Evidence for tolerance following repeated dosing in rats with ciproxifan, but not with A-304121

Pan, Jia Bao; Miller, Thomas R.; Kroeger, Paul E.; Bennani, Youssef L.; Komater, Victoria A.; Esbenshade, Timothy A.; Hancock, Arthur A.; Decker, Michael; Fox, Gerard B.

doi:10.1016/j.lfs.2006.04.002

Cited by 13 publications

(9 citation statements)

References 38 publications

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“…The mechanism of behavioural tolerance observed in the current sleep–wake studies in Ox+/+ and Ox−/− mice is not clear. Further studies are required with other H 3 antagonists to confirm this phenomenon, given that previous reports demonstrating tolerance in other behavioural parameters were compound specific (Pan et al. , 2006).…”

Section: Discussionmentioning

confidence: 88%

“…Recent studies have demonstrated that certain effects of particular H 3 antagonists may be susceptible to tolerance in preclinical species. For example, the effects of ciproxifan on food intake and locomotor activity were decreased following repeat dosing, but the effects of a non‐imidazole H 3 antagonist A304121 were maintained (Pan et al. , 2006).…”

Section: Discussionmentioning

confidence: 99%

“…, 2007; 2008). However, certain effects of other H 3 antagonists have been shown to tolerate out after repeat dosing in preclinical species (Pan et al. , 2006), although the effect of repeat dosing on the sleep–wake cycle has not been reported previously.…”

Section: Introductionmentioning

confidence: 99%

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Differential effects of acute and repeat dosing with the H₃ antagonist GSK189254 on the sleep–wake cycle and narcoleptic episodes in Ox−/− mice

Guo

Anaclet

Roberts

et al. 2009

British J Pharmacology

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Background and purpose: Histamine H3 receptor antagonists are currently being evaluated in clinical trials for a number of central nervous system disorders including narcolepsy. These agents can increase wakefulness (W) in cats and rodents following acute administration, but their effects after repeat dosing have not been reported previously. Experimental approach: EEG and EMG recordings were used to investigate the effects of acute and repeat administration of the novel H3 antagonist GSK189254 on the sleep-wake cycle in wild-type (Ox+/+) and orexin knockout (Ox-/-) mice, the latter being genetically susceptible to narcoleptic episodes. In addition, we investigated H3 and H1 receptor expression in this model using radioligand binding and autoradiography. Key results: In Ox+/+ and Ox-/-mice, acute administration of GSK189254 (3 and 10 mg·kg -1 p.o.) increased W and decreased slow wave and paradoxical sleep to a similar degree to modafinil (64 mg·kg -1 ), while it reduced narcoleptic episodes in Ox-/-mice. After twice daily dosing for 8 days, the effect of GSK189254 (10 mg·kg -1 ) on W in both Ox+/+ and Ox-/-mice was significantly reduced, while the effect on narcoleptic episodes in Ox-/-mice was significantly increased. Binding studies revealed no significant differences in H3 or H1 receptor expression between Ox+/+ and Ox-/-mice. Conclusions and implications:These studies provide further evidence to support the potential use of H3 antagonists in the treatment of narcolepsy and excessive daytime sleepiness. Moreover, the differential effects observed on W and narcoleptic episodes following repeat dosing could have important implications in clinical studies.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

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Differential effects of acute and repeat dosing with the H₃ antagonist GSK189254 on the sleep–wake cycle and narcoleptic episodes in Ox−/− mice

Guo

Anaclet

Roberts

et al. 2009

British J Pharmacology

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“…Recently, Pan et al (2006) demonstrated that the effects of ciproxifan on food intake and locomotor activity were susceptible to tolerance, whereas its effects on body weight were not. In the current study, we observed positive effects on cognitive function with GSK189254 in object recognition and attentional set shift paradigms following twice-daily dosing for 7 days, suggesting that the procognitive effects were not subject to tolerance.…”

Section: Novel H 3 Antagonist Gsk189254 Enhances Cognition In Rats 1043mentioning

confidence: 99%

GSK189254, a Novel H3 Receptor Antagonist That Binds to Histamine H3 Receptors in Alzheimer’s Disease Brain and Improves Cognitive Performance in Preclinical Models

Medhurst

Atkins²,

Beresford³

et al. 2007

The Journal of Pharmacology and Experimental Therapeutics

288

234

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6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) is a novel histamine H 3 receptor antagonist with high affinity for human (pK i ϭ 9.59 -9.90) and rat (pK i ϭ 8.51-9.17) H 3 receptors. GSK189254 is Ͼ10,000-fold selective for human H 3 receptors versus other targets tested, and it exhibited potent functional antagonism (pA 2 ϭ 9.06 versus agonist-induced changes in cAMP) and inverse agonism [pIC 50 Progressive decline in cognitive performance is a key characteristic of Alzheimer's disease (AD) and related dementias, and improving cognitive function in these diseases represents a complex challenge, given the involvement of numerous neurotransmitter systems and brain regions (CoreyBloom, 2002). Current therapies, such as cholinesterase inhibitors, provide only minimal benefit to a subset of patients and for a limited period, so a number of alternative Article, publication date, and citation information can be found at

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“…While promoting an acute loss of body weight in rat, ciproxifan (6) failed to maintain efficacy after subchronic dosing (15 days) [83]. Although rapid desensitization was observed following an H 3 R agonist administration, antagonists were not expected to follow the same tendency.…”

Section: Desensitizationmentioning

confidence: 99%

The Histamine H3 Receptor as a Therapeutic Drug Target for Metabolic Disorders: Status, Challenges and Opportunities

Plancher

2011

CTMC

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Since the histamine-3 receptor (H₃R) was cloned in 1999, huge efforts have been made by most of the key players in the pharmaceutical industry as well as in smaller biotech companies to increase the knowledge on this peculiar receptor, with the ultimate goal of bringing new drugs to the market. This review gives a survey on the most valuable chemical tools discovered so far and the significant pharmacological experiments on metabolic disease models published to date. Pharmacology of H₃R antagonists turns out to be very complex due to various functional activities, species selectivity, presence of H₃R isoforms and the poorly understood dichotomy in efficacy between CNS and metabolic disease models. Adding an extra layer of complexity, researchers have to cope with some recurrent safety concerns, some of them being tightly linked to the nature of the H₃R pharmacophore. Therefore this review also strives to summarize the major hurdles and some of the contradictions seen in the H₃R field, together with a brief overview of the clinical trials currently running.

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Evidence for tolerance following repeated dosing in rats with ciproxifan, but not with A-304121

Cited by 13 publications

References 38 publications

Differential effects of acute and repeat dosing with the H₃ antagonist GSK189254 on the sleep–wake cycle and narcoleptic episodes in Ox−/− mice

Differential effects of acute and repeat dosing with the H₃ antagonist GSK189254 on the sleep–wake cycle and narcoleptic episodes in Ox−/− mice

GSK189254, a Novel H3 Receptor Antagonist That Binds to Histamine H3 Receptors in Alzheimer’s Disease Brain and Improves Cognitive Performance in Preclinical Models

The Histamine H3 Receptor as a Therapeutic Drug Target for Metabolic Disorders: Status, Challenges and Opportunities

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Evidence for tolerance following repeated dosing in rats with ciproxifan, but not with A-304121

Cited by 13 publications

References 38 publications

Differential effects of acute and repeat dosing with the H3 antagonist GSK189254 on the sleep–wake cycle and narcoleptic episodes in Ox−/− mice

Differential effects of acute and repeat dosing with the H3 antagonist GSK189254 on the sleep–wake cycle and narcoleptic episodes in Ox−/− mice

GSK189254, a Novel H3 Receptor Antagonist That Binds to Histamine H3 Receptors in Alzheimer’s Disease Brain and Improves Cognitive Performance in Preclinical Models

The Histamine H3 Receptor as a Therapeutic Drug Target for Metabolic Disorders: Status, Challenges and Opportunities

Contact Info

Product

Resources

About

Differential effects of acute and repeat dosing with the H₃ antagonist GSK189254 on the sleep–wake cycle and narcoleptic episodes in Ox−/− mice

Differential effects of acute and repeat dosing with the H₃ antagonist GSK189254 on the sleep–wake cycle and narcoleptic episodes in Ox−/− mice