Selegiline effects on cocaine-induced changes in medial temporal lobe metabolism and subjective ratings of euphoria.

To test the effect of selegiline, a specific monoamine oxidase B (MAO-B) inhibitor, on the cerebral metabolic and euphorigenic effects of cocaine in experienced users, eight cocaine-dependent (CD) subjects were evaluated using a within-subjects design. Each subject participated in two pairs of [F-18]-fluorodeoxyglucose (FDG)-positron emission tomography (PET) scans (baseline scan followed 24 h later by a second scan obtained in conjunction with a 40-mg cocaine infusion) performed before and after a 1-week period of daily treatment with 10 mg selegiline administered orally. The hippocampus and amygdala were evaluated because of their hypothesized involvement in the addiction process, and the thalamus was evaluated as a comparison region. Following 7 days of selegiline treatment, the magnitude of the subjective euphoria ("high") produced by cocaine infusion was reduced by 40% (cocaine by selegiline interaction F = 7.15, df = 1.21, p = .014). Selegiline treatment also altered glucose utilization (normalized against whole brain counts) in the two limbic regions, but not the thalamus. In the amygdala, the effects of cocaine differed, depending upon whether or not patients were being treated with selegiline (cocaine by selegiline interaction F = 4.67, df = 1,19.8, p = .043). A different effect was observed in the hippocampus, where selegiline treatment decreased metabolic activity irrespective of whether cocaine was given (main effect F = 7.70, df = 1.20, p = .012). The concomitant changes in both the subjective experience of the "high" and normalized amygdala glucose utilization after selegiline treatment, suggest that a relationship exists between cocaine-induced euphoria and limbic metabolism. The data suggest that selegiline may be a useful adjunct in the treatment of cocaine dependence.

Treatment of early AIDS dementia in intravenous drug users: high versus low dose peptide T.

This placebo-controlled, double blind, cross-over study tested the efficacy of two different doses of Peptide T in the treatment of nine intravenous drug users with early AIDS dementia who were also receiving methadone and AZT. Subjects received Peptide T doses of either 15 or 1.5 mg daily for four weeks. Neuropsychological performance improved in four of five patients treated with the high dose, but at the lower dose, three of four patients showed no improvement on Peptide T when compared with placebo. When subjects who received the high dose were compared with those who received the low dose, a significant dose effect was found only during the active phase of the trial even after correction for differences in level of functioning at baseline.

University of Southern California Repeatable Episodic Memory Test.

The University of Southern California Repeatable Episodic Memory Test (USC-REMT) was developed to provide a brief assay of memory in clinical drug trials where the same subject is tested multiple times over days or weeks. Therefore, it had to be minimally affected by repeated testing. The test also provides a measure of subjective organization, a cognitive strategy that might be sensitive to frontal lobe dysfunction and HIV-related memory deficits. The USC-REMT has seven different lists, each composed of 15 semantically unrelated, high-frequency nouns. The words are presented in a different order on three study-test trials. After each study trial the subject recalls the words in any order. The test takes about 10 min to administer and score. The recall protocol can be scored for (a) global mnemonic efficiency, (b) primary and secondary memory, (c) subjective organization, (d) recall consistency and (e) recall as a function of serial position. We report initial data showing that the test is sensitive to memory decrements. Thirty-six HIV-1 seropositive men, at various stages of illness, recalled significantly fewer words and exhibited less subjective organization than 14 matched controls. The test had no significant practice effects over the first three administrations when separated by several days. The seven alternate lists are essentially equivalent. The USC-REMT appears to complement currently published verbal memory tasks.

Results of extended peptide T administration in AIDS and ARC patients.

We report here the extended Phase I testing of d-ala-Peptide-T-amide (Peptide T) in open trial. The drug was given intravenously in doses ranging from 0.1 to 3.2 mg/kg/day to 14 acquired immunodeficiency syndrome (AIDS) and AIDS-related complex (ARC) patients for 12 weeks. Following a 4-week off-drug period, the first 6 patients finishing the intravenous testing were continued on intranasal drug, 25 mg/day, for 8 weeks. Control subjects were tested on the same neuropsychologic tests, but did not receive drug. Minimal evidence of toxicity was found. Performance increments in cognitive and neuromotor function were observed in patients with moderate neuropsychologic impairment compared with controls. Changes in constitutional symptoms included weight gain averaging 2 kg and reported improved sense of well-being. The latter findings were independent of variation in cognitive and neuromotor function. Measures of immunologic function and antiviral activity did not change significantly during the study. These data provide a scientific rationale for Phase II testing of Peptide T in human immunodeficiency virus-1 (HIV-1) patients focusing on neuropsychiatric outcome.

Pharmacokinetics of peptide T in patients with acquired immunodeficiency syndrome (AIDS).

1. The pharmacokinetics of Dala1-peptide T-NH2 (peptide T) was determined during phase I clinical trials in patients with acquired immunodeficiency disease (AIDS) and AIDS related complex (ARC). Drug levels were determined by specific RIA, and in some cases with HPLC analysis, after intravenous (i.v.) or intranasal (i.n.), via metered sprayer, administration. 2. The plasma kinetics appeared to be bi-phasic with a first compartment half-life of 30 to 60 minutes and a second plasma clearance rate of 4 to 6 hours, observed for both routes of administration. Peptide T, in one individual was confirmed to be present at 6 hrs in plasma, determined after HPLC isolation followed by specific RIA. 3. Bioavailability, determined for a 2 mg test dose in six individuals was 9.3 +/- 6.9 nmol/L. Peak plasma levels of 41 +/- 30 nmol/L after 10 mg i.n., 2.8 +/- 5.9 nmol/L after 2 mg i.n., and 0.13 +/- 0.07 nmol/L after 0.4 mg i.n. were observed. In two individuals tested, peptide T was detected in CSF at levels 20% of the corresponding plasma level 90 and 145 minutes post i.v. administration. Peptide T was not detected in urine. I.N. administration was well tolerated for times up to 21 months.

Central nervous system effects of human immunodeficiency virus type 1.

Following its early entry into the central nervous system (CNS), HIV-1 alters cerebral cell architecture and may subsequently affect higher cognitive functions, leading eventually in some patients to HIV-1 encephalopathy. The CNS may also be the target of opportunistic infections and malignancy secondary to HIV-1 immunosuppression. Studies at the cellular, anatomical, and behavioral levels present evidence for significant involvement of the CNS in HIV-1 disease, while initial reports of treatment strategies hold promise for providing some amelioration in affected individuals.

Neuropsychological effects of early HIV-1 infection: assessment and methodology.

Studies of neuropsychological performance early in the course of human immunodeficiency virus-type 1, infection are reviewed. The studies differed on reporting the presence and severity of neuropsychological changes, and comparisons among studies are hampered by variations in the study populations, sample sizes, assessment methods, approaches to data analysis, and definitions of thresholds for abnormality. Recommendations that would facilitate comparisons among future studies include using markers for disease state, applying longitudinal designs, using common instruments for assessing neuropsychological status, selecting appropriate controls, controlling for co-factors, reporting raw scores as well as presumed indices of impairment, and relating impairment on neuropsychological tests to affected individuals' daily activities, if possible.

Design and application of an expert system for mobile phase optimisation in reversed-phase liquid chromatography.

The selection of the optimum composition for the mobile phase in reversed-phase high-performance liquid chromatography (HPLC) is a complex task; conventional approaches require the expenditure of significant amounts of time by the analyst, particularly for complex mixtures of solutes of biological origin. Some of the existing strategies for the automated optimisation of mobile phase composition (e.g. Simplex), may fail if the elution order of the components changes; or they may require that standards be chromatographed in order to establish the retention behaviour of each component in a mixture (e.g. resolution mapping). These problems may be overcome if the retention behaviour of each individual solute can be established from the chromatogram of the mixture. In this regard, components can be tracked by exploiting the spectral information generated by a rapid scanning photodiode array detector. Unfortunately this information is often insufficiently detailed to allow an unambiguous model of retention behaviour to be constructed. The system developed by the Authors uses these spectral data as a basis for constructing one or more hypothetical retention models, each of which is refined or rejected as further information is obtained during the progress of the experiment. To improve the reliability of the retention models proposed by the system, the spectral data are utilised in a number of tests designed to assess the purity of each chromatographic peak. The information so generated may be used in conjunction with any previously acquired spectral data both to select an appropriate method for extracting spectra for each component from the matrix of (A, lambda, t) data and to establish reliability parameters for the resultant spectra. The development and philosophy of the expert system developed for eluent optimisation in reversed-phase HPLC is discussed.

Central catecholamines, cognitive impairment, and affective state in elderly schizophrenics and controls.

Central catecholamine concentrations were determined in autopsy samples from older schizophrenic and control subjects for both the hypothalamus and the nucleus accumbens. The results of these analyses and demographic variables were regressed on antemortem measures of cognitive function and mood state. In the hypothalamus, there are significant direct relationships of homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) with depressed mood, as measured by an adaptation of the Hamilton Rating Scale for depression. In the nucleus accumbens, dopamine (DA) and MHPG had significant inverse relationships with antemortem cognitive function, as measured by an adaptation of the Mini Mental State Exam. Results in this sample indicate that after controlling for age, the catecholamine concentrations accounted for approximately 50% of the variance in the antemortem measures of mood or cognition, depending on the loci measured.

Platelet monoamine oxidase activity: demographic characteristics contribute to enzyme activity variability.

In a large (n = 459) sample of adults free of psychiatric, neurologic, and endocrinologic disease, platelet monoamine oxidase activity was analyzed by multiple regression of the demographic variables age, race, and gender on enzyme activity. Reported here are variations for all three demographic variables such that significantly greater enzyme activity is seen in female, older, and white subjects relative to male, younger, and black subjects. For each demographic group the data demonstrated a curvilinear relationship of age and enzyme activity with a nadir of activity at age 30. For this sample enzyme activity nearly doubled between subjects at age 30 and at age 80. We believe this study to be the first to report racial differences in this enzyme activity and to analyze normative data for this enzyme by multiple regression techniques.

Postmortem central catecholamines and antemortem cognitive impairment in elderly schizophrenics and controls.

Central catecholamine concentrations were determined in autopsy brain samples from 19 elderly schizophrenic patients and controls. Data from the hypothalamus and nucleus accumbens demonstrate altered catecholamine metabolism associated with cognitive impairment in these subjects. Both loci show decrements of norepinephrine concentrations, while the nucleus accumbens samples also show increased dopamine, dihydroxyphenylacetic acid, and 3-methoxy-4-hydroxyphenylglycol concentrations associated with dementia in these subjects. The data argue for examination of catecholamine metabolism with respect to dementia in a broad range of elderly subjects.

Peripheral catecholamine enzyme function and cognitive impairment of elderly schizophrenics and controls.

Alterations of peripheral and central catecholamine systems are found in both schizophrenic and demented subjects. Reported here are the results of bivariate and multivariate analyses of cognitive function and peripheral catecholamine enzyme activities in a group of elderly schizophrenic patients and controls. The entire sample shows an inverse relationship of platelet monoamine oxidase (MAO) activity with cognitive impairment after controlling for the effects of age, race, and gender. Schizophrenic subjects also demonstrated an inverse relationship of plasma dopamine beta hydroxylase (DBH) activity with cognitive impairment. Demented subjects were characterized in both groups as having increments in platelet MAO activity. Demented schizophrenic subjects also were characterized by increments in plasma DBH activity. Results from this sample are discussed with respect to findings from other studies and future research.