Dr. Walovitch is chief medical officer of WorldCare Clinical. Prior to joining WCC, he served as the senior vice president of clinical research at Acusphere, Inc., vice president of preclinical and clinical research at Epix Medical, and research pharmacologist and project clinician in the Imaging Agent Group at the DuPont Merck Pharmaceutical Company. Walovitch has a doctorate in pharmacology from the University of Illinois Medical Center and a bachelor’s degree in biology from the University of Illinois. He is an author of more than 100 peer-reviewed publications, mostly in the field of medical imaging.
Yes, tangible strides have been made for both Alzheimer’s disease and other CNS Drugs. Two examples follow:
1) For Alzheimer’s disease, tangible strides were made as early as the year 2000. Cerebral histamine H1 receptor binding was measured in vivo in 11 normal subjects (six young and five old) and 10 patients by positron emission tomography (PET) and [11C]doxepin, a radioligand for H1 receptors (Higuchi et al., 2000, Ref. 1). The parametric images describing the tracer kinetics were generated by either compartmental or graphical analysis. Images were examined statistically on region-of-interest and voxel-by-voxel bases. The binding potential of H1 receptors showed a significant decrease particularly in the frontal and temporal areas of the Alzheimer’s disease brain compared to the old, normal subjects. In addition, the receptor binding correlated closely to the severity of Alzheimer’s disease assessed by the Mini-Mental State Examination score within several brain areas. The ratio of K1 values between the brain areas and the cerebellum was used as a relative measure of regional cerebral blood flow which decreased in the frontal and temporal areas of the Alzheimer’s disease brain. However, the difference in the binding potential (i.e., the total concentration of receptor/equilibrium dissociation constant) between the Alzheimer’s disease patients and the old, normal subjects was greater than that in the cerebral blood flow, and the rate of decrease in the binding potential with the progression of Alzheimer’s disease was greater than the rate of decrease in the cerebral blood flow.
This study demonstrated a predominant disruption of the histaminergic neurotransmission in the neurodegenerative processes of Alzheimer’s disease. This study suggested that the decline of the histamine receptor binding might play a substantial role in the cognitive deficits
of Alzheimer’s disease patients
2) For CNS drugs, tangible strides were made as early as 2001 (Tagawa et al., 2001, Ref. 2). Sedative characteristics are well-known in clinical and over-the-counter (OTC) medications. Sedation is caused by their penetration into CNS through the blood-brain barrier and the consequent occupation of histamine H1-receptors. The binding potential of doxepin (BP=Bmax/Kd) for available brain H1-receptors was imaged on a voxel-by-voxel basis through graphical analysis. By setting regions of interest, the H1-receptor occupancy of drugs was calculated in several H1-receptor rich regions.
This study demonstrated the possibility of predicting H1-receptor occupancy by (+)-chlorpheniramine from its plasma concentration.
1) M. Higuchi, K. Yanai, N. Okamura, K. Meguro, H. Arai, M. Itoh, R. Iwata, T. Ido, T. Watanabe and H. Sasaki. Histamine H1 receptors in patients with Alzheimer’s disease assessed by positron emission tomography. Neuroscience Volume 99, Issue 4
2) M.Tagawa, M. Kano, N. Okamura, M. Higuchi, M. Matsuda, Y. Mizuki, H. Arai, R. Iwata, T. Fujii, S. Komemushi, T. Ido, M.i Itoh, H. Sasaki, T. Watanabe, and K. Yanai. Neuroimaging of histamine H1-receptor occupancy in human brain by positron emission tomography (PET): A comparative study of ebastine, a second-generation antihistamine, and (+)-chlorpheniramine, a classical antihistamine. Br J Clin Pharmacol, 52, 2001, pp. 501-509.