II. Effects of gradual taper, Arch Gen Psychiatry source
- Not checked yetcites [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
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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)”
What the sources say
- Not checked yetcites [200] Martnez-Cano, 1995, Benzodiazepine withdrawal syndrome seizures, Pharmacopsychiatry source
- Not checked yetcites [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 yetcites [203] Schweizer, 1998, Benzodiazepine dependence and withdrawal: a review of the syndrome and its clinical management, Acta Psychiatr Scand Suppl source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Clorazepate | Tranxene T-Tab | Yes | Anxiety, alcohol withdrawal, | Adjunctive treatment of partial seizures (75)”
What the sources say
- Not checked yetcites [75] Lacy, 2004
- Not checked yetcites [76] Schmidt, 2002
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Clobazam | Frisium | NA | Not FDA approved | First-line adjunctive treatment for treatment-resistant”
What the sources say
- Not checked yetcites [75] Lacy, 2004
- Not checked yetcites [76] Schmidt, 2002
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Lorazepam | Glucuronidation (24) | NA | 7-26 (39, 40) | NA”
What the sources say
- Not checked yetcites [24] Anderson, 2002
- Not checked yetcites [39] Greenblatt, 1979, Pharmacokinetics and bioavailability of intravenous, intramuscular, and oral lorazepam in humans, J Pharm Sci source
- Not checked yetcites [40] Greenblatt, 1982, Pharmacokinetic comparison of sublingual lorazepam with intravenous, intramuscular, and oral lorazepam, J Pharm Sci source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Diazepam | Demethylation (CYP 2C9, 2C19, 2B6, 3A4, | DMD (major), oxazepam (minor), | 21-70 (23, 38) | DMD: 49-179 (33, 38)”
What the sources say
- Not checked yetcites [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 yetcites [38] Kaplan, 1973, Pharmacokinetic profile of diazepam in man following single intravenous and oral and chronic oral administrations, J Pharm Sci source
- Not checked yetcites [24] Anderson, 2002
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one. The quote only partly states this claim.
None of the sources cited for this claim have been checked yet.
In the paper
“Midazolam | Versed | Yes | Anesthesia, preoperative and procedural | Second-line therapy for early status epilepticus”
What the sources say
- Not checked yetcites [75] Lacy, 2004
- Not checked yetcites [76] Schmidt, 2002
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Clonazepam | Klonopin | Yes | Panic disorder, epileptic | Second-line adjunctive treatment for partial and”
What the sources say
- Not checked yetcites [75] Lacy, 2004
- Not checked yetcites [76] Schmidt, 2002
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Midazolam | Hydroxylation (CYP 3A4 and 3A5) (25, 41, 42) | 1-hydroxymidazolam (minor) (24) | 1-4 (24) | 1 (24)”
What the sources say
- Not checked yetcites [25] Hobbs, 1996
- Not checked yetcites [41] Gorski, 1994, Regioselective biotransformation of midazolam by members of the human cytochrome P450 3A (CYP3A) subfamily, Biochem Pharmacol source
- Not checked yetcites [42] Kronbach, 1989, Oxidation of midazolam and triazolam by human liver cytochrome P450IIIA4, Mol Pharmacol
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Diazepam | Valium | Yes | Anxiety, alcohol withdrawal, | First-line treatment for early status epilepticus;”
What the sources say
- Not checked yetcites [75] Lacy, 2004
- Not checked yetcites [76] Schmidt, 2002
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one. The quote only partly states this claim.
None of the sources cited for this claim have been checked yet.
In the paper
“Lorazepam | Ativan | Yes | Anxiety, pre-anesthetic to induce amnesia, | First-line treatment for early status epilepticus”
What the sources say
- Not checked yetcites [75] Lacy, 2004
- Not checked yetcites [76] Schmidt, 2002
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one. The quote only partly states this claim.
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?
The cited source says what the claim attributes to it.
In the citing paper
“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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Special formulations of BZDs
“These simulations were briefly described by Kaplan and DuPont (72), but detailed results are reported herein.”
§ References
“71. Kaplan EM, Dupont RL. Benzodiazepines and anxiety disorders: a review for the practicing physician. Curr Med Res Opin 2005;21:941-50.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Metabolism and elimination
“short acting (<10 h; lorazepam, midazolam)”
§ Conclusions
“| Lorazepam | Glucuronidation (24) | NA | 7-26 (39, 40) | NA |”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Metabolism and elimination
“intermediate acting (10-24 h; clonazepam)”
§ Conclusions
“| Clonazepam | Nitroreduction (CYP 3A4), | NA | 19-60 (32) | NA |”
3 of 3
Citations
Cites
Goodman & Gilman's The Pharmacological Basis of Therapeutics
Brunton, L. L. (1985) · Cited by 7,321
Epilepsy: A Comprehensive Textbook
(2008) · JAMA · doi:10.1001/jama.300.4.443-a · Cited by 2,357
Macdonald, R. L., & Olsen, R. W. (1994) · Annual Review of Neuroscience · doi:10.1146/annurev.ne.17.030194.003033 · Cited by 1,975
A Comparison of Four Treatments for Generalized Convulsive Status Epilepticus
Treiman, D. M., Meyers, P. D., Walton, N. Y., Collins, J. F., Colling, C., Rowan, A. J., Handforth, A., Faught, E., Calabrese, V. P., Uthman, B. M., et al. (1998) · New England Journal of Medicine · doi:10.1056/nejm199809173391202 · Cited by 1,325
Which GABAA-receptor subtypes really occur in the brain?
McKernan, R. M., & Whiting, P. J. (1996) · Trends in Neurosciences · doi:10.1016/s0166-2236(96)80023-3 · Cited by 1,222
Benzodiazepine actions mediated by specific γ-aminobutyric acidA receptor subtypes
Rudolph, U., Crestani, F., Benke, D., Brünig, I., Benson, J. A., Fritschy, J.-M., Martin, J. R., Bluethmann, H., & Möhler, H. (1999) · Nature · doi:10.1038/44579 · Cited by 1,172
Molecular and neuronal substrate for the selective attenuation of anxiety
Löw, K., Crestani, F., Keist, R., Benke, D., Brünig, I., Benson, J. A., Fritschy, J.-M., Rülicke, T., Bluethmann, H., Möhler, H., et al. (2000) · Science · doi:10.1126/science.290.5489.131 · Cited by 946
Alldredge, B. K., Gelb, A. M., Isaacs, S. M., Corry, M. D., Allen, F., Ulrich, S., Gottwald, M. D., O'Neil, N., Neuhaus, J. M., Segal, M. R., et al. (2001) · New England Journal of Medicine · doi:10.1056/nejmoa002141 · Cited by 888
A new benzodiazepine pharmacology
Möhler, H., Fritschy, J. M., & Rudolph, U. (2002) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.300.1.2 · Cited by 716
Jerram, T. C. (1981) · Side effects of drugs annual · doi:10.1016/s0378-6080(81)80009-8 · Cited by 695
Research works printed but not linked: 26
- International Narcotics Control Board, Psychotropic Substances 2006
- Shorvon, 1995, Antiepileptic drugs, 763
- Anderson, 2002, Antiepileptic drugs, 187
- Hobbs, 1996, Goodman & Gilmans. The pharmacological basis of therapeutics, 361
- United Nations, 1997, Recommended methods for the detection and assay of barbiturates and benzodiazepines in biological specimens. Manual for use by national laboratories
- Flockhart, Drug interaction table (cytochrome P450 system)
- 47.Trileptal [package insert]. East Hanover, NJ: Novartis, 2007.
- Lacy, Anticonvulsants and antimicrobial cytochrome P-450 effects
- Goshman, 1999, Clinically significant P450 drug interactions, J Pharm Soc Wisconsin, 23
- Riss, The simulation of desmethyldiazepam (DMD) concentrations following missed daily doses of Tranxene-SD and Tranxene T-Tab
- Gastaut, 1965, Laction du diazepam (Valium) dans le traitement des formes non-convulsive de lepilepsie generalisee [in French], Rev Neurol (Paris), 112, 99
- Schmidt, 2002, Antiepileptic drugs, 206
- Schmidt, 1995, Antiepileptic drugs, 705
- Sato, 1995, Antiepileptic drugs, 725
- Sato, 1977, Clonazepam in the treatment of absence seizures: a double-blind clinical trial [abstract], Neurology, 27, 371
- Beck, 1973, Traitement des etats de mal epileptiques par le clonazepam [in French], Sem Hop Paris, 49, 21
- Bergamini, 1970, Elektroenzephalographische und klinische Bewertung des neuen Benzodiazepin Ro 54023 [in German], EEG EMG, 1, 182
- Bergamini, 1972, LAction du Ro 54023 dans le traitement des differentes formes depilepsie [in French]
- Gastaut, 1970, Properties anti-epileptiques exceptionneles dune benzodiazepine nouvelle le Ro 05-4023 [in French], La Vie Medicale, 51, 5175
- Gimenez-Roldan, 1972, Un nuevo medicamento eficaz en el trataimento del status epilepticus - Ro 5-4023 [in Spanish], Med Clin (Barc), 58, 133
- Tridon, 1973, Conduite du traitement des etats de mal epileptiques par le Ro 05-4023 (clonazepam) [in French], Sem Hop Paris, 49, 29
- 123.Midazolam HCl injection [package insert]. Weston, FL: Apotex Corp, 2000.
- Wolf, 1985, Clobazam. Human psychopharmacology and clinical application, 167
- Critchley, 1981, Clobazam, 159
- Wilson, 1985, Clobazam. Human psychopharmacology and clinical application, 172
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Cited by
Sorted by citations
Benzodiazepines revisited—will we ever learn?
Lader, M. (2011) · Addiction · doi:10.1111/j.1360-0443.2011.03563.x · Cited by 573
The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease
Huot, P., Johnston, T. H., Koprich, J. B., Fox, S. H., & Brotchie, J. M. (2013) · Pharmacological Reviews · doi:10.1124/pr.111.005678 · Cited by 335
Bohrey, S., Chourasiya, V., & Pandey, A. (2016) · Nano Convergence · doi:10.1186/s40580-016-0061-2 · Cited by 284
Alcohol withdrawal syndrome: mechanisms, manifestations, and management
Jesse, S., Bråthen, G., Ferrara, M., Keindl, M., Ben‐Menachem, E., Tănăsescu, R., Brodtkorb, E., Hillbom, M., Leone, M. A., & Ludolph, A. C. (2016) · Acta Neurologica Scandinavica · doi:10.1111/ane.12671 · Cited by 261
Pain Assessment and Treatment in Children With Significant Impairment of the Central Nervous System
Hauer, J., Houtrow, A. J., Feudtner, C., Klein, S. M., Klick, J. C., Linebarger, J., Norwood, K. W., Adams, R. C., Brei, T. J., Davidson, L. F., et al. (2017) · PEDIATRICS · doi:10.1542/peds.2017-1002 · Cited by 230
Metadata
- 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
- 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
- bronze
- doi.org
- Locations
- Acta Neurologica Scandinavica (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Clinical Neurology › 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.
A language model drew the claims from the paper on 2026-10-05, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-05 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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