Reduction of plasma renin substrate after parturition; role of renin

Plasma renin substrate concentration, renin activity, serum sex hormone binding globulin and total protein concentration were measured sequentially in 10 women after elective caesarean section. Plasma renin substrate concentration decreased from 5406 +/- 000 micrograms AI/l (mean +/- SD) at term to 2369 +/- 726 micrograms AI/l 6 days post partum. Plasma renin activity decreased from 6.2 +/- 3.3 micrograms AI/l/h at term to 4.2 +/- 4.0 micrograms AI/l/h 6 days after delivery. Serum sex hormone binding globulin decreased more slowly than plasma renin substrate concentration. Clearance of plasma renin substrate based on plasma renin activity was calculated. This consumption by renin could explain only 12% of the decrement in plasma renin substrate concentration at the steepest part of the plasma renin substrate disappearance curve. It is concluded that metabolic clearance of plasma renin substrate may be much greater than that calculated from plasma renin activity.     

Plasma homocysteine, a risk factor for cardiovascular disease, is lowered by physiological doses of folic acid

Elevated plasma homocysteine, an independent risk factor for cardiovascular disease (CVD) can be lowered by administration of pharmacological doses of folic acid. The effect of lower doses in apparently normal subjects is currently unknown but is highly relevant to the question of food fortification. Healthy male volunteers (n = 30) participated in a chronic intervention study (26 weeks). Folic acid supplements were administered daily at doses increasing from 100 micrograms (6 weeks), to 200 micrograms (6 weeks), to 400 micrograms (14 weeks). Fasting blood samples collected before, during and 10 weeks post intervention were analysed for plasma homocysteine, serum and red- cell folate levels. Results, expressed as tertiles of baseline plasma homocysteine concentration, showed significant (p < or = 0.001) homocysteine lowering in the top (10.90 +/- 0.83 mumol/l) and middle (9.11 +/- 0.49 mumol/l) tertiles only. In the low tertile, where the mean baseline homocysteine level was 7.07 +/- 0.84 mumol/l, no significant response was observed. Of the three folic acid doses, 200 micrograms appeared to be as effective as 400 micrograms, while 100 micrograms was clearly not optimal. There is thus a minimal level of plasma homocysteine below which folic acid has no further lowering effect, probably because an optimal folate status has been reached. A dose as low as 200 micrograms/day of folic acid is effective in lowering plasma homocysteine concentrations in apparently normal subjects. Any public health programme for lowering homocysteine levels, with the goal of diminishing CVD risk, should not be based on unnecessarily high doses of folic acid.      

Production, degradation, and circulating levels of 1,25-dihydroxyvitamin D in health and in chronic glucocorticoid excess.

The decreased intestinal absorption of calcium and accelerated bone loss associated with chronic glucocorticoid excess may be mediated by changes in vitamin D metabolism, leading to decreased availability of circulating 1,25-dihydroxyvitamin D. This hypothesis was examined in 14 patients with either endogenous or exogenous glucocorticoid excess. Analysis of paired serum samples (mean +/- SE) in 13 patients during euglucocorticoidism and during hyperglucocorticoidism showed that glucocorticoid excess resulted in small decreases of plasma 25-hydroxy-vitamin D concentrations (22 +/- 2- 18 +/- 2 ng/ml; P < 0.05) but no significant changes in plasma 1,25-dihydroxyvitamin D (32 +/- 8- 23 +/- 6 pg/ml) or serum immunoreactive parathyroid hormone (21 +/- 2- 18 +/- 2 muleq/ml). Additionally, we studied plasma kinetics of [3H]1,25-dihydroxyvitamin D3 after intravenous bolus administration in 10 hyperglucocorticoid patients and in 14 normal controls. Assessment with a three-compartment model showed no significant abnormalities in production rates (hyperglucocorticoid patients 1.2 +/- 0.3 micrograms/d, controls 1.5 +/- 0.2 micrograms/d) or metabolic clearance rates (hyperglucocorticoid patients, 18 +/- 2%; controls, 14 +/- 2%) or feces (hyperglucocorticoid patients, 60 +/- 9%, controls, 54 +/- 6%). We conclude that glucocorticoid excess does not effect plasma levels, production, or degradation of 1,25(OH)2D in humans. Thus, other mechanisms must be postulated to explain satisfactorily the abnormalities of bone structure and intestinal calcium absorption that may occur after chronic glucocorticoid therapy.     

Hyperlactataemia, hyperkalaemia and heart block in acute iron overload: the fatal role of the hepatic iron-incorporation rate in rats on ferric citrate infusions

An animal model is presented that provides constant and controllable conditions for approaching gradually, and within reasonable time, different stages of iron overload and, probably, an iron-induced mitochondrial disorder. Thirty-five rats were infused with ferric citrate, sodium citrate and saline at constant rates for 6-24 h. In the 200-3200 micrograms Fe h-1 loading range, the iron-incorporation capacity of the liver was not saturable and the fractional iron uptake by the liver remained at approximately 30% even at a loading rate of 3200 micrograms Fe h-1. Up to a loading rate of 200 micrograms Fe h-1, iron storage was not associated with toxic effects. Beyond this loading rate, however, the liver was no longer able to prevent a massive plasma iron increase on one side and hyperlactataemia on the other. These signs most probably represent hepatocellular decompensation with respect to a critical iron-storage rate. The product of plasma iron x exposition time was significantly correlated with increased plasma lactate levels (r = 0.89, P less than 0.005), whereas increased plasma iron levels per se were not. Hyperlactataemia was associated with hyperkalaemia and progressive cardiac conduction defects leading to cardiac arrest at lactate concentration of 9.1 +/- 4.3 mmol l-1. The hypothesis is discussed that toxicity in acute iron overload may entirely be due to hepatocellular (mitochondrial) damage, and not to multiple organ iron overload.     

Rifampin blood and tissue levels in patients undergoing cardiac valve surgery.

Single 600-mg capsules of rifampin were given orally to 26 patients as prophylaxis during cardiac valve replacement. Antibiotic concentrations were measured in blood (serum or plasma) and tissue (excised cardiac valve). The serum or plasma levels of rifampin in 18 patients who ingested this drug 2 h before they received preoperative opiates and anticholinergics intramuscularly were not significantly different from the levels in four normal volunteers who received the drug. These levels were 15.9 +/- 6.5 micrograms/ml (mean +/- standard deviation) 2 h after drug administration, 7.1 +/- 4.3 micrograms/ml 8 h after drug administration and 2 h after a mean of 1.4 h on cardiopulmonary bypass, and 1.6 +/- 1.6 micrograms/ml 24 h after drug ingestion. The valve tissue level was 3.8 +/- 2.7 micrograms/g (mean +/- standard deviation; n = 10). This value was 65% of the simultaneous serum and plasma levels and 31% of the peak serum and plasma levels. Eight patients who were given rifampin at the same time that they received other preoperative medications had significantly lower blood levels than the 18 patients who received rifampin 2 h earlier (P less than 0.001). No rifampin was detected in valves from seven of these patients. Decreased rifampin absorption due to simultaneous administration with opiates and anticholinergics was the probable reason for the low plasma and serum levels observed. These data suggest that, if properly dosed, rifampin administered orally gives high blood and valve tissue levels, which are affected minimally by cardiopulmonary bypass in patients undergoing cardiac valve surgery.     

Determination of tissue plasminogen activator in plasma samples by means of a radioimmunoassay

A solid phase double antibody radioimmunoassay for measuring tissue plasminogen activator (t-PA) in human plasma is described using purified human melanoma cell t-PA and specific goat anti-t-PA IgG. The concentration of t-PA antigen in citrated human plasma sampled at rest was 4.4 +/- 1.3 micrograms/l (mean +/- SD) for healthy individuals (n = 20). After 10 min of venous occlusion the level of t-PA antigen was increased to 13.9 +/- 6.2 micrograms/l. The accuracy was monitored by recovery experiments using plasma from nine healthy individuals and nine patients to which was added low (5 micrograms/l) and high (25 micrograms/l) levels of purified t-PA. The detection limit of the method was estimated as 0.08 micrograms/l. An excellent correlation was found on comparing the t-PA antigen increase with the t-PA activity increase obtained during venous occlusion. In plasma collected prior to venous stasis, the total concentration of detectable t-PA antigen is found mainly in an inactive form. In contrast the t-PA antigen released upon venous occlusion seems to be largely in an active form.     

Radioimmunoassay of human platelet-derived growth factor using monoclonal antibody toward a synthetic 73-97 fragment of its B-chain

A mouse monoclonal antibody toward a 73-97 fragment of human platelet-derived growth factor (hPDGF) B-chain was used to develop a radioimmunoassay (RIA) for serum hPDGF. By the single step procedure of the double antibody technique, the measurable range was 10-1,000 micrograms/l. The coefficients of variation within and between series were 10.2% and 12.1% respectively, and satisfactory dilution curves were obtained for sera from healthy subjects. The hPDGF levels in all plasma samples from 15 healthy subjects examined were below the detection limit (10 micrograms/l), whereas the mean hPDGF concentration (+/- SD) in serum samples of 60 healthy subjects was 31.9 +/- 20.4 micrograms/l. This value was significantly (p less than 0.01) higher than the mean for 21 patients with idiopathic thrombocytopenic purpura (12.6 +/- 4.5 micrograms/l). There was a significant positive (r = 0.481, p less than 0.01) but not a strong (r2 = 0.23) correlation between the peripheral blood platelet counts and serum hPDGF levels of all subjects. This RIA system should be useful clinically for measurement of serum hPDGF.     

Aminoterminal propeptides of type III procollagen in human cerebrospinal fluid

The concentrations of aminoterminal propeptides of procollagen type III were determined by radioimmunoassay in the cerebrospinal fluids of 64 patients with various neurological disorders, including 4 infant patients (less than 1 year). In cerebrospinal fluids of adult patients with normal composition (protein, glucose, cell count), adult patients with pathologic composition, and infant patients the peptide levels (mean value +/- S.D.) were 4.07 +/- 1.26 micrograms/l, 8.15 +/- 6.78 micrograms/l, and 56.9 +/- 31.0 micrograms/l, respectively. The concentrations ranged from 1.96 to 265 micrograms/l and were independent of the respective serum propeptide levels. No statistic correlation with other parameters was found. Gel chromatography revealed a high degree of molecular weight heterogeneity, a substantial portion of immunoreactive material was eluted even with the void volume of Sephacryl S 300. Different slopes of radioimmunoinhibition curves indicate heterogenous antigenicity among the propeptides from various patients. Interaction of the propeptides with fibronectin and/or heparin is probably not responsible for the heterogeneity. The diagnostic potential of cerebrospinal fluid propeptide levels for local connective tissue (collagen) turnover remains to be elucidated.     

Effect of meals on resorption of bismuth from an oral bismuth gallate/bismuth nitrate preparation

In a cross-over study in ten healthy volunteers the effect of food on the absorption of bismuth following a single oral dose of 1200 mg (= 12 Bismofalk tablets) was evaluated by measuring its serum levels (0 to 24 h) and urinary excretion (for seven days). If this high dose was ingested one hour prior to the breakfast maximal serum concentrations (16.5 +/- 13.7 micrograms/l; mean +/- SD) were rapidly achieved (tmax = 0.7 +/- 0.5 h). These levels and the low urinary recovery of 0.32 +/- 0.25 mg (corresponding to 0.027% of the dose) indicated a minimal absorption. If the tablets were taken one hour after the breakfast absorption was slightly delayed (tmax = 1.9 +/- 2.4 h), however, the extent appeared to be unchanged. In spite of the high dosage as well as the large interindividual variability in the urinary recovery and the serum concentrations potential "toxic" serum levels of 100 micrograms/l were never reached. Thus, it can be concluded that the bismuth preparation used is suitable for topical action.     

Metronidazole metabolism following oral benzoylmetronidazole suspension in children with giardiasis

A suspension of benzoylmetronidazole (6.4% w/v) was given orally at a dose of 15-25 ml, equivalent to 0.6-1 g metronidazole, once a day for three days to 11 children with giardiasis. Blood samples were collected after the first and third doses for analysis of plasma metronidazole and its main oxidative metabolite by high performance liquid chromatography. Peak metronidazole concentrations were 22.60 +/- 8.52 mg/l (mean +/- S.D.) after the first dose, and 30.22 +/- 10.06 mg/l after the third dose, occurring at 3.6 +/- 1.4 and 4.4 +/- 2.9 hours post-dose, respectively. Peak concentrations of the metabolite were 4.26 +/- 1.94 mg/l after the first dose and 7.96 +/- 3.63 mg/l after the third dose, occurring 7.2 +/- 1.6 and 9.1 +/- 3.3 h post-dose, respectively. Calculation of plasma metronidazole half-life and clearance values was not possible. This study shows that oral administration of metronidazole as its benzoyl ester slows the rate of metronidazole absorption, followed by sustained plasma concentrations and a prolonged elimination phase. Giardiasis does not appear to prevent metronidazole absorption. Concurrent giardiasis is unlikely to influence metronidazole therapy for systemic anaerobic infections.     

Carnitine deficiency and hyperammonemia in children receiving valproic acid with and without other anticonvulsant drugs

Plasma ammonia and total and free carnitine were measured in 84 children requiring anticonvulsant drugs: 32 patients (group A) on valproic acid alone, 28 children (group B) on polytherapy including valproic acid, and 24 patients (group C) on polytherapy without valproic acid. The other anticonvulsant drugs used in groups B and C were carbamazepine and phenobarbital. Plasma ammonia concentrations were elevated in both group A and B compared with controls. Group B patients showed significantly higher hyperammonemia than group A (59.9 +/- 16.3 micrograms/dl vs. 36.7 +/- 12.4 micrograms/dl; P < 0.05). Group C patients had plasma ammonia levels similar to those of controls (31.1 +/- 14.7 micrograms/dl vs. 29.7 +/- 12.1 micrograms/dl; NS). In both group A and group B patients, plasma ammonia levels were correlated with the valproic acid dosage (r = 0.32, P < 0.01) and with serum concentrations of valproic acid (r = 0.41, P < 0.001). Moreover, a significant correlation between plasma ammonia and duration of valproic acid therapy was found in the patients as a whole (r = 0.31, P < 0.01). Plasma total and free carnitine concentrations were significantly reduced in groups A and B (total carnitine 36.9 +/- 6.9 mumol/l vs. 32.9 +/- 9.7 mumol/l; free carnitine 28.9 +/- 5.1 mumol/l vs. 25.7 +/- 4.3 mumol/l, respectively) compared with group C patients who did not receive valproic acid and in whom values were similar to controls (total carnitine 46.1 +/- 9.0 mumol/l vs. 47.7 +/- 10.1 mumol/l; free carnitine 40.1 +/- 7.1 mumol/l vs. 42.9 +/- 8.0 mumol/l, respectively). Twenty-eight patients (18 of group A and 10 of group B) were re-evaluated and showed a complete normalization of plasma ammonia, and total and free carnitine levels which were similar to controls. Our data suggest that hyperammonemia is an important problem in patients receiving valproic acid, particularly in association with other anticonvulsant drugs. This increase of plasma ammonia and the concomitant reduction of carnitine seem to be transient and completely reversible.     

Plasma and serum lactoferrin levels in cystic fibrosis. Relationship with the presence of cystic fibrosis protein

Plasma lactoferrin concentrations were measured in blood of cystic fibrosis patients, heterozygotes and controls using a specific and sensitive enzyme immunoassay. 67 plasmas were studied (26 controls, 23 heterozygotes, 18 cystic fibrosis patients) and the results showed a statistically significant increase (p less than 0.05) of the level of plasma lactoferrin in cystic fibrosis patients (265 +/- 224 micrograms/l) compared to controls (168 +/- 100 micrograms/l) and heterozygotes (150 +/- 72 micrograms/l). Since it is well established that plasma lactoferrin level could be influenced by the number of neutrophils, a second set of experiments was performed on 20 cystic fibrosis patients on whom leukocyte counts were also made. When the 15 plasmas with normal neutrophils (in the range 2 to 6 giga/l) were considered, the mean lactoferrin level was 318 +/- 116 micrograms/l, still far above the normal values. For serum, a similar significant increase of lactoferrin concentration was observed in 33 cystic fibrosis patients (610 +/- 551 micrograms/l) compared to the values observed for 25 controls (237 +/- 155 micrograms/l) and 37 heterozygotes (272 +/- 231 micrograms/l). Cystic fibrosis protein (CFP) was identified in the same sera by isoelectric focusing and the intensity of the band was closely related to the increase of lactoferrin concentration in cystic fibrosis patients. In contrast, no difference in serum lactoferrin concentrations was observed between heterozygotes with or without CFP, indicating that the increased CFP concentration cannot be due only to altered granulocyte function.     

Pharmacokinetics of dexamethasone administered orally in obese patients

Dexamethasone pharmacokinetics was studied after oral administration of two Décadron tablets in six healthy controls and in eight obese patients whose weight was at least 20% above that of the ideal body weight. The absorption (0.30 +/- 0.09 h and 0.29 +/- 0.08 h) and elimination (4.52 +/- 0.57 h and 3.71 +/- 1.05 h) half-lives were not significantly different. Maximum plasma concentrations were similar (11.95 +/- 1.00 micrograms/l and 10.93 +/- 0.94 micrograms/l) but the lag-time was significantly higher in the obese patients (0.49 +/- 0.12 h and 0.13 +/- 0.04 h). A positive correlation was observed between the AUC and the total body weight (r = 0.738, p less than 0.01). Mean predexamethasone cortisol level was significantly lower in the obese patients (189.20 +/- 52.7 micrograms/l and 256.90 +/- 58 micrograms/l). The pharmacokinetics modifications were not sufficient to explain the increased false positive frequency in the dexamethasone suppression test of the hypothalamic-pituitary-adrenal axis in obesity.     

PLASMA KININ-PRECURSOR LEVELS IN CLINICAL INTESTINAL INFLAMMATION

Plasma kinin-precursor (kininogen) concentrations were measured in the peripheral venous blood of 7 untreated patients with inflammatory bowel diseases, 12 healthy subjects, and 5 uncomplicated fracture cases. The mean plasma kininogen levels were significantly raised (P less than 0.025) in patients with intestinal inflammation (7.0 +/- 1.0 micrograms BK Eq/ml), as compared with the value found in healthy subjects (5.7 +/- 0.7 micrograms BK Eq/ml), and in fracture cases (5.0 +/- 1.2 micrograms BK Eq/ml). The packed cell volume did not differ (P greater than 0.05) between patients and control groups. Thus, the raised plasma kininogen levels observed in patients were not the result of nonspecific changes in plasma volume. It is suggested that raised plasma kininogen might be due to increased synthesis to provide substrate for excessive kinin-formation, to a potent inflammatory agent, or to high synthesis of acute-phase reactants. The possible significance of this observation is discussed.     

Serum transferrin receptor assay in iron deficiency anaemia and anaemia of chronic disease in the elderly

The most common cause of anaemia in the elderly is anaemia of chronic disease (ACD). However, iron deficiency anaemia (IDA) may coexist, and can be difficult to diagnose. The serum transferrin receptor (sTfR) blood test may be a better indicator of iron status as it is not affected by inflammation nor by advancing age. We evaluated it in four groups (10 males, 10 females each): 'young' controls, 'elderly' controls, IDA and ACD. All patients in the IDA group had elevated sTfR levels (mean +/- SD 65.2 +/- 17.7 nmol/l). All 'young' controls had normal sTfR (22.3 +/- 7.3 nmol/l) and ferritin levels (92.7 +/- 61.1 micrograms/l). Although all subjects in the 'elderly' controls and ACD group had normal, and raised or normal serum ferritin, respectively (88 +/- 62.3 micrograms/l; 631.2 +/- 509.5 micrograms/l), three (15%) 'elderly' controls and four (20%) ACD patients had raised sTfR levels, suggesting depleted iron stores. Bone-marrow aspirates were available in 3/4 ACD patients with raised sTfR. Haemosiderin was absent in two. The sTfR blood test is comparable to serum ferritin in diagnosing IDA in the elderly but also seems capable of differentiating ACD from IDA. Its potential as a non-invasive test of iron status, especially in elderly anaemic patients, deserves further evaluation.     

Plasma pharmacokinetics and tissue penetration of a novel antifungal triazole, Bay R 3783, and its long-lasting active metabolite, Bay U 3625, in rabbits

The plasma pharmacokinetics and tissue penetration of Bay R 3783 (BR), a new antifungal triazole, and one of its active metabolites, Bay U 3625 (BU), were studied in rabbits. Plasma levels of BR and BU were determined simultaneously in five rabbits for six days after a single oral dose of 20 or 40 mg/kg BR. For BR, the mean Cmax was 1.9 +/- 0.4 mg/l, the Tmax 2.0 +/- 0.7 h, the AUC alpha 7.5 +/- 1.6 mg.h/l, and the terminal plasma T1/2 2.1 +/- 0.1 h. For BU, the mean Cmax was 0.84 +/- 0.09 mg/l, the Tmax 24 +/- 4 h, the AUC alpha 61.9 +/- 6.5 mg.h/l, and the plasma T1/2 was 48 +/- 3 h. In a multi-dose study, the plasma BR clearance during wash-out gradually diminished, suggesting possible metabolite inhibition of BRs biotransformation. No hepatic or renal toxicity was seen after 28 days of dosing with BR 40 mg/kg/d. Both BR and BU penetrated well into tissues, with tissue drug concentrations over three times higher than in plasma at multiple tissue sites. Persistence of BU in plasma, however, resulted in prolonged, higher tissue levels of BU than of BR. We conclude that BR is converted to a long-lasting active metabolite BU, that persistence of BU in tissue is prolonged, and that these properties may permit BU to contribute significantly to the antifungal activity of BR.     

PHARMACOKINETICS OF LIDOCAINE AND BUPIVACAINE IN RETROBULBAR AND FACIAL BLOCK

Analgesia can be obtained during ophthalmic surgery by regional anesthesia using local anesthetic agents. As in other indications, neurological complications may occur, especially because the site of injection is close to the central nervous system. In order to evaluate the risk of retrobulbar and facial block obtained after 40 mg lidocaine and 20 mg bupivacaine injection, pharmacokinetics of both drugs was evaluated in plasma obtained from 11 patients. In addition, 3 cerebrospinal fluid samples were analyzed. Maximal plasma concentration was 0.73 +/- 0.33 micrograms.ml-1 for lidocaine and 0.19 +/- 0.06 micrograms.ml-1 for bupivacaine, obtained 24.7 +/- 23.0 min and 12.0 +/- 3.7 min after the end of injection, respectively. CSF/plasma ratio was in the range 0.05-0.26 for lidocaine and 0.56-1.33 for bupivacaine. In all patients, regional anesthesia was sufficient to perform surgery without any other analgesic drug. No sign of cardiovascular or respiratory toxicity was observed during the study.     

Circulating levels of calcitonin gene-related peptide in patients with medullary thyroid carcinoma

Calcitonin gene-related peptide, originally found in rat medullary thyroid carcinoma cells, was measured by radioimmunoassay in plasma samples with added aprotinin from 17 normal volunteers and 21 patients with medullary thyroid carcinoma. The concentrations were below 75 pmol/l in all 17 normal subjects with a mean of 33 +/- 19 pmol/l plasma. In the patients, the plasma calcitonin gene-related peptide concentrations ranged from below 5 pmol/l to 236 pmol/l, although the mean (36 +/- 48 pmol/l) was not significantly different from the mean normal level. Increase in the plasma calcitonin gene-related peptide level was observed in 2 of 5 patients in response to infusion of 4.3 mg/kg of calcium for 10 minutes and in 3 of 5 patients in response to infusion of 4 micrograms/kg of tetragastrin for 5 minutes. These observations suggest that measurement of calcitonin gene-related peptide level may be helpful in determination of diseases in which the level of calcitonin is of less diagnostic value.     

Plasma ferritin in old age. Influence of biological and pathological factors in a large elderly population

The effects of biological (age, sex, weight) and pathological factors on plasma ferritin concentrations were documented in 776 unselected elderly patients aged 80.9 +/- 9.7 yr. A marked shift towards high values (159 +/- 142 micrograms/l) was observed in this elderly population together with the persistence of the well-known sex-related difference in ferritin levels (higher levels in men). Twenty-five percent of the population had high levels of ferritin (greater than or equal to 220 micrograms/l) but 75% of these high values (i.e. 18.5% of the population) could be readily explained by their known association with a particular pathology (inflammatory syndrome, renal failure, cardiovascular diseases, alcoholism). Only 6% of the population had unexplained high ferritin concentrations. Therefore, our data strongly suggest that the repeatedly reported increase of ferritin in the aged population is merely related to an age-associated pathology and may not be a normal physiological event occurring during the process of aging.     

Pharmacokinetics of bacampicillin using a compartment model with zero-order absorption

The pharmacokinetics of bacampicillin, a prodrug of ampicillin which is absorbed from the gastrointestinal tract, were studied in 10 healthy male volunteers after administration of 1,200 mg in a single oral dose. The pharmacokinetic analysis was carried out by applying a single-compartment kinetic model with zero-order absorption. The apparent duration of absorption (T) was about 1 h for all subjects. The peak plasma concentrations (Cmax) were 17.89 +/- 1.82 micrograms/ml, and the mean plasma half-life during beta-phase was 1.17 +/- 0.14 h. The area under the curve was 41.22 +/- 5.29 micrograms.h/ml. The mean urinary recovery during 24 h amounted to 76.4 +/- 3.65% of the dose.