Lamotrigine (BW430C), a potential anticonvulsant. Effects on the central nervous system in comparison with phenytoin and diazepam.

Cohen, A. F.; Ashby, Lynn S.; Crowley, David C.; Land, G.; Peck, A. W.; Miller, AA

doi:10.1111/j.1365-2125.1985.tb05120.x

Cited by 135 publications

(69 citation statements)

References 26 publications

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“…Pharmaco-electroencephalography was measured to provide nonspecific measures of CNS functions [23]. EEG signals were obtained from leads Fz-Cz and Pz-Oz.…”

Section: Electroencephalographymentioning

confidence: 99%

Central nervous system effects of alcohol at a pseudo‐steady‐state concentration using alcohol clamping in healthy volunteers

Zoethout¹,

Schoemaker²,

Zuurman³

et al. 2009

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The acute effects of alcohol are often studied after oral administration, and alcohol exposure is controlled by adaptation of the dose to weight, and sometimes to sex or demographic variables.• Measurements of the alcohol effects are usually performed at fixed time intervals after intake.• In only a few studies has alcohol been administered intravenously to by-pass the variability in absorption, but plasma levels often vary after administration and efforts to maintain constant levels are rare. WHAT THIS STUDY ADDS• The pharmacodynamic central nervous system (CNS) effects of alcohol or drug-alcohol interactions can be more accurately investigated if alcohol is administered intravenously and alcohol levels are kept within tightly controlled limits.• In the current study we introduce a clamping procedure to study the acute effects of a constant alcohol level of 0.6 g l -1 for 5 h on a wide range of CNS domains.• The obtained pseudo-steady-state levels with very little inter-and intravariability allow the separation of concentration-and time-dependent changes in alcohol effects. AIMIn determining the acute effects of alcohol, it is helpful if alcohol concentrations are maintained at stable levels, to facilitate the interpretation of the results. Recently, an alcohol clamping method was developed that resulted in stable alcohol concentrations for hours. The aim of this study was to test a range of central nervous system (CNS) effects under pseudo-steady-state conditions. METHODSTo achieve a pseudo-steady state of 0.6 g l -1 , breath alcohol concentrations (BrAC) were frequently measured and fed back into a spreadsheet-based program to guide intravenous dosing. CNS effects were frequently measured throughout the clamp. RESULTSThe clamping paradigm resulted in a pseudo-steady-state BrAC of 0.61 g l -1(coefficient of variation 6.2%). A plateau was maintained from 25 to 300 min and caused significant effects on smooth pursuit eye movements [-9.7%, 95% confidence interval (CI) -12.4, -7.1], adaptive tracking (-3.4%, 95% CI -4.5, -2.2), visual analogue scale (VAS) alertness (-13 mm, 95% CI -20, -6), VAS alcohol effects (16 mm, 95% CI 7, 25) and body sway (21.3%, 95% CI 1.8, 45). Some effects (like smooth pursuit eye movements) closely followed the relatively stable alcohol concentrations, whereas others (such as body sway and VAS alcohol effects) fluctuated during the plateau phase. CONCLUSIONSMost CNS effects of alcohol showed a trend to change over time, despite stable concentrations. Other variables remained stable under pseudo-steady-state conditions. The intravenous clamping method provides precise control over BrAC levels and allows frequent repetition of different CNS measurements. These features make this technique eminently suitable to study the complex pharmacodynamic effects of acute alcohol administration.

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“…Pharmaco-electroencephalography was measured to provide nonspecific measures of CNS functions [23]. EEG signals were obtained from leads Fz-Cz and Pz-Oz.…”

Section: Electroencephalographymentioning

confidence: 99%

Central nervous system effects of alcohol at a pseudo‐steady‐state concentration using alcohol clamping in healthy volunteers

Zoethout¹,

Schoemaker²,

Zuurman³

et al. 2009

Brit J Clinical Pharma

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“…This has been particularly noted with benzodiazepine sedation, in which sedation is significantly correlated with saliva levels [16]. This phenomenon was noted particularly in the PK group and could explain the transient increase in salivary levels to baseline levels that was seen, 10 min after the bolus administration of propofol and ketamine, when the level of sedation appeared to lighten.…”

Section: Discussionmentioning

confidence: 86%

Decreased intraoral secretions during sedation-analgesia with propofol-ketamine and midazolam-ketamine combinations

Morse

Sano

Kanri

2001

Journal of Anesthesia

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“…The promising activity and tolerability of lamotrigine led to its progression to clinical studies, with phase I studies confirming its safety and potential superiority to established drugs such as phenytoin and diazepam [71]. Lamotrigine was first approved in 1994 as an antiepileptic drug for the treatment of partial seizures.…”

Section: Lamotriginementioning

confidence: 99%

Standalone Drugs

Proudfoot

2010

Analogue‐Based Drug Discovery II

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In volume I of Analogue-Based Drug Discovery we focused on analogue drugs with a double similarity, that is, those that are similar to another drug from both chemical and pharmacological viewpoints. These were referred to as structural and pharmacological analogues or, alternatively, full analogues. One special class of these analogues is considered to be direct analogues if they have identical pharmacophores -that is, they can be described by a general structure that includes most of the chemical skeleton. The book also discussed some examples of structural analogues, in which the similarity is limited to their chemical structures since they possess different pharmacological properties. We also proposed the term pharmacological analogues for drugs that have completely different chemical structures but similar pharmacological properties.Analogues are based on following a lead compound, and if this compound were a drug that opened up a new therapeutic treatment then we use the term pioneer drug. Such a drug is often referred to as first in class. One can subdivide pioneer drugs into those that have analogues and those that do not. Thus, the latter group provides a special subclass called standalone drugs,

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Lamotrigine (BW430C), a potential anticonvulsant. Effects on the central nervous system in comparison with phenytoin and diazepam.

Cited by 135 publications

References 26 publications

Central nervous system effects of alcohol at a pseudo‐steady‐state concentration using alcohol clamping in healthy volunteers

Central nervous system effects of alcohol at a pseudo‐steady‐state concentration using alcohol clamping in healthy volunteers

Decreased intraoral secretions during sedation-analgesia with propofol-ketamine and midazolam-ketamine combinations

Standalone Drugs

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