H3 Receptor Miniseries: Discovery of histamine H3 antagonists for the treatment of cognitive disorders and Alzheimer's disease

1. Jorge D. Brioni*,
2. Tim Esbenshade,
3. Tiffany Garrison,
4. Scott Bitner and
5. Marlon Cowart

+ Author Affiliations

1.      Abbott Laboratories

1. * Corresponding author; email: jorge.brioni@abbott.com

Abstract

H3 antagonists increase the release of brain histamine, ACh, NE and DA, neurotransmitters that are known to modulate cognitive processes. The ability to release brain histamine support the effect on attention and vigilance, but histamine also modulates other cognitive domains like short-term and long-term memory. A number of H3 antagonists including BF2.649, PF-03654746, GSK189254, MK-0249, JNJ-17216498 and ABT-288 have advanced to the clinical area for the potential treatment of human cognitive disorders. H3 antagonists exhibited wake promoting effects in humans and efficacy in narcoleptic patients indicating target engagement but some of them were not efficacious in ADHD and schizophrenic patients. Preclinical studies have also shown that H3 antagonists activate intracellular signaling pathways that may improve cognitive efficacy as well as disease modifying effects in Alzheimer's. Ongoing clinical studies will be able to determine the utility of H3 antagonists for the treatment of cognitive disorders in humans.

Vitamins B12, B6, and folic acid for cognition in older men

Vitamins B12, B6, and folic acid for cognition in older men -- Ford et al., 10.1212/WNL.0b013e3181f962c4 -- Neurology

Received April 5, 2010
Accepted June 17, 2010
A. H. Ford MD^*, L. Flicker MD, H. Alfonso PhD, J. Thomas RN, R. Clarnette MD, R. Martins PhD, and O. P. Almeida MD

From the Centre for Medical Research & School of Psychiatry and Clinical Neurosciences (A.H.F., H.A., R.M., O.P.A.) and the Centre for Medical Research & School of Medicine and Pharmacology (L.F., J.T.), WA Centre for Health & Ageing, University of Western Australia, Perth, WA; and the WA Centre for Alzheimer's Disease Research and Care (R.C., R.M.), Edith Cowan University, Perth, WA, Australia.

^* To whom correspondence should be addressed. E-mail: andrew.ford@uwa.edu.au.

Objective: To investigate whether supplementing older men with vitamins B₁₂, B₆, and folic acid improves cognitive function.

Methods: The investigators recruited 299 community-representative hypertensive men 75 years and older to a randomized, double-blind controlled clinical trial of folic acid, vitamin B₆, and B₁₂ supplementation vs placebo over 2 years. The primary outcome of interest was the change in the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog). A secondary aim of the study was to determine if supplementation with vitamins decreased the risk of cognitive impairment and dementia over 8 years.

Results: The groups were well-balanced for demographic and biochemical parameters. There was no difference in the ADAS-cog change from baseline to 24 months between the placebo (0.8, SD 4.0) and vitamins group (0.7, SD 3.4). The adjusted scores in the treatment groups did not differ over time (placebo 0.2 lower, z = 0.71, p = 0.478). There was a nonsignificant 28% decrease in the risk of cognitive impairment (odds ratio 0.72, 95% confidence interval 0.25–2.09) and dementia (hazard ratio 0.72, 95% confidence interval 0.29–1.78) over 8 years of follow-up.

Conclusions: The daily supplementation of vitamins B₁₂, B₆, and folic acid does not benefit cognitive function in older men, nor does it reduce the risk of cognitive impairment or dementia.

Classification of evidence: This study provides Class I evidence that vitamin supplementation with daily doses of 400 μg of B₁₂, 2 mg of folic acid, and 25 mg of B₆ over 2 years does not improve cognitive function in hypertensive men aged 75 and older.

Screening for mild traumatic brain injury in the presence of psychiatric comorbiditie

	Arch Phys Med Rehabil. 2010 Jul;91(7):1082-6. Screening for mild traumatic brain injury in the presence of psychiatric comorbidities. Chapman JC, Andersen AM, Roselli LA, Meyers NM, Pincus JH. War Related Illness and Injury Study Center, Veterans Affairs Medical Center, Washington, DC, USA. Julie.Chapman@va.gov Abstract OBJECTIVE: To determine whether or not a battery of neurobehavioral tests, the Brief Objective Neurobehavioral Detector (BOND), could detect mild traumatic brain injury (mTBI) among a group of psychiatric inpatients with numerous substance-related and medical comorbidities. The 16-item BOND is comprised of neurologic examination tasks and has been shown to correlate with radiologic and cognitive findings in previous studies. DESIGN: Masked comparison. SETTING: Inpatient psychiatric unit at the Veterans Affairs Medical Center in Washington, DC. PARTICIPANTS: Patients (N=51) sequentially admitted for suicidal ideation in the context of various psychiatric disorders. INTERVENTIONS: No intervention. MAIN OUTCOME MEASURE: BOND total and subtest scores. RESULTS: Forty-three patients were eligible and analyzed. Twenty-seven had sustained an mTBI in the distant past, and 16 had never sustained a traumatic brain injury (TBI) (non-TBI group). On average, the mTBI group demonstrated a significantly greater number of abnormal subtests on the BOND (mean, 7.22) than did the non-TBI group (mean, 4.50; P=.003). Although the BOND significantly correlated with the presence of mTBI, it did not correlate with any of the psychiatric, substance-related, or medical comorbidities. Multiple regressions indicated that the BOND total score was not explained by age, posttraumatic stress disorder diagnosis, or any combination of the psychiatric, substance-related, or medical comorbidities. High rates of sensitivity (70%) and specificity (69%) were found. CONCLUSIONS: The results of this pilot study suggest that the inexpensive, brief, and objective BOND instrument may be a useful screening tool for the detection of subtle neurologic brain abnormalities after mTBI, even in the presence of substantial comorbidities.
	PMID: 20599047 [PubMed - indexed for MEDLINE]