Benzodiazepine‐induced reduction in activity mirrors decrements in cognitive and psychomotor performance

Dawson, Jean; Boyle, Julia; Stanley, Neil; Johnsen, Sigurd; Hindmarch, Ian; Skene, Debra J.

doi:10.1002/hup.961

Cited by 14 publications

(10 citation statements)

References 43 publications

(54 reference statements)

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“…The hypotheses tested herein were that benzolamide, which remains an orphan drug since its first testing in humans more than 50 years ago and never tested under field conditions for AMS prevention, is effective in increasing arterial oxygenation and preventing AMS during a high‐altitude expedition. Underlying this proposed effectiveness and possible superiority of benzolamide over acetazolamide is the likelihood that benzolamide has fewer CNS side effects than acetazolamide, when tested in a rigorous double‐blinded placebo‐controlled fashion with an active comparator, lorazepam, known to alter CNS function (Dawson et al …”

Section: Introductionmentioning

confidence: 99%

Benzolamide improves oxygenation and reduces acute mountain sickness during a high‐altitude trek and has fewer side effects than acetazolamide at sea level

Wolff

Hedges

Nathan³

et al. 2016

Pharmacology Res & Perspec

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Acetazolamide is the standard carbonic anhydrase (CA) inhibitor used for acute mountain sickness (AMS), however some of its undesirable effects are related to intracellular penetrance into many tissues, including across the blood–brain barrier. Benzolamide is a much more hydrophilic inhibitor, which nonetheless retains a strong renal action to engender a metabolic acidosis and ventilatory stimulus that improves oxygenation at high altitude and reduces AMS. We tested the effectiveness of benzolamide versus placebo in a first field study of the drug as prophylaxis for AMS during an ascent to the Everest Base Camp (5340 m). In two other studies performed at sea level to test side effect differences between acetazolamide and benzolamide, we assessed physiological actions and psychomotor side effects of two doses of acetazolamide (250 and 1000 mg) in one group of healthy subjects and in another group compared acetazolamide (500 mg), benzolamide (200 mg) and lorazepam (2 mg) as an active comparator for central nervous system (CNS) effects. At high altitude, benzolamide‐treated subjects maintained better arterial oxygenation at all altitudes (3–6% higher at all altitudes above 4200 m) than placebo‐treated subjects and reduced AMS severity by roughly 50%. We found benzolamide had fewer side effects, some of which are symptoms of AMS, than any of the acetazolamide doses in Studies 1 and 2, but equal physiological effects on renal function. The psychomotor side effects of acetazolamide were dose dependent. We conclude that benzolamide is very effective for AMS prophylaxis. With its lesser CNS effects, benzolamide may be superior to acetazolamide, in part, because some of the side effects of acetazolamide may contribute to and be mistaken for AMS.

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Section: Introductionmentioning

confidence: 99%

Benzolamide improves oxygenation and reduces acute mountain sickness during a high‐altitude trek and has fewer side effects than acetazolamide at sea level

Wolff

Hedges

Nathan³

et al. 2016

Pharmacology Res & Perspec

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“…Lorazepam is a benzodiazepine with high affinity for gamma‐aminobutyric acid (GABA) receptors that negatively affects a broad range of cognitive functions (Stewart, 2005). The lorazepam challenge was chosen because its C max is well known and its deleterious effects on cognition in healthy adults are well described (Dawson et al ., 2008; Maruff et al ., 2006; Mintzer and Griffiths, 2003; Snyder et al . 2005; Stewart, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…The present study had two main aims: (1) compare effect sizes of lorazepam vs. placebo groups at C max using means and standard errors generated by paired‐sample t ‐tests, RM‐ANOVA, and LMM; and (2) compare effect sizes of ascending slopes (baseline, 1 h, C max ) generated using t ‐tests of change from baseline scores, AUC, and LMM. Given that acute administration of benzodiazepines, such as lorazepam, is known to slow processing speed and reduce attention, memory, and executive function (Dawson et al ., 2008; Maruff et al ., 2006; Snyder et al ., 2005; Stewart, 2005), we hypothesized that performance on all of the cognitive tasks would decline to a greater extent under lorazepam than under placebo. We further hypothesized that, because LMM permits estimation of fixed effects independent of random effects, they would yield larger effect sizes on all tests at C max and over the ascending slopes.…”

Section: Introductionmentioning

confidence: 99%

A comparison of statistical approaches used to evaluate change in cognitive function following pharmacologic challenge: an example with lorazepam

Pietrzak

Fredrickson²,

Snyder

et al. 2010

Human Psychopharmacology

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“…Clinicians prefer BZD with an intermediate halflife to extensively sedating long half-life BZDs [42,43]. Lorazepam has been reported to impair motoric function in humans [8] and mice [11]. In the current study, mice were injected with lorazepam (0.5 mg/kg) in the afternoon, and next morning they were tested for motoric function using Rotarod apparatus.…”

Section: Bzd Injection and Motoric Testmentioning

confidence: 94%

“…One common problem with BZD therapy is that patients often experience motor incoordination and movement disorders. For example, BZDs increase the risk for falls [3][4][5], automobile accidents [6], slow motor reaction, and the inaccuracy of motor tasks [7][8][9]. Animal studies have also shown that diazepam and lorazepam provoke motoric deficit [10,11].…”

Section: Introductionmentioning

confidence: 99%

Purkinje-neuron-specific down-regulation of p38 protects motoric function from the repeated use of benzodiazepine

Jung¹,

Metzger²

2013

ABB

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Benzodiazepine (BZD) is the most prescribed CNS depressant in America to treat hyper-excitatory disorders such as anxiety and insomnia. However, the chronic use of BZD often creates adverse effects including psychomotor deficit. In this study, we investigated a novel mechanism by which chronic BZD impedes motoric function in female mice. We used female mice because BZD use is much more prevalent in female than male populations. We tested the hypothesis that the accumulation of p38 (stress-activated protein) in cerebellar Purkinje neurons mediates motoric deficit induced by chronic BZD. To test this hypothesis, we generated transgenic mice that lack p38 in cerebellar Purkinje neurons by crossing Pcp2 (Purkinje cell protein 2)-Cre mice with p38 loxP/loxP mice. p38-knockdown mice and wild-type mice received BZD (lorazepam, 0.5 mg/kg) for 14 days. During this period, they were tested for motoric performance using Rotarod assay in which a quicker fall from rotating rod indicates poorer motoric performance. Cerebellum was then collected to detect p38 in Purkinje neurons and to measure mitochondrial respiration using immunohistochemistry and real-time XF respirometry, respectively. Compared to vehicletreated mice, BZD-treated mice showed poorer motoric performance, a higher number of Purkinje neurons containing p38, and lower mitochondrial respiration. These effects of BZD were much smaller in p38-knockdown mice. These results suggest that the excessive accumulation of p38 in cerebellar Purkinje neurons contributes to motoric deficit associated with chronic BZD. They also suggest that Purkinje neuronal p38 mediates BZD-induced mitochondrial respiratory inhibition in cerebellum. Our findings may provide a new mechanistic insight into chronic BZD-induced motoric deficit.

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Benzodiazepine‐induced reduction in activity mirrors decrements in cognitive and psychomotor performance

Cited by 14 publications

References 43 publications

Benzolamide improves oxygenation and reduces acute mountain sickness during a high‐altitude trek and has fewer side effects than acetazolamide at sea level

Benzolamide improves oxygenation and reduces acute mountain sickness during a high‐altitude trek and has fewer side effects than acetazolamide at sea level

A comparison of statistical approaches used to evaluate change in cognitive function following pharmacologic challenge: an example with lorazepam

Purkinje-neuron-specific down-regulation of p38 protects motoric function from the repeated use of benzodiazepine

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