The effects of chlormethiazole on single unit activity in rat brain; interactions with inhibitory and excitatory neurotransmitters

Gent, J P; Wacey, T.A.

doi:10.1111/j.1476-5381.1983.tb10713.x

Cited by 23 publications

(9 citation statements)

References 17 publications

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“…Contrary to some previous observations ( Gent & Wacey, 1983 ; Hales & Lambert, 1992 ), chlormethiazole could not potentiate responses to glycine in the present study. Several possibilities could explain this apparent discrepancy.…”

Section: Discussioncontrasting

confidence: 99%

“…It is also possible that chlormethiazole has a direct potentiating eect on some subtypes of glycine receptors that would be dierent from those which are predominant in the preparation used in the present study. Such a subunit selectivity could explain the previously noticed variability in the degree of potentiation induced by chlormethiazole on the electrical activity of brainstem neurones (Gent & Wacey, 1983).…”

Section: Discussionmentioning

confidence: 74%

“…In the present paper, whole‐cell recordings from ventral spinal cord neurones and combined applications of ICS 205,930 with either Zn 2+ , ethanol or propofol were used in order to determine whether the mechanism of potentiation of glycine responses by low concentrations of ICS 205,930 can be discriminated from the mechanisms involved in the effects of these other modulators. The effects of chlormethiazole, another molecule reported to potentiate glycine responses ( Gent & Wacey, 1983 ; Hales & Lambert, 1992 ), were also reinvestigated.…”

Section: Introductionmentioning

confidence: 99%

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Mode of action of ICS 205,930, a novel type of potentiator of responses to glycine in rat spinal neurones

Chesnoy-Marchais

1999

British J Pharmacology

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1 The e ect of a novel potentiator of glycine responses, ICS 205,930, was studied by whole-cell recordings from spinal neurones, and compared with that of other known potentiators, in an attempt to di erentiate their sites of action. 2 The ability of ICS 205,930 (0.2 mM) to potentiate glycine responses persisted in the presence of concentrations of Zn 2+ (5 ± 10 mM) that were saturating for the potentiating e ect of this ion. 3 Preincubation with 10 mM Zn 2+ before application of glycine plus Zn 2+ had an inhibitory e ect, which did not result from Zn 2+ entry into the neurone, since it persisted with either 10 mM internal EGTA or 10 mM internal Zn 2+ . To test whether the potentiating e ects of ICS 205,930 and Zn 2+ interact, both compounds were applied without preincubation. 4 The potentiating e ect of ICS 205,930 was similar for responses to glycine and for responses to glycine plus Zn 2+ , provided the concentrations of agonist were adjusted so as to induce control responses of identical amplitudes. 5 ICS 205,930 remained able to potentiate glycine responses in the presence of ethanol (200 mM). 6 ICS 205,930 also retained its potentiating e ect in the presence of the anaesthetic propofol (30 ± 90 mM), which strongly potentiated glycine responses but, in contrast with ICS 205,930, also markedly increased the resting conductance. 7 The anticonvulsant chlormethiazole (50 ± 100 mM) neither potentiated glycine responses nor prevented the e ect of ICS 205,930, even though it increased the resting conductance and potentiated GABA A responses. 8 The mechanism of action of ICS 205,930 appears to be di erent from those by which Zn 2+ , propofol or ethanol potentiate glycine responses.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

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Mode of action of ICS 205,930, a novel type of potentiator of responses to glycine in rat spinal neurones

Chesnoy-Marchais

1999

British J Pharmacology

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“…The main covariates affecting plasma clearance were body weight and the coexisting premedication of liver enzyme-inducing CNS Drug Reviews, Vol. 10 drugs such as phenytoin and carbamazepine. Variables such as creatinine clearance, however, were not significantly affected.…”

Section: Pharmacokinetics/pharmacodynamicsmentioning

confidence: 99%

“…The main covariates affecting plasma clearance were body weight and the coexisting premedication of liver enzyme-inducing CNS Drug Reviews, Vol. 10 There was a rapid rise in the plasma concentration to~1.5 ìg/mL followed by a steady state which declined rapidly following cessation of the infusion.…”

Section: Pharmacokinetics/pharmacodynamicsmentioning

confidence: 99%

The Pharmacology of Chlormethiazole: A Potential Neuroprotective Agent?

Wilby

Hutchinson

2004

CNS Drug Reviews

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Chlormethiazole is a thiazole derivative with a long history of use as a sedative agent. The mode of action of the drug has been partly worked out and has been established with recognition that its mechanism of action involves potentiation of GABA activity, the major intrinsic inhibitory neurotransmitter. Animal models of stroke ranging from rodents to primates have suggested an optimistic role for chlormethiazole in preventing both anatomical and functional deleterious effects of stroke. Phase III clinical trials, therefore, proceeded but unfortunately with very little success. Recently, the animal models have been revisited in an attempt to identify causes for this discrepancy between the results from preclinical and clinical studies. This review studies the pharmacological roots of chlormethiazole from its origin through to its licensed and novel applications. Emphasis is placed on discussing the animal experiments which led to its grooming as a neuroprotective agent and also on the human trials. The review seeks to explain the discrepancies between animal and human studies, which include short survival times of experimental subjects, speed of drug administration and fundamental differences between species. The primate model of stroke perhaps offers the nearest alternative to phase III trials and has recently been used to compare a number of newer neuroprotective agents with greater efficacy than chlormethiazole. In addition, novel approaches involving human neurochemical analyses in vivo are described which may help bridge the gap between animal models and future phase III trials.

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The effects of antiallergic and bronchodilator drugs on platelet-activating factor (PAF-acether) induced bronchospasm and platelet aggregation

Lewis¹,

Dervinis²,

Chang³

1984

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Platelet activating factor (PAF-acether) is a potential mediator of asthma and inflammation. Recently, the suggestion was made that inhibition of PAF-acether by disodium cromoglycate (DSCG) might be partly responsible for the effectiveness of DSCG in asthma. We have extended these studies and examined the effects of antiallergic and bronchodilator drugs on PAF-acether induced bronchospasm after i.v. administration in guinea pigs and in vitro platelet aggregation in rabbits. Neither DSCG nor Wy-41,195, a potent orally effective antiallergic, altered either of the PAF-acether responses. Furthermore, aerosolized ipratropium, promethazine, ketotifen and FPL 55712 failed to affect the PAF-acether-induced bronchospasm. The same drugs were also ineffective against platelet aggregation induced by PAF-acether. In contrast, aerosolized thiazinamium chloride inhibited the bronchospasm and also inhibited PAF-acether-induced platelet aggregation. Thiazinamium chloride possessed weak antiaggregatory effects against ADP and was without effect against arachidonic acid-induced platelet aggregation. Both lipoxygenase and cyclooxygenase products of arachidonic acid metabolism appear to be involved in PAF-acether bronchospasm since i.v. administered lipoxygenase inhibitors (phenidone, BW755c and NDGA) and indomethacin independently inhibited this in vivo response. However, these drugs failed to alter platelet aggregation to PAF-acether. Thiazinamium chloride may be capable of directly antagonizing the PAF-acether-induced platelet aggregatory response and, in addition, inhibiting the synthesis and/or effects of bronchoconstrictor amines and endogenously generated arachidonic acid metabolites.

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The effects of chlormethiazole on single unit activity in rat brain; interactions with inhibitory and excitatory neurotransmitters

Cited by 23 publications

References 17 publications

Mode of action of ICS 205,930, a novel type of potentiator of responses to glycine in rat spinal neurones

Mode of action of ICS 205,930, a novel type of potentiator of responses to glycine in rat spinal neurones

The Pharmacology of Chlormethiazole: A Potential Neuroprotective Agent?

The effects of antiallergic and bronchodilator drugs on platelet-activating factor (PAF-acether) induced bronchospasm and platelet aggregation

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