The effect of food on cabergoline pharmacokinetics and tolerability in healthy volunteers

The effect of food on the pharmacokinetics and tolerability of cabergoline in man was investigated. For this purpose an open, randomized, single-dose study was conducted in 12 healthy male volunteers who received 1 mg cabergoline as tablets both under fasting conditions and after a breakfast containing a substantial amount of carbohydrates, fat, and proteins, in a crossover fashion. The two treatments were separated by a 4 week washout period. Plasma and urine were collected up to 336 and 168 h respectively after administration and cabergoline concentration was measured in both fluids using a validated radioimmunoassay. Tolerability assessment included haematology, blood chemistry, and urinalysis, blood pressure and heart rate measurements, and ECG. Under both fasting and fed conditions low but persistent cabergoline plasma levels were observed in the present study up to 2 weeks after drug intake, in agreement with the long-lasting prolactin-lowering activity of the drug. In subjects receiving cabergoline under fed or fasting conditions, Cmax values averaged 44 and 54 pg mL(-1), AUC(0-336 h) averaged 6392 and 5331 pg h mL(-1), Ae(0-168 h) averaged 12.7 and 11.9 micrograms, and t1/2 averaged 109.7 and 101.3 h, respectively. No statistically significant difference was found when Cmax, AUC(0-336 h), t1/2, and Ae(0-168 h) from subjects treated under fasting and fed conditions were compared. Median tmax values in subjects treated under fasting or fed conditions were identical (2.5 h). The statistical analysis applied to the parameters chosen to evaluate the variations in the blood pressure profiles observed either supine or standing did not show any significant difference between the fed and fasting conditions. Heart rate values were not significantly modified after cabergoline under either fed or fasting conditions. Laboratory evaluation showed some minor deviations from normal, which were not clinically relevant (only one subject showed an occasional and transient elevation in alkaline phosphatase which disappeared in the subsequent laboratory evaluations) and were considered for the most part not to be drug related. Eleven subjects reported adverse events (one after both treatments, five only after drug intake under fasting conditions, and five only after drug intake with food.     

Distinguishable patterns of connectivity in serum immunoglobulins from SLE patients and healthy individuals

Given that normal individuals maintain significant levels of serum autoantibodies that share many characteristics with those found in association with autoimmune diseases (AID), it has been proposed that disease could result from defects in supraclonal regulation, namely deviations of normal patterns of immunoglobulin (Ig) connectivity. Using conventional methods, together with a recently developed technique to quantitatively score a variety of V-region-dependent serum IgG interactions, the authors have now compared serum Ig connectivity in a group of patients with systemic lupus erythematosus (SLE) to healthy controls. The results demonstrate the existence of V-region interactions of serum IgG and IgM in SLE patients and healthy donors, with comparable connectivity titres, diversity and average affinities (microM range), but a wider individual variation and a tendency for higher F(ab')2 directed reactivities in the group of SLE patients. Multivariate statistics analysis of the data derived from reactivity patterns on F(ab')2 subsets, however, distinguished the two groups of donors, and demonstrated a larger dispersion and wider time-dependent variations in the patient population, as compared to healthy controls. The authors conclude that SLE is associated with circulating antibody repertoires that deviate from the patterns and levels of V-region connectivity characteristic of healthy individuals. These findings may shed light on the mechanisms of disease maintenance, and on the basis for the therapeutic effects of normal polyclonal Igs at high doses.     

Lack of effect of olanzapine on the pharmacokinetics of a single aminophylline dose in healthy men

STUDY OBJECTIVE: To test whether olanzapine, an atypical antipsychotic, is an inhibitor of cytochrome P450 (CYP) 1A2 activity, we conducted a drug interaction study with theophylline, a known CYP1A2 substrate. DESIGN: Two-way, randomized, crossover study. SETTING: Clinical research laboratory. SUBJECTS: Nineteen healthy males (16 smokers, 3 nonsmokers). INTERVENTIONS: Because the a priori expectation was no effect of olanzapine on theophylline pharmacokinetics, a parallel study using cimetidine was included as a positive control. In group 1, 12 healthy subjects received a 30-minute intravenous infusion of aminophylline 350 mg after 9 consecutive days of either olanzapine or placebo. In group 2, seven healthy subjects received a similar aminophylline infusion after 9 consecutive days of either cimetidine or placebo. MEASUREMENTS AND MAIN RESULTS: Concentrations of theophylline and its metabolites in serum and urine were measured for 24 and 72 hours, respectively. Plasma concentrations of olanzapine and its metabolites were measured for 24 hours after the next to last dose and 168 hours after the last olanzapine dose. Olanzapine did not affect theophylline pharmacokinetics. However, cimetidine significantly decreased theophylline clearance and the corresponding formation of its metabolites. Urinary excretion of theophylline and its metabolites was unaffected by olanzapine but was reduced significantly by cimetidine. Steady-state concentrations of olanzapine (15.3 ng/ml), 10-N-glucuronide (4.9 ng/ml), and 4'-N-desmethyl olanzapine (2.5 ng/ml) were observed after olanzapine 10 mg once/day and were unaffected by coadministration of theophylline. CONCLUSION: As predicted by in vitro studies, steady-state concentrations of olanzapine and its metabolites did not affect theophylline pharmacokinetics and should not affect the pharmacokinetics of other agents metabolized by the CYP1A2 isozyme.     

Isotope effect in the binding of tritium and 14C-labelled cortisol to corticosteroid-binding-globulin in serum

We have determined the free cortisol concentration in serum using either the Amicon MPS-1 ultrafiltration-centrifugation method (I) or equilibrium dialysis (II). If procedure I was used we found that [1,2,6,7-3H]-, and [4-14C]cortisol had a lower affinity than unlabelled cortisol for corticosteroid binding globulin (CBG). The binding affinity (Ka) to three separate CBG-containing samples was 8-18 times lower for [1,2,6,7-3H]cortisol and 30-90 times lower for [4-14C]cortisol, when compared with that of unlabelled cortisol. This difference in affinity to CBG was not observed if method II was used for the free cortisol determinations. The observed isotope effect in method I is not caused by unspecific binding to material such as the Amicon MPS-1 chamber or to impurities in the tracer. We suggest that the centrifugation step during ultrafiltration changed the conformation of CBG, thereby reducing its affinity for labelled cortisol. It is concluded that incorrect results will be obtained if radiolabelled is cortisol used for determining the free cortisol content of plasma with the Amicon MPS-1 device.     

Investigations on the pharmacokinetics of alpha-lipoic acid in healthy volunteers

Recent medical publications postulate a connection between the Chronic Fatigue Syndrome (CFS) and disturbed regulation of the circulation, manifesting itself during orthostatic stress testing. Four studies were published on the circulatory response on prolonged head up tilt testing. Numerous CFS patients displayed postural tachycardia or syncope during the test. However, many CFS patients examined had had orthostatic symptoms prior to the examination. It is not certain that cardiovascular dysregulation is present in CFS patients without orthostatic symptoms. It is also not clear whether such a dysregulation would be the effect of physical inactivity or a manifestation of a subtle form of autonomic neuropathy.     

Peripheral and central pharmacokinetics of apomorphine and its effect on dopamine metabolism in humans

Apomorphine is a dopamine receptor agonist increasingly used in the treatment of Parkinson's disease (PD). In the present study, we examined the plasma and ventricular cerebrospinal fluid (CSF) pharmacokinetics of apomorphine as well as its effects on dopamine metabolism in six patients (one woman and five men, mean age 79.5 years) without evidence of PD who underwent 48-h intracranial pressure monitoring for suspected normal pressure hydrocephalus. Maximal plasma apomorphine concentration (25.04 ng/ml) is found 20 min after subcutaneous injection (50 micrograms/kg), and the mean area under the curve is 1,439.37 ng/ml for 120 min. In contrast to plasma values, the maximal ventricular CSF apomorphine concentration (1.08 ng/ml) is found 30 min after injection and the mean area under that curve is 7% of that of plasma (96.69 ng/ml for 120 min). Apomorphine administration causes a significant reduction in ventricular CSF concentrations of dopamine and of its major metabolites sulfoconjugated dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA). This effect starts 10 min after the injection of apomorphine, is maximal after 30 min (free dopamine, -30%; sulfoconjugated dopamine, -28%; HVA, -21%; DOPAC, -31%) and is still present, although to a lesser extent (-5 to -10%), 120 min after the injection of apomorphine. This study shows that in humans a dose of apomorphine commonly used in PD causes significant inhibition of dopamine metabolism lasting > 120 min. In addition to their symptomatic effects, dopamine agonists such as apomorphine may play a role in preventing or slowing the neurodegeneration in PD by autoreceptor-mediated inhibition of dopamine metabolism.     

Effects of terbinafine on the pharmacokinetics of digoxin in healthy volunteers

STUDY OBJECTIVE: To assess the potential effects of terbinafine, a new synthetic allylamine antifungal agent, on the pharmacokinetics of a single 0.75-mg oral dose of digoxin. DESIGN: Randomized, double-blind, placebo-controlled, crossover study consisting of two treatment periods. SUBJECTS: Sixteen healthy men and women volunteers. INTERVENTIONS: During treatment A, placebo was administered once/day for 12 days; during treatment B, terbinafine 250 mg was administered orally once/day for 12 days. The washout period between treatments was at least 2 weeks. A single 0.75-mg oral dose of digoxin was administered on day 8 of each period. Blood samples were collected after administration of digoxin to determine pharmacokinetics. MEASUREMENTS AND MAIN RESULTS: Compared with placebo, terbinafine did not alter the time course of the digoxin serum levels. Although the time to maximum peak concentration with terbinafine was slightly reduced, the maximum concentration and area under the serum drug concentration-time curve from time zero to 120 hours were not significantly different with terbinafine than with placebo. No drug-related side effects were reported with either active treatment, and no clinically significant changes in vital signs, physical examination results, electrocardiograms, or clinical laboratory results were observed. CONCLUSIONS: No special dosage adjustments for digoxin appear to be necessary during concomitant therapy with terbinafine.     

Association of low C2 and C4 serum levels with the HLA-DW2 allele in healthy individuals

HLA typed unrelated healthy individuals (HLA-DW2 positive n = 64, and HLA-DW2 negative n = 72) were investigated for their C2 functional activity and C4 serum protein levels. For the C2 and C4 levels a bimodal distribution was found in HLA-DW2 positive and HLA-DW2 negative individuals. HLA-DW2 positive persons had a significantly higher incidence of low C2 and C4 serum levels. Our data support the concept that genes governing C2 as well as C4 serum levels are in linkage disequilibrium with the HLA-DW2 allele of the major histocompatibility complex.     

Effect of terbinafine on theophylline pharmacokinetics in healthy volunteers

Twelve healthy volunteers were enrolled in an open-label, randomized, crossover study. Subjects received single doses of theophylline (5 mg/kg) with and without multiple-dose terbinafine, and 11 blood samples were collected over 24 h. The study phases were separated by a 4-week washout period. Theophylline serum data were modeled via noncompartmental analysis. When the control phase (i.e., no terbinafine) was compared to the treatment phase (terbinafine), theophylline exposure (the area under the serum concentration-time curve from time zero to infinity) increased by 16% (P = 0.03), oral clearance decreased by 14% (P = 0.04), and half-life increased by 24% (P = 0.002). No significant changes in other theophylline pharmacokinetic parameters were evident.     

The relationship between free and total hydroxyproline concentration in blood serum and urinary excretion of hydroxyproline in healthy individuals

The quantitative measurement of the IgG subclass composition of the sera from sixteen patients with cystic fibrosis has revealed grossly elevated levels of IgG4 in seven patients. The possible significance of this observation is discussed in relation to recent reports of a high incidence of immediate-type hypersensitivity in such patients.     

Comparative pharmacokinetics of cefamandole, cephapirin, and cephalothin in healthy subjects and effect of repeated dosing

Studies on cyclic activity of the thyroid and seasonal variations in oxygen consumption (VO2) under experimental conditions in which surfacing was either allowed or prevented were made in H. fossilis to try to establish a relationship between these measures and to ascertain the possible role of the thyroid in the regulation of metabolic rate. A good correlation was found between the activity of the thyroid and VO2 in this species. This finding was further confirmed by the administration of L-thyroxine or thiouracil to this fish. The thyroxine-and thiouracil-treated animals showed significantly higher (P less than 0-05) and lower (P less than 0-01) rates of VO2 respectively, thus indicating the probable role of the thyroid in the regulation of metabolic rate.     

Interphase analysis of X-aneuploidy using fluorescent in situ hybridization in various tissues of healthy individuals]

We hypothesized that in patients with chronic heart failure mesenteric venous congestion leads to increased bowel permeability, bacterial translocation, and thereby endotoxin release; the increased endotoxin challenge then causes immune activation with increased soluble CD14 levels and tumor necrosis factor (TNF)-alpha production. Patients with high soluble CD14 levels (indicative of endotoxin-cell interaction) have markedly increased plasma levels of TNF-alpha, soluble TNF receptors 1 and 2, and intracellular adhesion molecule-1, supporting this hypothesis.     

Acute exposure to mercury from amalgam: no short-time effect on the peripheral blood lymphocytes in healthy individuals

Mercury, released from dental amalgam, has been considered to adversely affect the human immune system. This study has been performed in order to evaluate if an acute low-dose mercury exposure, achieved by total amalgam removal in 10 healthy individuals, would affect the immunocompetent cells in human blood when the mercury level in blood and plasma was increasing. Induction of lymphocyte proliferation, measured as spontaneous de novo DNA synthesis, and total T cells, CD4+ T cells, CD8+ T cells, and B cells, was studied prior to and 7, 31, and 48 h after amalgam removal. In addition, the levels of interleukin-6 (IL-6) and C-reactive protein (CRP) in serum/plasma were measured. Despite a significant increase of the plasma mercury levels within 24 h after intervention, no significant influence on the peripheral blood lymphocytes could be detected during the first 48 h. The serum IL-6 levels increased significantly within 48 h after intervention, but were still low and within normal range. No influence on the CRP levels up to 7 d after amalgam removal was detected.     

Kinetics of dodecanedioic acid and effect of its administration on glucose kinetics in rats

Dodecanedioic acid (C12), a saturated aliphatic dicarboxylic acid with twelve C atoms, was given as an intraperitoneal bolus to male Wistar rats, with the aim of evaluating C12 suitability as an energy substrate for parenteral nutrition. The 24 h urinary excretion of C12 was 3.9% of the administered dose. C12 kinetics were investigated by a one-compartment model with saturable tissue uptake and reversible binding to plasma albumin. The analysis of plasma concentration and urinary excretion data from different animals yielded the population means of the kinetic parameters: renal clearance was 0.72 ml/min per kg body weight (BW) (much smaller than inulin clearance in the rat), and maximal tissue uptake was 17.8 mumol/min per kg BW corresponding to 123.7 J/min per kg BW. These results encourage the consideration of C12 as a possible substrate for parenteral nutrition. To investigate the effect of C12 administration on glucose kinetics, two other groups of rats, one treated with an intraperitoneal bolus of C12 and the other with saline, were subsequently given an intravenous injection of D[-U-14C]glucose in a tracer amount. Radioactivity data of both control and C12-treated rats were analysed by means of a two-compartment kinetic model which takes into account glucose recycling. The estimates of glucose pool size (2.3 mmol/kg BW) and total-body rate of disappearance (82.1 mumol/min per kg BW) in control rats agreed with published values. In C12-treated rats, the rate of disappearance appeared to be reduced to 36.7 mumol/min per kg BW and the extent of recycling appeared to be negligible.     

Lack of effect of food on the steady state pharmacokinetics of BMS-181101, an antidepressant, in healthy subjects

An annual atmospheric pollen survey was performed for 14 consecutive years in the autumn at Sakado city, Saitama prefecture. The survey was performed on the transition of pollen dispersion of major allergen plants: ragweed (Ambrosia spp.), Humulus japonicus, Artemisia spp. and Gramineae. 1. Annual total pollen count of ragweed showed marked increases beginning from 1991. Total pollen count in 1991 was 8.8 times and that in 1996 was 18.6 times that in 1983. This increase is probably caused by marked proliferation of giant ragweed which is left without mowing as it is on a dry riverbed, and consequently produces much more pollen than short ragweed. 2. Annual increases in total pollen counts of other major plants which disperse their pollen in the same season as ragweed were 0.95 times in 1991 and 0.5 times in 1996 that in 1983 for Humulus japonicus, 0.68 times in 1991 and 1.5 times in 1996 that in 1983 for Artemisia spp. and 1.3 times in 1991 and 1.4 times in 1996 that in 1983 for Gramineae. None of these species showed a marked increase of pollen dispersion although they showed some annual variation. The above findings suggest that changes in the proliferous state of various allergenic plants due to environmental change should be considered with respect to characteristics of pollen allergy.     

The effect of live measles vaccines on serum vitamin A levels in healthy children

In chordate phylogeny, changes in the nervous system, jaws, and appendages transformed meek filter feeders into fearsome predators. Gene duplication is thought to promote such innovation. Vertebrate ancestors probably had single copies of genes now found in multiple copies in vertebrates and gene maps suggest that this occurred by polyploidization. It has been suggested that one genome duplication event occurred before, and one after the divergence of ray-finned and lobe-finned fishes. Holland et al., however, have argued that because various vertebrates have several HOX clusters, two rounds of duplication occurred before the origin of jawed fishes. Such gene-number data, however, do not distinguish between tandem duplications and polyploidization events, nor whether independent duplications occurred in different lineages. To investigate these matters, we mapped 144 zebrafish genes and compared the resulting map with mammalian maps. Comparison revealed large conserved chromosome segments. Because duplicated chromosome segments in zebrafish often correspond with specific chromosome segments in mammals, it is likely that two polyploidization events occurred prior to the divergence of fish and mammal lineages. This zebrafish gene map will facilitate molecular identification of mutated zebrafish genes, which can suggest functions for human genes known only by sequence.     

Effect of grapefruit juice on the pharmacokinetics of microemulsion cyclosporine and its metabolite in healthy volunteers: does the formulation difference matter?

BACKGROUND: A number of automated devices for pretransfusion testing have recently become available. This study evaluated a fully automated device based on column agglutination technology (AutoVue System, Ortho, Raritan, NJ). STUDY DESIGN AND METHODS: Some 6747 tests including forward and reverse ABO group, Rh type and phenotype, antibody screen, autocontrol, and crossmatch were performed on random samples from 1069 blood donors, 2063 patients, and 98 newborns and cord blood. Also tested were samples from 168 immunized patients and 53 donors expressing weak or variant A and D antigens. Test results and technician times required for their performance were compared with those obtained by standard methods (manual column agglutination technology, slide, semiautomatic handler). RESULTS: No erroneous conclusions were found in regard to the 5028 ABO group and Rh type or phenotype determinations carried out with the device. The device rejected 1.53 percent of tests for sample inadequacy. Of the remaining 18 tests with discrepant results found with the device and not confirmed with the standard methods, 6 gave such results because of mixed-field reactions, 10 gave negative results with A2 RBCs in reverse ABO grouping, and 2 gave very weak positive reactions in antibody screening and crossmatching. In the samples from immunized patients, the device missed one weak anti-K, whereas standard methods missed five weak antibodies. In addition, 48, 34, and 31 of the 53 weak or variant antigens were detected by the device, the slide method, and the semiautomated handler, respectively. Technician time with the standard methods was 1.6 to 7 times higher than that with the device. CONCLUSION: The technical performance of the device compared favorably with that of standard methods, with a number of advantages, including in particular the saving of technician time. Sample inadequacy was the most common cause of discrepancy, which suggests that standardization of sample collection can further improve the performance of the device.     

Short-term memory: no evidence of effect of rapid-repetitive transcranial magnetic stimulation in healthy individuals

The effect of rapid-repetitive transcranial magnetic stimulation (rr-TMS) on the immediate verbal and visuospatial memory span was assessed by computerized neuropsychological testing in 11 healthy volunteers. The objective was to test whether rr-TMS may be utilized as a non-invasive tool for evaluation of memory function. The subjects had to memorize series of numbers (Digit-Span test) or the position of cubes (Corsi-Block test) shown to them on a computer screen and actively reproduce them immediately after the presentation. Synchronous with the appearance of each item an rr-TMS train of 550 ms duration was delivered to the left or right anterolateral parietal as well as superior and posterior lateral temporal region at 50 Hz and with approximately 1.0 T stimulation intensity. Statistical comparison of memory performance during rr-TMS and baseline testings without stimulation revealed no significant changes. No adverse effects were observed. Thus, rr-TMS does not affect short-term memory performance in healthy individuals under the stimulation conditions described above.