Pharmacokinetic and pharmacodynamic responses to chronic administration of the selective serotonin reuptake inhibitor citalopram in rats

The number of drugs used to treat affective disorders such as depression is rapidly increasing. Citalopram (CIT), an antidepressant, is a selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI). In the present study, rats were treated with 10 mg/kg/d racemic CIT for two weeks with use of osmotic pumps, and the following were monitored: open-field behavior, racemic and enantioselective concentrations of CIT and metabolites in blood, brain parenchyma, and extracellular space, and the brain extracellular monoamine levels. The racemic CIT concentration in serum was estimated about tenfold lower than in brain parenchyma but much higher than in brain extracellular fluid. The major CIT metabolites, demethylcitalopram (DCIT) and didemethylcitalopram (DDCIT) were 20% and 30%, respectively, of the amounts of CIT in serum and even lower in the brain parenchyma. The S-enantiomer/R-enantiomer ratios for CIT and DCIT were about 1.01 and 0.31, respectively, in blood and brain. There was a clear correlation between the different drug components within and between blood and brain compartments. Citalopram had no measured effect on open-field behavior, but it elevated extracellular 5-HT and decreased 5-HIAA levels. No correlations between any of the drug components and the brain monoamines were found. In summary, the drug components after chronic dosing correlated well between the periphery and the brain, but not with the brain monoamine concentrations. Further studies investigating the combined pharmacokinetic/dynamic effects could take advantage of blood drug monitoring for the commonly used novel antidepressant drugs.     

Altered adaptive behaviour expressed in an open-field paradigm in experimental hepatic encephalopathy

Chronic hepatic encephalopathy (HE) encounters a neuropsychiatric syndrome arising as a complication to liver dysfunction. Patients with chronic HE display a great variety of neuropsychiatric symptoms including such mental derangements as adaptational difficulty, and deteriorated learning and memory capacity. The portacaval shunt (PCS) in the rat is a widely used model for experimental chronic HE. In the present study, the adaptive capacity of unhabituated PCS rats and sham-operated control rats were studied by measuring two exploratory behaviours (locomotion and rearing) during 5 or 60 min, at four consecutive days or nights with 24 h between sessions. The results revealed that PCS and sham-operated control rats showed parallel behavioural outcome over the four sessions in the 5-min trial. However, at the four consecutive test sessions in the 60-min trials, the sham-controls displayed a continuing decrease in overall activity between sessions whereas the PCS rats evidenced a repeated and stable activity level. These results indicate a presence of a long-term habituation deficiency as exhibited by the PCS rats. Additionally, the results indicate that differences in normal open-field motor behaviour between PCS rats and controls may not be found if such tests are conducted repeatedly during night-time but may emerge when tested repeatedly during daytime. The results may also be interpreted as a possible impaired learning/memory capacity in PCS rats. However, further investigations of how the PCS procedure affects entities of adaptation and learning ability are needed before any conclusions may be drawn since this is the first report of such an impairment in experimental chronic HE when represented by the PCS rat.     

Inter-subject variability and normal limits of the SITA Standard, SITA Fast, and the Humphrey Full Threshold computerized perimetry strategies, SITA STATPAC.

PURPOSE: To establish and evaluate inter-subject variability and normal threshold limits for the new SITA strategies and to compare them with those obtained with the traditional Humphrey Full Threshold algorithm. METHODS: Data from 330 eyes of 330 normal subjects were collected at 10 centres in order to establish limits of normality for the new SITA strategies and thus, to make it possible to subject SITA fields to computer-assisted visual field analysis. Two visual field tests were obtained with each of the SITA Standard, SITA Fast, and the Full Threshold algorithms. RESULTS: Inter-subject variance was 31% smaller with SITA Standard and 41% smaller with SITA Fast than with Full Threshold (p<0.0001). Age-dependent decrease of differential light sensitivity was also significantly smaller with both SITA algorithms than with Full Threshold (p<0.0001), 23% and 25% respectively. Mean sensitivity was somewhat higher with both SITA Standard (29.5 dB) and SITA Fast (29.9 dB) as compared to Full Threshold (28.3 dB) (p<0.0001). Normal limits were tightened between 9 to 29% at different significance levels with SITA. CONCLUSION: SITA test results from eyes with normal visual fields will on average be more even from centre to mid-periphery as compared with Full Threshold fields. They will also appear slightly lighter in grey-scale representations. Because of smaller inter-subject variance, shallower depressions are needed in SITA fields for statistical and clinical significance.     

Comparing significance and magnitude of glaucomatous visual field defects using the SITA and Full Threshold strategies.

PURPOSE: To evaluate and compare visual field test results as presented by the Statpac interpretation tools in tests obtained with the new short SITA Standard and the even shorter SITA Fast strategies to the traditional Humphrey Full Threshold strategy. SUBJECTS AND METHODS: One eye of each of 44 glaucoma patients was examined four times with each of the Humphrey SITA Standard, SITA Fast, and Full Threshold strategies. Another 21 eyes of 21 normal subjects had one eye examined once with each of the three strategies. RESULTS: Average light sensitivity was highest with the shortest SITA Fast strategy and lowest with the longest Full Threshold strategy. Magnitude of field loss as defined by the Statpac Mean Deviation (MD) did not differ between the three strategies. In the glaucoma patients, both SITA strategies showed larger number of significantly depressed points in Statpac probability maps than the Full Threshold strategy. In the normal subjects SITA Standard showed more significantly depressed points, close to the statistically expected number, at the lowest probability level (p<5%) than both Full Threshold and SITA Fast. At higher probability levels (p<1%) SITA Standard and Full Threshold showed similar numbers of significantly depressed points. CONCLUSION: Both SITA Standard and SITA Fast identified at least as much significant glaucomatous field loss as the Full Threshold using the Statpac interpretation tools.     

Optic nerve head sector analysis recognizes glaucoma most effectively around disc poles

PURPOSE: To analyze the topography of normal and glaucomatous discs with the goal of developing improved strategies to discriminate between normal and glaucomatous eyes. SUBJECTS AND METHODS: Raster tomography was performed in both eyes of 225 healthy subjects and in 296 eyes of 214 glaucoma patients. Cup area, average cup radius, rim area and minimal rim width were measured in 24 sectors around the optic nerve head at nine different depths from the reference plane. Receiver Operating Curves (ROC) for numerous combinations of parameter, sector and depth were calculated and compared. RESULTS: Discrimination between glaucomatous and normal eyes varied widely between single sectors of the optic disc, and was best at the vertical poles of the disc, intermediate in nasal sectors and worst in temporal sectors. When single sectors or combinations of sectors at the superior pole were combined with their counterparts at the inferior pole of the optic nerve, the gain in sensitivity exceeded the loss in specificity, and discrimination improved. Separation declined dramatically if any of the 8 temporal sectors were involved in such analysis. Depth influenced discrimination only slightly. CONCLUSION: Single sectors located close to the vertical meridian yielded better discrimination than global measurements. When two or more sectors at the superior pole were combined with each other, as well as with their counterparts at the inferior pole, discrimination improved even further. Localized changes concurred frequently, but asymmetrically at both poles of the disc. The depth from reference plane used to define the cup was not critical for separation between normal and glaucomatous eyes.     

Sleep disturbances,nightmares and other possible central nervous disturbances in a population sample of women,with special reference to those on antihypertensive drugs

Summary Of 1302 women aged 44–66 years in a population study in Göteborg, Sweden, in 1974–75, who were representative of women of all the ages studied in the area, 165 were taking antihypertensive drugs, mostly -blockers and diuretics. The prevalence of sleep disturbances, nightmares, tiredness and melancholia or depression was studied in the total population sample, and a comparison was made between women who were or were not taking antihypertensive drugs. In the entire population sample no significant difference was found between the various age strata studied, although with increasing age there was a trend towards fewer complaints of nightmares, but a larger number of sleep disturbances as a whole. No difference was found between women taking or not taking various types of single-drug therapy or combinations of antihypertensive drugs.     

A population based screening of abdominal aortic aneurysms (AAA)

The prevalence of abdominal aortic aneurysm (AAA) in a defined population of elderly men and its correlation to some risk factors were studied in the population cohort "men born in 1914 from Malm?". A total of 499 were invited to attend and 375 (75%) did so. The aorta could be visualised with ultrasound in 364 patients, 39 (10.7%) of whom had aneurysmal changes. The presence of an AAA was related to the findings at a general health examination undertaken 5 years previously. Tobacco and alcohol consumption, impaired lung function and a history of angina pectoris were related to the presence of an AAA. No relationship was found between an AAA and hypertension, hyperlipidaemia or hyperglycaemia. A decreased tissue elasticity as a common denominator for the lung function impairment and development of AAA is discussed.     

Automatic perimetry in a population survey

Automatic perimetry was performed in 2998 eyes of 1511 subjects comprising 78% of all persons born 1907--1921 and resident in a certain small area. Unreliable or abnormal tests were repeated. The average number of tests per person was 2.25. About 90% of all tests in normal eyes were performed in less than 3 min. The screening was considered negative in 2887 eyes, incomplete in 20 eyes and positive in 91 eyes (3%). Eighteen of the positives were previously unknown glaucomatous defects. There was only one unexplained "false positive". We concluded that the method is quick, sensitive, specific and dependable. The apparatus is simple to manage and cheap to run.     

Increased proportions of B cells with spontaneous production of interleukin‐10 in HIV‐infected individuals are normalized during combination antiretroviral therapy: a longitudinal study

Interleukin‐10 (IL‐10)‐producing B cells (B10 cells) may inhibit HIV‐specific T cells and are elevated in untreated HIV infection. We aimed to determine the effect of combination antiretroviral treatment (cART) on the proportion of B10 cells. Furthermore, we compared B10‐cell proportions in HIV‐infected progressors and viremic controllers. This was a prospective study including HIV‐infected progressors, viremic controllers and healthy controls. Progressors initiating cART were followed for 6 months. Purified B cells were stimulated with CpG, alone or in combination with HIV gp120, and the proportion of B10 cells was measured by flow cytometry. Without stimulation, the B10‐cell proportion was higher in progressors than in healthy controls, while viremic controllers and healthy controls had comparable proportions. Moreover, the proportion of CD24^hiCD38^hi transitional B cells was higher in progressors than in healthy controls. After initiation of cART, the proportion of B10 cells and transitional B cells decreased. In conclusion, progressors had elevated B10‐cell proportions, while viremic controllers displayed normal proportions. After initiation of cART, the B10‐cell proportion decreased. This could limit B10‐cell‐mediated suppression of specific CD8⁺ T‐cell responses.