Disposition of 5-fluorouracil after intravenous bolus doses of a commercial formulation to cancer patients.

A high-pressure liquid chromatographic method that is used to determine the pharmacokinetic disposition of 5-fluorouracil from the plasma compartment is presented. The method requires only 0.5 ml of plasma for each determination and is sensitive to 0.1 mg of drug per liter. Novel methodology with the use of an ion-specific electrode technique for the determination of urinary excretion kinetics of 5-fluorouracil and its metabolites is also presented. This study demonstrated a much greater variability for the disposition of 5-fluorouracil by cancer patients than has been reported previously. The apparent volume of distribution for this drug varied more than 37-fold. Its plasma half-life varied more than 19-fold, and its urinary excretion half-life varied almost 400-fold. These data are compatible with the hypothesis that this variation could account, at least in part, for the variable therapeutic and toxic response to 5-fluorouracil. The methodology presented in this study is sufficiently simple and sensitive to allow assessment of this hypothesis by investigating cancer patients who receive therapeutic doses of 5-fluorouracil.

Application of automated REM analysis in depression.

Application of automated rapid-eye-movement (REM) analysis can characterize individual REM periods in depressed patients. Average REM count for the individual REM periods generally demonstrated considerable decreases in the second half of the REM period and differentiated patients who subsequently did not respond well to tricyclic antidepressants. These findings suggest that, even as late as six hours into a night of sleep, significant differences among depressed patients are present, based on treatment responder groups. Furthermore, a reevaluation of the previous emphasis on REM abnormalities in the first hour or two of the night may be indicated.

Distribution of REM latency in depression.

While shortened REM latency is now considered the most consistent sleep feature observed among patients suffering from primary depressive episodes, and one which has generated a variety of hypotheses regarding possible mechanisms, few studies have employed long-term longitudinal designs. In the present investigation, REM latency was examined in 22 hospitalized depressed patients who were studied nightly during a 5-week protocol were bimodally distributed medication during that period; REM latencies were bimodally distributed with peaks occurring shortly after sleep onset and again 30-40 min later. Very short REM latencies (less than or equal to 20 min) were neither uncommon nor isolated events and persisted over time in this patient sample. These findings are discussed in relation to findings on shortened REM latency in other study populations.

An automated analysis of REM sleep in primary depression.

The REM sleep of 23 nonpsychotic patients with primary depression was studied by means of an automated REM analyzer during a drug-free period and again during amitriptyline administration. Initial drug administration (50 mg) was associated with an immediate reduction in the number, average frequency, and average size of the rapid eye movements. The average REM size remained suppressed with continued drug administration while the average REM frequency showed a rebound which was responsible for a partial recovery of the number of REMs and total REM intensity to predrug levels. With regard to individual REM periods, REM frequency and REM intensity were redistributed during tricyclic administration so that the second REM period became more "intense" than the first REM period. This automated REM analysis technique provides an objective set of measures for characterizing discrete aspects of REM sleep during a depressive episode and for evaluating the changes in REM sleep during psychotropic trials.

Neuropsychological assessment and EEG sleep in affective disorders.

The neuropsychological test performance of 76 hospitalized, depressed patients meeting RDC for the presence of affective disorder was assessed as part of a protocol involving amitryptyline (n = 53) or placebo (n = 23). Tests included the Trail-making Test (TMT), the Benton Visual Retention Test, and the Shipley-Hartford Scale. Clinical ratings and data concerning the characteristics of EEG sleep were also obtained. Analysis of data collected after a drug-free period of 2 weeks and again at the end of the protocol yielded the following conclusions. Base-line performance was inferior to norms for these tests, but for the TMT, scores were not as poor as that expected for brain-damaged patients. Poor performance was often associated with older age, the presence of psychotic features, and prolonged sleep latencies. Baseline Hamilton Rating Scale (HRS) was predicted best by TMT part B. However, this association was not as strong as that between HRS and poor sleep efficiency. Treatment with drug or placebo had little differential effect upon test performance over the course of the protocol. It is suggested that further research should utilize tests which have specificity in localizing cerebral lesions, so that any focal deficits in brain function in depression might be identified.

EEG sleep, depression, and aging.

To date little attention has been paid to the possible age-dependent relationships of EEG sleep measures in depression or to the implications of such relationships for diagnostic sensitivity and specificity. In a study of 108 patients with major depressive disorders (67 inpatients, 41 outpatients), age was shown to be a very powerful determinant of electroencephalographic (EEG) sleep patterns. Thus, among other sleep variables, sleep efficiency, delta sleep percent, and REM latency all showed significant linear declines with increasing age. Similar trends were seen in both inpatients and outpatients. Some variables were without age trends (age-stable), including sleep latency, REM sleep percent, and REM activity. These findings confirm those of an earlier report from our laboratory [45] and suggest that age-corrected sleep variables can be developed for clinical diagnostic application. Thus, using normative data from Gillin et al. [19] for comparison, a sensitivity level of 65% for age-corrected REM latency was demonstrated, together with a specificity of 95% and a diagnostic confidence of 92%. Data from a pilot study comparing EEG sleep measures in depression and dementia are also presented; these data suggest the potential utility of EEG sleep measures in the differential diagnosis of these two disorders, especially in patients with mixed symptoms. Additional areas for further research are reviewed with enumeration of specific testable hypotheses.

Sleep and treatment prediction in endogenous depression.

The prediction of clinical response in depression has been based primarily on clinical symptoms and history. Recently, psychobiologic measures have been used to increase the accuracy of clinical prediction. In 34 drug-free patients with primary endogenous depression treated with amitriptyline, the application of EEG-monitored sleep criteria alone was more significant than clinical status alone in the prediction of clinical response. Prolonged REM latency and reduced difficulty in sleep onset following the administration of amitriptyline were the main sleep variables contributing to this prediction equation. These data suggest a strong relationship between clinical outcome and psychobiologic profile in patients with endogenous depression after a "pharmacologic probe" with a tricyclic antidepressant.

Effects of aging on EEG sleep in depression.

Many of the same electroencephalographic sleep measures which differentiate between normals and depressed patients have also shown differences among age groups within a normal population. The present study examines sleep measures in 87 inpatients with a major depressive syndrome, examining the specific sleep variables which are correlated with age between 18 and 60 years. REM latency shows a distinct decline with age, an effect not well demonstrated in normals. Thus, REM latency may differ from variables which measure aspects of awakening and which show a clear age trend in normal subjects. Since many sleep measures are greatly skewed or have truncated distributions, the present paper provides several alternative styles of measurement which allow comparisons to be made easily and also facilitate multivariate testing.

Electroencephalographic sleep recordings and depression in the elderly.

Eighteen patients over the age of 60 who were experiencing a major depressive episode were studied on a Clinical Research Unit after they had been drug-free for at least two weeks. All-night electroencephalographic (EEG) recordings revealed considerable fragmentation of sleep, a mean sleep efficiency of 58 percent, and very little delta sleep. The findings of reduced sleep time, shortened REM latency, and high REM density were similar to those in depressed patients under the age of 60. These preliminary findings support the application of EEG sleep recordings as a tool for the differential diagnosis of depression in the elderly.

Interactive effects of brain catecholamines and variations in sexual and non-sexual arousal on copulatory behavior of male rats.

In pargyline pretreated male rats, an intraventricular 6-hydroxydopamine procedure which resulted in subtotal brain catecholamine (CA) depletion produced a mild defict in copulatory behavior followed by rapid recovery. Challenges employed to study the behavioral capacities of these 'recovered' animals revealed: (1) a heightened sensitivity to acute treatment with the CA synthesis inhibitor alpha-methyl tyrosine (AMT) as reflected in a reinstatement and exaggeration of the original copulation deficit; (2) a greater dependence on the sexual eliciting properties of the female, since abolishing her soliciting behavior also reinstated and exaggerated the sexual dysfunction; and (3) a pattern of behavioral impairment indicating increased difficulty in both initiating sexual activity and maintaining copulatory performance. Furthermore, in males not copulating after 6-OHDA/AMT treatment, copulation could easily be induced by the simple application of a non-specific activating stimulus. On the basis of these data and parallel findings reported for other behaviors, we have concluded that: (1) both the initiation and maintenance of copulatory behavior in the male rat is the part dependent on normal functioning in one or more of the brain CA-containing systems; and (2) this copulatory deficit is symptomatic of a broader functional impairment reflecting reduced behavioral responsiveness to stimuli that normally elict appetitive or approach responses but not to stimuli requiring more automatic, inhibitory responses.

Electroencephalographic sleep findings in depressed outpatients.

We compared the electroencephalographic (EEG) sleep characteristics of 20 outpatients with those of 20 age-matched inpatients with major primary depressive disorders. Both groups showed similar patterns of sleep disturbance: reduced rapid eye movement (REM) sleep latencies, sleep efficiencies, and slow wave sleep. While the inpatients had greater REM activity in the first REM period than did the outpatients, both groups showed evidence of greater REM sleep time and REM activity during the first half of the night than do normals. The outpatients demonstrated a level of adaptation in that more REM sleep time and activity were present on night 2 than on night 1.

EEG sleep in outpatients with generalized anxiety: a preliminary comparison with depressed outpatients.

To develop further perspective on the psychophysiology of generalized anxiety disorder and primary depression, all-night electroencephalographic (EEG) sleep measures in outpatients with diagnoses of generalized anxiety disorder and primary (nondelusional) depression were compared. Both groups had difficulty initiating and maintaining sleep, and diminished amounts of slow-wave sleep. Compared to patients with generalized anxiety disorder, depressives had a shorter rapid eye movement (REM) latency, greater REM sleep percent and eye movement activity, and a different temporal distribution of REM sleep. Anxious patients showed few changes from first to second night, whereas depressives showed increases in several REM sleep indexes. The combination of REM sleep latency and REM percent correctly classified 86.7% of patients. These data may provide a more direct measure of central nervous system arousal and sleep/wake function than previous studies in the psychophysiology of anxiety. They also lend support to the clinical distinction between generalized anxiety disorder and primary depression and to the classification of anxiety states as disorders of initiating and maintaining sleep.

RBC and plasma choline levels in control and depressed individuals: a critical evaluation.

Red blood cell (RBC) and plasma choline (Ch) were measured in 78 depressed, drug-free patients and in 23 normal, drug-free control subjects. RBC Ch levels displayed a huge variability among the patients, in contrast to those measured in normal controls. Plasma Ch levels, on the other hand, were more consistent within each group, and were correlated with age among the two populations studied. RBC Ch levels would appear to be independent of plasma Ch levels, and to be highly individualized and reproducible within each subject. A segment of the depressed population exhibited significantly higher RBC Ch levels than those seen in the normal control population. A clinical correlation of RBC and plasma Ch levels within the depressed population indicated that the patients with RBC Ch levels exceeding 35 nmole/ml might represent a diagnostically distinct subpopulation with specific clinical characteristics. Results presented here, although preliminary, suggest a role for RBC Ch as a biological marker in certain categories of depressive illness.

Hydrolytic release, and identification by g.l.c.-m.s., of 3-deoxy-D-manno-2-octulosonic acid in the lipopolysaccharides isolated from bacteria of the Vibrionaceae.

The identification of the peracetylated methyl glycosides of 3-deoxy-D-manno-2-octulosonic acid (KDO) methyl esters was achieved by g.l.c.-m.s. These peracetylated methyl glycoside methyl esters were obtained from fully acetylated lipopolysaccharides and core oligosaccharides of representative strains of the Vibrionaceae family by the following sequence of mild reactions: acetolysis, methanolysis, and acetylation. KDO was shown to be present in all of the lipopolysaccharides (LPS), a result in direct contrast to the generally accepted view of the absence of this compound in LPS from this family of bacteria.

Structure of the core oligosaccharide in the lipopolysaccharide isolated from Aeromonas salmonicida ssp. salmonicida.

The core oligosaccharide isolated from the lipopolysaccharide of Aeromonas salmonicida ssp. salmonicida has been investigated by methylation analysis, NMR spectroscopy (13C and 1H), oxidation with periodate and chromium trioxide, and Smith degradation. The following structure is proposed: [Formula: see text]

Determination of plasma catecholamines in dogs after experimental gingival retraction with epinephrine-impregnated cord.

Blood catecholamine levels were determined by high-performance liquid chromatography after placement of the cord around two teeth in a random sequence of the following treatments: (1) untreated cord to intact gingival crevice (C), (2) epinephrine cord to intact crevice (E1), and (3) epinephrine cord to a crevice disrupted with a tapered diamond bur to simulate a subgingival procedure such as in crown preparation (E2). Each cord was left in place for 30 min while blood was drawn from the external jugular vein at 0, 5, 10, 20 and 30 min, and at 10 and 30 min after removal of the cord. Catecholamine values were compared to baseline (time 0) measurements. Treatment C resulted in no significant change in blood catecholamines. Treatment E1 caused a significant increase (p less than 0.01) in blood epinephrine levels, reaching a 641 per cent increase at 30 min. Treatment E2 produced a highly significant increase (p less than 0.001) in blood epinephrine with a greater than 5000 per cent increase 10 min after cord removal. Norepinephrine and dopamine levels were not significantly altered by any of the treatments.

Effect of enrofloxacin on digoxin clearance and steady-state serum concentrations in dogs.

The effect of enrofloxacin on the oral clearance and steady-state concentrations of digoxin in serum was evaluated in dogs. Digoxin was administered orally to six healthy adult Beagle dogs following a multiple-dose regimen of 0.0625 mg every 12 h for 23 days. From days 14 to 23 enrofloxacin was administered orally at a dosage of 2.5 mg/kg every 12 h, with subjects receiving enrofloxacin 2 h prior to digoxin. Trough serum concentrations of digoxin were measured using an immunoassay technique. On days 13 and 22, dogs were catheterized for multiple blood sample collection during the 12 h digoxin dosing interval and serum samples were analyzed for digoxin concentrations. In general, steady-state digoxin concentrations in trough serum were not significantly different during enrofloxacin treatment than before enrofloxacin administration. Similarly, digoxin oral clearance was not significantly different between pre-enrofloxacin and digoxin + enrofloxacin periods. We conclude that enrofloxacin is unlikely to have a significant impact on digoxin disposition in dogs.

Acute response of urine pH following ammonium chloride administration to dogs.

To test the acidifying ability of the distal portion of the nephrons in healthy dogs, 0.2 g of NH4Cl/kg of body weight was given PO. Samples for venous blood gas analysis and urine pH were taken hourly for 6 hours. Systemic acidemia developed, as evidenced by a statistically significant (P less than 0.05) decrease in blood pH 1 hour after NH4Cl administration. Four hours after administration, mean urine pH decreased to a low of 5.16 +/- 0.1 and was less than 5.5 3 hours after administration. Changes in urine pH 2 hours after administration were statistically significant (P less than 0.05). In human beings, NH4Cl loading is used to detect patients with distal renal tubular acidosis (defective hydrogen ion secretion by the distal nephrons) and normal acid/base values. Distal renal tubular acidosis is diagnosed if urine pH fails to decrease to less than 5.5 after NH4Cl administration. On the basis of the findings of this study, a similar value would be valid for dogs.

Urine-blood carbon dioxide tension gradient in healthy dogs.

The urine-blood carbon dioxide tension (PCO2) gradient was measured in 10 healthy mature Beagles after alkalinization of the urine by administration of sodium bicarbonate. The mean (+/- SD) urine-blood PCO2 gradient was 65.92 +/- 14.42 mm of Hg, with range of 38.2 to 82.2 mm of Hg. Mean urine PCO2 was 110.21 +/- 14.19 mm of Hg, with range of 84.1 to 127.3 mm of Hg. Because urine-blood PCO 2 gradient less than 30.0 mm of Hg or urine PCO2 less than 55 mm of Hg in people is diagnostic for a defect in distal nephron acidification, similar values might be applicable to diseases in dogs.

Relationship between urine ammonium ion excretion and urine anion gap in dogs.

Acidemia stimulates renal ammonia production and excretion. This adaptive response allows increased H+ secretion and generation of new bicarbonate. To determine whether a relationship existed between urine ammonium (NH4+) concentration and excretion and urine anion gap (Na+ + K(+)- Cl-), ammonium chloride (NH4Cl) was administered per OS for 5 days to induce systemic acidemia in 12 healthy Beagles. During NH4Cl administration, a strong, statistically significant (P less than 0.0001) relationship was apparent between urine NH4+ concentration measured in millimoles per liter and urine anion gap. Regression equation: urine [NH4+] = 8.2 - 0.416 x urine anion gap; r = -0.897. A statistically significant (P = 0.0001) relationship existed between urine NH4+ excretion measured in millimoles per kilogram of body weight per day and urine anion gap. Regression equation: urine NH4+ excretion = 0.74 - 0.38 x urine anion gap; r = -0.768. As urine NH4+ concentration or excretion increased, urine anion gap became more negative. Before NH4Cl administration (no systemic acidemia), a weak, but statistically significant (P = 0.015) relationship was observed between urine NH4+ concentration and urine anion gap. Regression equation: urine [NH4+] = 65.2 - 0.141 x urine anion gap; r = -0.41. However, a relationship was not evident between urine NH4+ excretion and urine anion gap before NH4Cl administration. Hence, urine anion gap is a reliable index of urine NH4+ concentration and excretion only in dogs with metabolic acidosis. In human beings with distal renal tubular acidosis, NH4+ excretion is inappropriately low and results in a positive urine anion gap.(ABSTRACT TRUNCATED AT 250 WORDS)