milameline and Alzheimer-Disease

RU 35926/CI-979 (milameline) is a partial muscarinic agonist with promnestic effects in animal models. Preliminary animal studies suggest that this agent has the capacity to reverse cholinergic dysfunction and that it may impact on regional cerebral blood flow (rCBF). A total of 10 subjects with Alzheimer's disease (AD) of mild severity underwent high resolution split-dose single photon emission computed tomography (SPECT) during performance of a verbal recognition and control task, both before and after 18 weeks treatment with melameline or placebo. SPECT images were coregistered with individual's magnetic resonance imaging scans allowing extraction of rCBF values from multiple anatomical regions of interest (ROI). The effect of milameline was examined in eight individuals who were found after unblinding to be taking active drug. Effects of milameline were most apparent in the frontal regions, basal ganglia and thalamus. In the group as a whole, the greatest increase in rCBF due to milameline treatment was observed in the left globus pallidus. Response to milameline treatment was associated with increases in rCBF in the cingulate gyrus bilaterally, and less so for the left thalamus. Milameline-related increases in rCBF values were exaggerated by the verbal recognition task. Milameline has a demonstrable effect on cerebral blood flow in mild AD. Consistent with emerging animal data, the effects on rCBF appear most prominent in frontal and subcortical regions in AD subjects. The effects on rCBF appear to be augmented by the performance of a cognitively demanding task, raising the possibility that such tasks could assist in building an awareness of the functional neuropsychopharmacology of drugs designed for cognitive enhancement.

Topics: Alzheimer Disease; Cerebrovascular Circulation; Dihydropyridines; Double-Blind Method; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Muscarinic Agonists; Neuropsychological Tests; Oximes; Prefrontal Cortex; Psychomotor Performance; Recognition, Psychology; Tomography, Emission-Computed, Single-Photon

To assess the feasibility of using MRI measurements as a surrogate endpoint for disease progression in a therapeutic trial for AD.. A total of 362 patients with probable AD from 38 different centers participated in the MRI portion of a 52-week randomized placebo-controlled trial of milameline, a muscarinic receptor agonist. The therapeutic trial itself was not completed due to projected lack of efficacy on interim analysis; however, the MRI arm of the study was continued. Of the 362 subjects who underwent a baseline MRI study, 192 subjects underwent a second MRI 1 year later. Hippocampal volume and temporal horn volume were measured from the MRI scans.. The annualized percent changes in hippocampal volume (-4.9%) and temporal horn volume (16.1%) in the study patients were consistent with data from prior single-site studies. Correlations between the rate of MRI volumetric change and change in behavioral/cognitive measures were greater for the temporal horn than for the hippocampus. Decline over time was more consistently seen with imaging measures, 99% of the time for the hippocampus, than behavioral/cognitive measures (p < 0.001). Greater consistency in MRI than behavioral/clinical measures resulted in markedly lower estimated sample size requirements for clinical trials. The estimated number of subjects per arm required to detect a 50% reduction in the rate of decline over 1 year are: AD Assessment Scale-cognitive subscale 320; Mini-Mental Status Examination 241; hippocampal volume 21; temporal horn volume 54.. The consistency of MRI measurements obtained across sites, and the consistency between the multisite milameline data and that obtained in prior single-site studies, demonstrate the technical feasibility of using structural MRI measures as a surrogate endpoint of disease progression in therapeutic trials. However, validation of imaging as a biomarker of therapeutic efficacy in AD awaits a positive trial.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alzheimer Disease; Biomarkers; Brain; Dihydropyridines; Disease Progression; Feasibility Studies; Female; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Muscarinic Agonists; Neuroprotective Agents; Neuropsychological Tests; Oximes; Predictive Value of Tests; Reference Values; Sample Size; Sex Distribution; Treatment Outcome

The purpose of this study was to evaluate the effectiveness of activation versus baseline SPECT in detecting the regional cerebral blood flow (rCBF) changes in Alzheimer's disease (AD) patients after milameline (CI979/RU35926) treatment.. Ten patients with AD who took part in a milameline drug trial were examined by (99m)Tc-hexamethylpropyleneamine oxime SPECT before and after the medication. A split-dose technique was used for the acquisition of baseline and activation images within a single session. Two patients were unable to complete the activation challenges. rCBF changes were assessed using the statistical parametric mapping program. Both increased and decreased contrasts were used to test rCBF changes on activation and baseline images, respectively. rCBF changes caused by activation were also examined before and after milameline treatment.. Decreased rCBFs were observed at the temporal cortex on both sides of the brain and at the left parietal cortex on the activation SPECT images after milameline, whereas no statistically significant rCBF change was found on the baseline SPECT images. Memory stress caused not only increased rCBF in many areas of the brain, including the parietotemporal cortex, but also decreased rCBF at the splenium of the corpus callosum.. Cognitive activation scans are more effective than baseline scans in detecting rCBF changes in AD patients after milameline.

Topics: Alzheimer Disease; Brain; Cerebrovascular Circulation; Cognition; Dihydropyridines; Humans; Neuropsychological Tests; Oximes; Radiopharmaceuticals; Technetium Tc 99m Exametazime; Tomography, Emission-Computed, Single-Photon

CI-979 ((E)-1,2,5,6-tetrahydro-1-methyl-3-pyridinecarboxaldehyde, O-methyloxime monohydrochloride), a novel muscarinic agonist, is being investigated as a potential treatment for Alzheimer's disease (AD). The objective of the present study was to determine the safety and tolerance of multiple, rising, oral doses of CI-979 in patients with AD. Ten male patients aged 59 to 74 years (mean 65 years) who met NINCDS criteria for AD were randomized to receive either CI-979 (eight patients) or placebo (two patients) according to a double-blind, parallel-group, rising-dose design. Doses were 0.5-mg q6h, 1-mg q12h, 1-mg q6h, 2-mg q12h, 2-mg q6h, 2.5-mg q6h, and 3-mg q6h. All doses were to be administered sequentially for 3 days each with the exception of the 2.5-mg q6h dose, which was to be administered for 1.5 days. Five patients receiving CI-979 discontinued study medication because of adverse events; two after receiving 2-mg q6h (10 doses), two after 2.5-mg q6h (5 doses), and one after 3-mg q6h (4 doses). The study was terminated following administration of the fourth 3-mg dose due to the nature and intensity of adverse events. Cholinergic symptoms including diaphoresis, hypersalivation, nausea, diarrhea, hypotension, chills, headache, flatulence, and urinary frequency and signs suggestive of parkinsonism (cogwheeling, tremor, pillrolling, posturing, and shuffling gait) were dose-limiting. The frequency and intensity of adverse events increased with increasing CI-979 dose. No other clinically significant CI-979-related changes occurred in physical examinations, clinical laboratory measurements, electrocardiograms, or ophthalmologic examinations. Steady-state trough plasma CI-979 concentrations increased in proportion to dose. In summary, CI-979 doses of 1-mg q6h were well tolerated by all patients; 2-mg q6h was tolerated by most patients, and 2.5-mg and 3-mg doses were poorly tolerated, Dose titration to a maximum of 2-mg q6h will therefore be used in initial efficacy trials of CI-979 in patients with AD.

Topics: Aged; Alzheimer Disease; Dihydropyridines; Double-Blind Method; Humans; Male; Middle Aged; Oximes; Placebos; Psychotropic Drugs

In vitro and in vivo characterization in rodents and monkeys shows that CI-979/RU35926 is a partial muscarinic agonist with equal affinity for the five subtypes of muscarinic receptors. It activates central cholinergic receptors as shown by its ability to decrease body temperature, enhance local cortical blood flow and increase cortical arousal measured by QEEG. Further, it reverses spatial memory deficits in rats with ibotenic acid-induced lesions of forebrain cholinergic neurons. Signs of peripheral cholinergic stimulation appear at doses higher or equal to those necessary to produce central activity. In a single-dose tolerance study in young, healthy human volunteers, CI-979/RU35926 was well tolerated at doses of 0.002-1.0 mg with cholinergic symptoms such as hypersalivation and sweating, observed at 2-4 mg. It demonstrated linear pharmacokinetic behavior over a dose range of 0.1 to 4 mg and elimination half-life varied from 2-5 hours. Measurement of unchanged drug in urine suggests that the drug was extensively metabolized. Thus, the safety profile supported further clinical evaluation and CI-979/RU35926 is currently in Phase II clinical trials.

Topics: Adolescent; Adult; Alzheimer Disease; Animals; Behavior, Animal; Body Temperature; Brain; Cerebrovascular Circulation; CHO Cells; Cricetinae; Cross-Over Studies; Denervation; Dihydropyridines; Double-Blind Method; Drug Evaluation, Preclinical; Electroencephalography; Gastrointestinal Motility; Humans; Ibotenic Acid; Macaca mulatta; Male; Maze Learning; Middle Aged; Muscarinic Agonists; Oximes; Rats; Receptors, Muscarinic; Swimming

Topics: Alzheimer Disease; Carbamates; Cholinesterase Inhibitors; Dihydropyridines; Donepezil; Humans; Indans; Muscarinic Agonists; Oximes; Phenylcarbamates; Piperidines; Pyridines; Rivastigmine; Tacrine; Thiadiazoles

This paper reviews the scientific and ethical issues surrounding the conduct of bridging studies in patients with Alzheimer's disease (AD). Bridging studies, so called because they facilitate the transition from phase I to phase II development, are late phase I safety/tolerance studies which determine the maximum tolerated dose (MTD) in patients before initiating phase II efficacy studies. Determining the MTD in patients is important because we have found that AD patients appear to respond to cholinergic compounds differently from normal volunteers, reaching a different MTD. Preliminary evidence of dose-related efficacy with two cholinergic compounds lends support to our contention that determination of the highest tolerated dose maximizes the potential to detect efficacy. We will review the early clinical development of several cholinergic compounds and make recommendations for the design and conduct of bridging studies based on our experience. A fixed-dose panel design with dosages based on the MTD determined in normal volunteers is recommended. In order to minimize risk to the patients, ensuring that scientific benefits outweigh the risks, a bridging study must be supported by detailed preclinical toxicology, by a clinical research unit that is prepared to handle unexpected contingencies, and by the oversight of a competent, multi-disciplinary review board. Patients should be in good physical health (excluding AD), and a comprehensive informed consent procedure must be instituted. Carefully planned and well run bridging studies represent a scientifically and ethically sound approach to drug development in the Alzheimer's population.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Clinical Trials as Topic; Dihydropyridines; Ethics, Medical; Humans; Nootropic Agents; Oximes; Physostigmine; Psychotropic Drugs; Pyridines; Tacrine; Thiadiazoles