Govind T. Vatassery

Vitamin E and memantine in Alzheimer's disease: Clinical trial methods and baseline data

Alzheimers disease (AD) has been associated with both oxidative stress and excessive glutamate activity. A clinical trial was designed to compare the effectiveness of (i) alpha‐tocopherol, a vitamin E antioxidant; (ii) memantine (Namenda), an N‐methyl‐D‐aspartate antagonist; (iii) their combination; and (iv) placebo in delaying clinical progression in AD.

Haloperidol Concentrations in Patients With Alzheimer's Dementia

To investigate the relationship between clinical response and haloperidol blood concentrations in Alzheimers dementia (AD) patients with behavior problems, 29 AD inpatients were assigned to a fixed oral dosage of haloperidol (0.5 mg, 1.0 mg, or 2.0 mg) every 12 hours for 3 weeks. BEHAVE-AD ratings and concentrations of plasma and RBC haloperidol and reduced haloperidol were obtained on Days 8, 15, and 22. Although no significant linear or curvilinear relationships were apparent between percent of change on BEHAVE-AD and plasma or RBC haloperidol concentrations, a good response (change ≥ 30%) was observed in 55% of the patients who entered the study.

Use of the sulfo-phospo-vanillin reaction in a routine method for determining total lipids in human cerebrospinal fluid

Adult human cerebrospinal fluid (CSF) was assayed for total lipid levels by the sulfo-phospho-vanillin color reaction. Lipids in a 1-2 ml sample of CSF are extracted with a 2:1 chlofoform-methanol mixture and the solvent extract, after equilibration with 0.74 percent potassium chloride, is evaporated to dryness. The lipid in the residue is estimated by the sulfo-phospho-vanillin reaction. The extraction process is essentially quantitative for lipid mixtures normally found in CF. The technique has an average coefficient of variation of 1.5 percent and the recovery of added lipids is nearly quantitative. It can be used as a rapid routine method for estimating CSF total lipids and several samples can be processed simultaneously. Estimations of total lipid levels using the sulfo-phospho-vanillin reaction agree quite well with the results obtained by densitometric quantitation of charred lipids. A preliminary analysis of 22 samples of adult human CSF containing normal levels of total protein gave an average total lipid level of 0.78 (+/- 0.07 SEM) mg/dl. Total lipid levels in CSF did not significantly correlate with age. However lipid levels in CSF show a significant positive correlation with CSF total protein levels.

Blunting of the neurotensin mRNA response to haloperidol in the striatum of aging rats: possible relationship to decline in dopamine D2 receptor expression

Neuroleptic drugs such as haloperidol (H) induce a rapid increase in neurotensin/neuromedin N (NT/N) gene expression in the dorsolateral striatum (DLSt) and nucleus accumbens (NA) in young adult rats. This effect may be mediated by post-receptor effectors that are activated by dopamine D2 receptor antagonism. The regional pattern of induction of neurotensin gene expression correlates with the side effect profile of particular neuroleptics. As motor side effects of H differ in aged animals, we hypothesized that the regional expression of the neurotensin gene may differ between young and old animals. We administered H or saline acutely to 3, 14, and 25 month-old Fischer 344 rats, followed by in situ hybridization and quantitative autoradiography for NT/N mRNA. There was a significant age effect on the H-induced NT/N mRNA response in the DLSt, but not the NA, of older animals. In addition to the blunted NT/N mRNA response, significant decreases in D2 receptor mRNA were observed in the lateral striatum of another group of young, middle-aged, and aged rats. Age-related blunting of the NT/N mRNA response to H in the DLSt may be due in part to a decrease in D2 receptors in this structure.

Deletion of apolipoprotein E gene modifies the rate of depletion of alpha tocopherol (vitamin E) from mice brains.

Our previous reports show that apolipoprotein E (apoE) influences the dynamics of alpha tocopherol (vitamin E) in brain. In this investigation, the patterns of depletion of alpha tocopherol from tissues of apoE deficient and wild type mice were compared after the animals were fed vitamin E deficient diets. Alpha tocopherol concentrations in specific regions of the brain and peripheral tissues at different times were determined by HPLC with electrochemical detection. ApoE deficiency significantly retarded the rate of depletion of alpha tocopherol from all regions of the brain. In addition, comparison of the rates of depletion of alpha tocopherol in both apoE deficient and wild type animals showed that cerebellum behaved differently from other areas such as cortex, hippocampus and striatum. This reinforces the uniqueness of cerebellum with regard to vitamin E biology. Patterns of depletion of tocopherol from peripheral tissues were different from brain. Serum tocopherol was higher in apoE deficient animals and remained higher than wild type during E deficiency. Depletion of liver tocopherol also tended to be unaffected by apoE deficiency. Our current and previous observations strongly suggest that apoE has an important role in modulating tocopherol concentrations in brain, probably acting in concert with other proteins as well.

Haloperidol decanoate pharmacokinetics in red blood cells and plasma.

Red blood cell (RBC) and plasma concentrations of haloperidol (H) and reduced haloperidol (RH) were determined in nine patients (five men, four women) who had been receiving monthly injections of haloperidol decanoate (HD) for at least 3 months. A very sensitive high performance liquid chromatography method was used to measure H and RH, which could be detected at levels as low as 0.1 ng/ml. Blood samples for H and RH were drawn at the end of weeks 1, 2, 3, and 4 of a 4-week cycle. Monthly HD dosages ranged from 50 mg to 200 mg. At each time point RBC H did not differ significantly from plasma H. RBC RH and plasma RH did not change significantly over time and were consistently lower than RBC H and plasma H. However, RBC RH levels were higher than plasma RH levels. Also, the ratios of RBC RH/H were higher than were the ratios of plasma RH/H, which reflect an accumulation of RH intracellularly. HD dosage was highly correlated with both RBC H and plasma H, but RBC RH and plasma RH were not significantly related to dosage at any time point. Significant correlations were observed between HD dosage and prolactin concentration at week 1 and between prolactin concentration and RBC H and plasma H at weeks 1 and 4. Blood concentrations of H and RH and the corresponding standardized areas under the curve were not significantly related to smoking.

Haloperidol and reduced haloperidol in saliva and blood

A total of 18 outpatients (17 male, 1 female) ranging in age from 36-66 years old were on a constant dosage of haloperidol in equally divided doses at 9:00 a.m. and 9:00 p.m. for at least 1 month. DSM-III-R diagnoses included schizophrenia (N = 9), schizoaffective disorder (N = 3), bipolar disorder (N = 4), organic mental disorder (N = 1), and delusional disorder (N = 1). Blood samples for steady-state concentrations of plasma and red blood cell haloperidol (H) and reduced haloperidol (RH) were drawn at 9:00 a.m. (12 hr trough). The haloperidol dosage was held at 9:00 a.m. until samples of whole saliva and parotid saliva could be collected for flow rates and concentrations of H and RH. Haloperidol dosages ranged from 1 mg/day to 60 mg/day (mean 11 +/- 15). Correlation coefficients were calculated for saliva concentrations versus blood levels and for saliva secretion rates versus blood levels. The correlations between whole saliva measures and blood concentrations were all higher than the correlations between parotid saliva measures and blood concentrations. In one case the higher correlation reached statistical significance. There was only one case in which substitution of saliva secretion rate improved the correlation between measures with saliva concentration. Our findings suggest that saliva measures of H and RH are useful alternatives to plasma concentrations in monitoring maintenance haloperidol treatment.

Comparison of manual methods of determination of albumin in human cerebrospinal fluid by the bromcresol green and immuno-precipitation methods

Simultaneous determinations of albumin concentrations in human cerebrospinal fluid were made by three different manual methods: bromcresol green dye-binding technique of Doumas et al., a modification of the latter with color measurement shortly after the addition of dye as proposed by Ingwersen and Raabo and finally by an immuno-precipitation technique. Results obtained by the immuno-precipitation method correlated significantly with the dye-binding method of Doumas et al., (r = 0.93) and the procedure of Ingmersen and Raabo (r = 0.94). Data from the two dye-binding techniques correlated significantly with one another also (r = 0.98). However, the immuno-precipitation technique gives albumin values lower than the dye-binding procedures. The latter presumably estimates other proteins which can also bind bromcresol green. The data corroborates the conclusions of earlier investigators that immuno-precipitation method is more specific for albumin assays.

P4-363: A randomized clinical trial of vitamin E and memantine in Alzheimer's disease

grees of hepatic impairment and in healthy control subjects. Methods: This study utilized an open-label, single-dose, parallel group design with six subjects in each cohort. Subjects were classified with mild hepatic impairment or moderate hepatic impairment based on the Child-Pugh Classification System. Control subjects were matched based on age and weight ranges. Each subject was admitted to the study center at least 12 hours prior to administration of a single 800mg tarenflurbil dose. Blood and urine samples were collected prior to dosing through 72 hours following dosing for pharmacokinetic and safety assessments. A blood sample was collected for CYP2C9 genotyping. Safety endpoints included adverse events, physical examinations, 12-lead electrocardiogram, vital signs, hematology, blood chemistry, and urinalysis. Results: The mean AUC(0) for control subjects was 539 203 hr* g/mL, whereas the values for subjects with mild or moderate hepatic impairment were 474 388 or 325 52 hr* g/mL, respectively. The difference was statistically significant when control subjects were compared to subjects with moderate impairment. Mean apparent oral clearance CL/F was statistically increased in mildly impaired subjects 2236 829 mL/hr/kg and in moderately impaired subjects 2512 384 mL/hr/kg compared to 1647 542 mL/hr/kg in subjects with normal hepatic function. A close inspection revealed that these differences were due to the occurrence of three control subjects with *3/wt genotype which is known to reduce clearance of CYP2C9 substrates. When subjects of similar genotype were compared, there were no significant differences. There were no apparent differences between groups in the extent of protein binding of the drug. Conclusions: Although tarenflurbil is extensively metabolized prior to excretion, no decrease in tarenflurbil clearance was observed in patients with mild or moderate hepatic impairment. Therefore, no dose adjustments should be required in treating individuals with mild or moderate hepatic impairment.