Adjustment of phenprocoumon dosage utilizing a pharmacokinetic model

According to a pharmacokinetic model, the adjustment of a phenprocoumon (PPC) standard dosage based on experimentally determined means values of the parameters volume of distribution and biological half-life will yield in more than 50% of the individuals the desired plasma PPC concentration. In 25 patients it was tested, whether the thus derived loading and maintenance doses, 376.8 and 35.2 micrograms PPC per kg b. wt., resp., actually lead to the predicted optimum plasma PPC concentration of 2.0 micrograms/ml. After initiating dosage, the plasma PPC concentrations were determined over a time period of 30 days. As predicted by the model, in 72% of the patients the average steady-state plasma PPC concentrations were within the range of 1.7 and 2.3 micrograms/ml. The data obtained were used to newly calculate mean values of the volume of distribution, the biological half-life, and the total body clearance of PPC. The mean biological half-life of PPC derived was somewhat shorter than that used for the calculation of the standard dose. Quick-values were estimated concomitantly with the plasma PPC concentrations. They revealed an optimum anticoagulation (15-25%) in 96% of the patients.     

Sheep model for study of maternal adrenal gland function during pregnancy

Our goal was to develop a model for the study of maternal adrenal gland regulation and the effects of maternal cortisol secretion on fetal homeostasis. At about 108 days of gestation, before the time of rapid fetal growth or fetal adrenocortical maturation, ewes, under halothane anesthesia with controlled ventilation and positioned in sternal recumbency, were adrenalectomized. Ewes were treated with aldosterone by intravenous infusion (3 micrograms/kg of body weight per day) to induce normal late-gestation aldosterone concentration. Ewes were also treated with cortisol; for 2 postoperative days, this infusion (1 to 2 micrograms/kg per min) induced plasma concentration similar to that associated with stress. Thereafter, the dosage of cortisol was reduced to induce plasma values similar to normal late-gestation cortisol concentration in ewes (1 mg/kg per day), or to values in nonpregnant ewes (0.6 mg/kg per day). Administration of cortisol and aldosterone was required to prevent electrolyte imbalance and signs of hypoadrenocorticism. With steroid replacement, plasma protein, electrolyte, and glucose concentrations in adrenalectomized ewes were not different from those in sham-operated pregnant ewes. Of 11 adrenalectomized ewes, one died as a result of failure of the infusion pump, and one died as a result of inappropriate treatment for hypoglycemia. Of the remaining ewes, two aborted fetuses, three ewes each delivered one live and one dead fetus, two delivered live singleton fetuses, and two delivered twins. Therefore, this model of relative hypoadrenocorticism in pregnancy is feasible and practical for studying the influence of maternal cortisol concentration on maternal and fetal homeostasis.     

Effect of acute and chronic administration of L- thyroxine and methimazole on blood levels of tryptophane, serotonin and 5-hydroxyindoleacetic acid in plasma of rats]

The effects of hyperthyreosis induced by the administration of thyroxine and hypothyreosis induced by the administration of methimazole on the levels of tryptophane, serotonin and 5-hydroxyindoleacetic acid in low-platelet blood plasma have been studied in Wistar rats. Thyroxine administration (120 micrograms/kg/24 h, intraperitoneally) lasting 7 days caused a decrease in serotonin concentration by 38 per cent. The level of this amine in rats receiving thyroxine during three months was elevated by almost three times. Tryptophane concentration did not change following thyroxine administration. Methimazole administration lasting 14 days (oral dose 15 mg/kg/24 h) caused an increase in tryptophane concentration by 34 per cent and in serotonin concentration by 24 per cent. Long-term hypothyreosis induced by methimazole administration lasting three months caused an 39 per cent increase in tryptophane and 38 per cent increase in serotonin concentration. Neither hyperthyreosis induced by thyroxine administration nor hypothyreosis induced by methimazole++ caused any changes in the concentration of 5-hydroxyindoleacetic acid. The importance of serotonin in pathogenesis of clinical symptoms accompanying the states of deficit or excess of thyroid hormones needs further elucidation.     

Lithium-stimulated recovery of granulopoiesis after sublethal irradiation is not mediated via increased levels of colony stimulating factor (CSF)

We have previously demonstrated that lithium (Li) is an effective agent in accelerating the recovery of granulopoiesis following sublethal (2 Gy) whole body irradiation. In this report, studies are described that further define this Li-mediated recovery by measuring the levels of colony-stimulating factor (CSF) present in serum from mice administered 105 micrograms/mouse (total dose) of ultra-pure Li2CO3 for 3 days immediately following irradiation. On days 1-28 following the last lithium dose, the serum was tested for its CSF activity against both normal non-adherent derived bone marrow target cells and non-adherent marrow cells from mice administered cyclophosphamide (200 mg/kg body weight). Serum was assayed at 0.01, 0.1, 1 and 10 per cent final concentration. No significant difference in the total number of CFU-GM was observed from normal marrow using either serum from irradiated mice or lithium-treated and irradiated mice, although the irradiation did produce a 300 per cent rise in CFU-GM colonies compared to normal serum (days 4 and 10-15). From regenerating marrow, we observed a significant difference (P less than or equal to 0.01) in CFU-GM cultured with serum at 0.1 per cent concentration from irradiated and lithium-treated mice compared to irradiated mice without lithium. The presence of CSF was confirmed by its reduced activity in the presence of anti-(CSF). These results suggest (Li) may increase the sensitivity of CFU-GM to CSF, thereby producing more CFU-GM ultimately providing more circulating granulocytes.     

Influence of alpha or beta adrenergic antagonists on catecholamine dependent metabolic effects in pigs

In 4 Piétrain-pigs and 4 crossbred (Duroc X Landrace) pigs (32-47 kg body weight; b.w.) the effect of an intravenous injection of epinephrine (80 micrograms/kg b.w.) or isoprenaline (55 micrograms/kg b.w.) was investigated during a continuous infusion of 0.9% NaCl-solution (1 ml/min and pig), propranolol or phentolamine (priming dose 100 micrograms/kg b.w. and thereafter 2 micrograms/kg and min over 45 min) on the plasma concentration of glucose, lactate, free fatty acids (FFS) and free over 45 min) on the plasma concentration of glucose, lactate, free fatty acids (FFS) and free glycerol. Furthermore the effect of a continuous infusion of the blocking agents alone was examined in the 4 crossbred animals. Lipolysis was stimulated via beta-adrenergic receptors and was inhibited through an alpha-adrenergic mediated effect in pigs. The lean Piétrain-pigs showed a significant higher response than the crossbred pigs. The catecholamine induced increase in plasma glucose and lactate was equal in both breeds. The rise of glucose concentration resulted from an alpha- and beta-adrenergic component, with the alpha-adrenergic effect dominating. Compared to isoprenaline, the higher increase in plasma lactate after adrenaline injection is attributed to clinical reactions.     

The assay of fentanyl and its metabolites in plasma of patients using gas chromatography with alkali flame ionisation detection and gas chromatography—mass spectrometry

Fentanyl was determined using gas chromatography (GC) and alkali flame ionisation detection (AFID), in the plasma of patients who had received a high single dose (up to 60 μg/kg body weight). The relative standard deviation is 6% for 11 ng/ml while the calculated detection limit is 3.3 ng of fentanyl per 1 ml of plasma. The concentration of fentanyl in patients ranged from 40 to 3 ng/ml of plasma in the first hour after administration. In the plasma of patients treated with fentanyl two metabolites could be detected and identified using GC—AFID and GC—MS.     

Hormonal consequences of subcutaneous 6-methoxy-2-benzoxazolinone pellets or injections in prepubertal male and female rats

Prepubertal 27-day-old female rats maintained in a 14L:10D cycle (lights on 06:00 h) were injected s.c. at 13:00 h with saline or 2, 20 or 200 micrograms 6-methoxy-2-benzoxazolinone (6-MBOA) and killed 25-27 h later. No significant differences in body, pituitary or ovarian weight were noted. Differences in uterine weight (mg/100 g body weight) and in circulating free thyroxine index fit the pattern of a reduction after the lower doses with reversal of this effect after the highest dose. A dose-related rise in plasma prolactin concentration was accompanied by a significant increase in pituitary prolactin at the lowest (2 micrograms) dose. When 27-day-old prepubertal male and female rats maintained in a 14L:10D cycle were implanted with a beeswax pellet or a wax pellet that contained 100 micrograms or 1 mg 6-MBOA and killed 3 days later between 14:00 and 16:00 h, body and absolute ventral prostate weights (but not weights of other accessory organs, testes or relative ventral prostate weights) in males were lower. Pituitary (but not plasma) prolactin concentrations were higher after the lower dose compared to the controls; pituitary and plasma values of LH and FSH were unchanged. In females, reproductive variables were unchanged except for a reduction of pituitary prolactin after the 1 mg dose. Triiodothyronine and its free index were elevated after the higher dose in males and the lower dose in females. The free thyroxine index appeared raised after the larger dose only in males.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of electrophoresis of the head region on benzylpenicillin penetration across the blood-brain barrier

A procedure for administration of sodium benzylpenicillin (SB) to the brain was developed and tested on 22 rabbits. SB was administered drop-like intravenously in a dose of 200,000 units/kg body weight in combination with electrophoresis of the head area. It was shown spectrophotometrically that a single administration of SB increased its concentration in the liquor and brain tissues by 366.7 and 500 per cent respectively as compared to the control values. Practically no shifts in the EEG and ECG were observed which was indicative of safety of SB administration by that route. The procedure for intraorgan administration of SB in combination with electrophoresis may be recommended for clinical use.     

ACTH,cortisol and glucose responses after administration of vasopressin in cattle and sheep

The present study compared the effects of vasopressin on plasma concentrations of corticotropin, cortisol and glucose in cattle and sheep. After intravenous injection of 1, 0.1 and 0.01 g vasopressin per kg body weight, the plasma vasopressin concentration increased proportionally to the injected dose, and this increase was similar in cattle and sheep. Doses of 1 and 0.1 g per kg body weight of vasopressin triggered significant responses of corticotropin, cortisol and glucose in cattle and sheep. The corticotropin response to both doses was significantly greater in sheep, whereas the glucose response was greater in cattle. The cortisol response did not differ between species. The lowest dose of vasopressin (0.01 g per kg body weight) still induced a significant cortisol response without a substantial effect on plasma corticotropin, suggesting that a direct action of vasopressin on the adrenals may contribute to the observed cortisol response. The results demonstrate that vasopressin increases plasma levels of corticotropin, cortisol and glucose in cattle, as it does in sheep, but the intensities of the corticotropin and glucose responses to vasopressin differ between cattle and sheep. The reasons for these differences remain to be clarified.Abbreviations ACTH corticotropin - AVP vasopressin - bw body weight     

Fractional cholesterol esterification rate and muscle cholesterol of healthy young men

A group of fourteen healthy young male volunteers was examined to define more exactly the relations between lecithin cholesterol acyltransferase activity (LCAT), fractional cholesterol esterification rate (FER), total cholesterol (TC) and its free and esterified fractions (FC, CE) in skeletal muscles under physiological conditions. The mean values (+/- S.D.) of LCAT activity (95.4 +/- 16.3 mumol .1(-1) per hour), and FER (7.45 +/- 1.54% per hour) corresponded to published data on normolipidaemic healthy men of normal body weight. The mean value of TC in muscles was 332 +/- 83 micrograms per 100 mg of non-collagen protein, of which 14 +/- 7.4 per cent was formed by cholesterol esters. There was positive correlation between TC in muscles and age. Significant positive correlations between FER and the content of esterified cholesterol in muscles, and between FER and the proportion of esterified to total muscle cholesterol were found. These results suggest a close interrelation of cholesterol ester metabolism in the plasma and in slow pool tissues.     

Metabolic effects of low aflatoxin B1 levels on broiler chicks.

The effects of daily ingestion of aflatoxin B1 (AFB1) on growth, feed intake, plasma glucose, plasma cholesterol, plasma amino acids, plasma albumin, plasma ceruloplasmin, muscle amino acids, liver lipid, and bone strength were studied. For 3 weeks, beginning at an age of 2 days, broiler chicks were dosed daily per os with 50 or 100 micrograms of AFB1 per kg of body weight. Body weight and feed consumption were recorded daily, and metabolic responses were determined at 3 weeks. Treatment with AFB1 did not significantly alter body weight or feed intake. Relative liver weight showed a significant increase at the highest dose, with a significant concomitant increase in liver lipid and decrease in hepatic zinc. Relative spleen and heart weights were not affected by the toxin. Plasma glucose and cholesterol were significantly elevated at the highest dose. AFB1 significantly decreased plasma lysine and histidine and significantly increased muscle histidine, arginine, and valine. AFB1 decreased plasma albumin and markedly increased plasma ceruloplasmin. Dimensions of the long bones (femur and tibiotarsus) were not altered by the toxin. However, AFB1 caused a significant linear decline in the resistance of bone to breakage ("bone breaking strength"). The results indicate that low levels of AFB1 reduced bone strength in broiler chicks. The alterations in blood parameters indicated that AFB1 can disrupt metabolism even at low levels.     

Transhepatic transport of taurocholic acid in normal and mutant analbuminemic rats

To elucidate a possible function of plasma albumin in vectorial transport of various cholephilic organic anions, such as bile acids, plasma clearance and transhepatic transport of radioactive taurocholate were studied in vivo in normal and mutant analbuminemic rats. Intravenous administration of taurocholate was followed by its rapid disappearance from the circulation in both animal groups. However, plasma clearance of taurocholate was significantly larger in analbuminemic (68.3 ml/min per kg of body weight) than in normal rats (29.8 ml/min per kg of body weight) at a dose of 8 mumol/kg of body weight. The increased plasma clearance in analbuminemic rats was accompanied by a more prompt biliary secretion of the ligand than occurred in normal animals; 79 and 42% of the injected dose was recovered in analbuminemic and normal rat bile, respectively, within 10 min after administration. Ultrafiltration analysis revealed that the binding of taurocholate to serum protein(s) was significantly lower in analbuminemic rats as compared with that in normal rat serum; 24 and 76% of taurocholate bound to protein fractions of analbuminemic and normal rat serum, respectively, at 0.5-mM ligand concentration. Binding of taurocholate to cytosolic proteins of normal and analbuminemic liver were similar; 23 and 28% of taurocholate bound to protein fractions from analbuminemic and normal rat, respectively, at 10 mg protein/ml and 20-microM ligand concentration. These results indicate that plasma albumin does not play a role in directing circulating taurocholate to the liver and that transhepatic transport of the bile acid increases with the increase in concentration of unbound ligand in the circulation.     

Metabolic effects of low aflatoxin B1 levels on broiler chicks

The effects of daily ingestion of aflatoxin B1 (AFB1) on growth, feed intake, plasma glucose, plasma cholesterol, plasma amino acids, plasma albumin, plasma ceruloplasmin, muscle amino acids, liver lipid, and bone strength were studied. For 3 weeks, beginning at an age of 2 days, broiler chicks were dosed daily per os with 50 or 100 micrograms of AFB1 per kg of body weight. Body weight and feed consumption were recorded daily, and metabolic responses were determined at 3 weeks. Treatment with AFB1 did not significantly alter body weight or feed intake. Relative liver weight showed a significant increase at the highest dose, with a significant concomitant increase in liver lipid and decrease in hepatic zinc. Relative spleen and heart weights were not affected by the toxin. Plasma glucose and cholesterol were significantly elevated at the highest dose. AFB1 significantly decreased plasma lysine and histidine and significantly increased muscle histidine, arginine, and valine. AFB1 decreased plasma albumin and markedly increased plasma ceruloplasmin. Dimensions of the long bones (femur and tibiotarsus) were not altered by the toxin. However, AFB1 caused a significant linear decline in the resistance of bone to breakage ("bone breaking strength"). The results indicate that low levels of AFB1 reduced bone strength in broiler chicks. The alterations in blood parameters indicated that AFB1 can disrupt metabolism even at low levels.     

Metabolism and Distribution of I-labelled Albumin in the Pig

The biological behaviour of porcine (131)I-albumin has been investigated in 11 normal pigs, weight appr. 20 kg. Mean values obtained from the experiments are: Albumin degradation: 15.1 +/- 2.1 per cent/day (0.18 +/- 0.01 g/kg/day), extravascular: intravascular albumin ratio: 1.71 +/- 0.29. Fecal excretion of radio-activity ranged from 0.77-1.87 per cent of the dose (mean: 1.11 per cent) during the first 4 days of the experiment.The results are discussed with special reference to the r?le of the gastrointestinal tract in health and in various digestive disorders.     

Basal plasma aldosterone levels and tetracosactid-induced increase of aldosterone secretion in conscious male rabbits: lack of correlation with glucocorticosteroid levels

The adrenocortical secretory activity under basal conditions and after treatment with tetracosactid (1-24ACTH) has been investigated in chronically cannulated male rabbits. Basal plasma concentrations of glucocorticosteroids (0.74 micrograms/100 ml) and aldosterone (78 pg/ml) have been determined in a greater number of animals. No significant positive correlation between basal glucocorticosteroid and aldosterone plasma levels could be found. After intravenous injection of 2.5, 5.0, 10.0 and 20.0 micrograms/kg body weight tetracosactid glucocorticosteroid concentrations were significantly elevated between 40--100 min after administration; aldosterone release, on the other hand, was significantly increased only after injection of 10.0 or 20.0 micrograms/kg body weight tetracosactid between 20--60 min after injection. After administration of high tetracosactid doses glucocorticosteroid and aldosterone plasma concentrations were significantly correlated (10.0 micrograms/kg: r = 0.62; 20.0 micrograms/kg: r = 0.26). Because of the relative insensitivity of the zona glomerulosa cells to tetracosactid administered intravenously, it is concluded that ACTH is only of minor importance in the regulation of aldosterone secretion in the rabbit.     

Simple assay for glycerophospholipid hydrolase activity of postheparin plasma.

An assay using radioactive substrates is described that permits rapid determinations of glycerophospholipid-hydrolyzing activity in postheparin plasma or its fractions. Optimal conditions are described for hydrolysis of phosphatidylcholine and phosphatidylethanolamine. A minimum of only 2 mul of normal postheparin plasma is used and no extraction of the reaction products is required before their separation by thin-layer chromatography. We found that after an optimal heparin dose of 60 units/kg body weight the rate of hydrolysis for diacyl glycerophosphocholine and diacyl glycerophosphoethanolamine is 1.16 mumoles/ml per hr and 22.4 mumoles/ml per hr, respectively.     

Quantitative aspects of granulocytic progenitor cell (CFUc) mobilization from extravascular sites in dogs using dextran sulphate (DS)

The relationship between the increase in the blood CFUc concentration after intravenous injection of dextran sulphate (DS) and the pre-existing levels of spontaneously circulating CFUc was studied in dogs. After 15 mg DS/kg body weight the CFUc numbers per ml blood rose by a factor of 3.7 over the pre-injection values, from 78 +/- 11 (SEM) to 359 +/- 50, in normal dogs, and increased by a factor of 3.9 in 0.84-Gy-r-irradiated animals which had a reduced initial CFUc concentration per ml, from 35 +/- 8 to 116 +/- 43. The injection of 20 mg DS/kg body weight into unirradiated dogs caused an increase, by a factor of 11.5, of the pre-injection CFUc concentration, from 101 +/- 20 to 921 +/- 106. On the basis of the mobilization curves for individual dogs, a significant correlation was found between the normal blood CFUc value and the number of CFUc mobilized by DS for both dose levels. From the descending part of the mobilization curves obtained after 15 mg DS/kg body weight, kinetic parameters of canine circulating CFUc were derived. The mean blood transit time (t) was 1.4 +/- 0.5 hr and the half time (T/2) was 1.0 +/- 0.4 hr.     

Longitudinal study of the dietary selenium intake of exclusively breast-fed infants during early lactation in Korea and Japan.

213 samples of human breast milk were collected from 51 healthy Korean women. Selenium content of the samples was determined by atomic absorption spectrometry with hydride generation. The selenium content of Korean milk decreased with increase of days after birth: The arithmetic mean of selenium content was higher in colostrum (< 4 days) 34 micrograms/kg (SD +/- 11, n = 44) than in transitional milk 21 micrograms/kg (SD +/- 8, n = 78) or in mature milk (> 10 days) 13 micrograms/kg (SD +/- 6, n = 91). The daily dietary selenium intake of 0-1 month aged Korean infants fed on breast milk is estimated to be around 10 micrograms per day (3 micrograms/kg body weight) regardless of days postpartum, resulting from the calculation of our selenium data and daily milk intake during early lactation. The same result on selenium intake for Japanese newborns, as well as Korean infants, is also estimated to be around 10 micrograms per day (3 micrograms/kg body weight) regardless of days postpartum.     

Plasma lipids and high density lipoproteins during oral contraception with different combinations of ethinyl estradiol and levonorgestrel.

Seventy-five menstruating women seeking contraceptive advice were randomly allocated to treatment with combined oral contraceptives containing either ethinyl estradiol 50 micrograms + levonorgestrel 250 micrograms (50/250), ethinyl estradiol 30 micrograms + levonorgestrel 150 micrograms (30/150) or ethinyl estradiol 50 micrograms + levonorgestrel 125 micrograms (50/125). The concentrations of cholesterol, triglycerides, phospholipids, high density lipoprotein (HDL)-cholesterol and HDL-phospholipids were determined after one, three and six months and compared to the mean of two determinations of the same parameters before medication. Triglycerides increased by 18--42 per cent after 1--6 months of treatment with 50/125. The HDL-cholesterol and HDL-phospholipids were reduced by 10 per cent during 50/250 treatment. No other parameters showed any consistent alteration in any of the treatment groups. Raised triglyceride concentration and/or decreased HDL concentration increases the risk for cardiovascular disease. It is therefore suggested that in order not to alter the HDL concentration a combined oral contraceptive agent should not contain more gestagen-androgen than corresponding to 125--150 micrograms of levonorgestrel. To avoid a rise of the triglyceride level the weight relation between levonorgestrel and ethinyl estradiol should be about 5:1.     

Multiple subcutaneous injections of somatostatin induce tachyphylaxis of the suppression of plasma insulin, but not glucagon, in the rat

The time course of pancreatic effects of somatostatin was studied over a period of 2 h in unanesthetized unrestrained rats after administration of the peptide by intravenous infusion and by single and multiple subcutaneous injections. During infusion of 10 and 30 micrograms/kg per min, somatostatin continuously suppressed plasma insulin and plasma glucagon. Plasma glucose was significantly increased at the lower dose, but not affected at the higher dose. Single subcutaneous injections of 0.3 and 3 mg/kg decreased plasma insulin and glucagon dose-dependently for 20-60 min without affecting plasma glucose. Multiple subcutaneous injections of somatostatin (one to four doses of 3 mg/kg, administered at intervals of 30 min) caused an initial decrease of plasma insulin (at 30 min), a rebound-increase at 60 and 90 min, and a final return to control values by 120 min. Plasma glucagon remained continuously suppressed. Plasma glucose increased significantly at 60 and 90 min and tended to return towards control values thereafter. In conclusion, pancreatic B cells - but not A cells - of the rat develop tachyphylaxis to somatostatin within 2 h after multiple subcutaneous injections of the peptide. By this mode of administration, 'selective' suppression of plasma glucagon can be achieved with somatostatin in the rat.