Scientific and ethical concerns in clinical trials in Alzheimer's patients: the bridging study

Cutler, Neal R.; Sramek, John J.

doi:10.1007/bf00194329

Cited by 23 publications

(5 citation statements)

References 28 publications

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“…Further bridging tolerance studies in elderly human volunteers and probable Alzheimer's patients were carried out as there is some evidence that these patients may tolerate the drug differently than normal healthy individuals (31,109). Healthy elderly volunteers were administered xanomeline at doses up to 50 mg t.i.d., while patients with probable Alzheimer's disease received xanomeline at doses up to 115 mg t.i.d.…”

Section: Clinical Studiesmentioning

confidence: 99%

Xanomeline and the Antipsychotic Potential of Muscarinic Receptor Subtype Selective Agonists

2003

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Binding studies initially suggested that the muscarinic agonist, xanomeline, was a subtype selective muscarinic M 1 receptor agonist, and a potential new treatment for Alzheimer's disease. However, later in vitro and in vivo functional studies suggest that this compound is probably better described as a subtype selective M 1 /M 4 muscarinic receptor agonist. This subtype selectivity profile has been claimed to explain the limited classical cholinomimetic side effects, particularly gastrointestinal, seen with xanomeline in animals. However, in both healthy volunteers and Alzheimer's patients many of these side effects have been reported for xanomeline and in the patient population this led to a >50% discontinuation rate. Clearly, the preclinical studies have not been able to predict this adverse profile of xanomeline, and this suggests that either xanomeline is not as subtype selective as predicted from preclinical research or that there are differences between humans and animals with regard to muscarinic receptors. Nevertheless, in Alzheimer's patients xanomeline dose-dependently improves aspects of behavioral disturbance and social behavior including a reduction in hallucinations, agitation, delusions, vocal outbursts and suspiciousness. The effects on cognition are not as robust and mainly seen at the highest doses tested. These effects in Alzheimer's patients have given impetus to the suggestion that muscarinic agonists have potential antipsychotic effects. The current review assesses the antipsychotic profile of xanomeline within the framework of the limited clinical studies with cholinergic agents in man, and the preclinical research on xanomeline using various models commonly used for the assessment of new antipsychotic drugs. In general, xanomeline has an antipsychotic-like profile in various dopamine models of psychosis and this agrees with the known interactions between the cholinergic and dopaminergic systems in the brain. Moreover, current data suggests that the actions of xanomeline at the M 4 muscarinic receptor subtype might mediate its antidopaminergic effects. Particularly intriguing are studies showing that xanomeline, even after acute administration, selectively inhibits the firing of mesolimbic dopamine cells relative to dopamine cell bodies projecting to the striatum. This data suggest that xanomeline would have a faster onset of action compared to current antipsychotics and would not induce extrapyramidal side effects. The preclinical data on the whole are promising for an antipsychotic-like profile. If in a new formulation (i.e., transdermal) xanomeline has less adverse effects, this drug may be valuable in the treatment of patients with psychosis.

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Section: Clinical Studiesmentioning

confidence: 99%

Xanomeline and the Antipsychotic Potential of Muscarinic Receptor Subtype Selective Agonists

2003

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“…Thus, an even higher dose of brasofensine may both be tolerated and effective in patients with Parkinson's disease; a bridging study may help to clarify this possibility. 23,24…”

Section: Discussionmentioning

confidence: 99%

Brasofensine Treatment for Parkinson's Disease in Combination with Levodopa/Carbidopa

et al. 2002

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“…In our experience with cholinesterase inhibitors, we have found an altered (usually higher, but sometimes lower) tolerance to these compounds in patients versus healthy subjects; therefore, the optimization of these compounds via bridging studies (late Phase I studies in which the safety/tolerability of new compounds is tested in patients prior to conducting Phase II studies) has played an important role in the development of AChEIs for use in the Alzheimer population. [35][36][37][38][39][40] Bridging studies attempt to define the MTD in the patient population in order to help define the upper limit of the dose range to be tested in Phase II studies. This process is a significant aspect of the development of new cholinergic compounds because most of these compounds have demonstrated efficacy at doses that approximate the MTD.…”

Section: The Limitations Of Cholinesterase Inhibitors and The Role Of Bridging Studiesmentioning

confidence: 99%

Cholinesterase Inhibitors: A Therapeutic Strategy for Alzheimer Disease

1999

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Relative to placebo, new AChEIs in development provide modest improvements in cognition for patients with mild to moderate AD, with improved tolerability profiles and more convenient dosing relative to tacrine. The availability of a wide array of AChEIs soon to be accessible to patients with AD will provide additional options to those who cannot tolerate or do not respond to drugs currently used for AD.

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Scientific and ethical concerns in clinical trials in Alzheimer's patients: the bridging study

Cited by 23 publications

References 28 publications

Xanomeline and the Antipsychotic Potential of Muscarinic Receptor Subtype Selective Agonists

Xanomeline and the Antipsychotic Potential of Muscarinic Receptor Subtype Selective Agonists

Brasofensine Treatment for Parkinson's Disease in Combination with Levodopa/Carbidopa

Cholinesterase Inhibitors: A Therapeutic Strategy for Alzheimer Disease

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