The objective of the study was to demonstrate the bioequivalence of subcutaneously (s.c.) and intravenously (i.v.) administered fixed, high-dose low-molecular-weight heparin (LMWH) on anti-activated factor X activity (anti-FXa). Secondary objectives were the analysis of the pharmacodynamic effects on Heptest, thrombin inhibition, tissue factor pathway inhibitor (TFPI), and the urinary excretion of LMWH in the randomized cross-over study following i.v. and s.c. application of 8000 anti-FXa units LMWH Certoparin in 18 healthy subjects. The bioequivalence following s.c. administration was demonstrated from the antilog of the point estimator for the application differences (s.c. minus i.v.) by an area under the activity-time curve (0-24 h) of 101% (range, 93-110%). LMWH was bioequivalent also on Heptest and TFPI, and was 50% on thrombin inhibition. The urinary excretion of biologically active material was 4.1 and 3.6% following i.v. and s.c. administration, respectively. Differences in the pharmacodynamic parameters of the assays indicate specific biological actions of high and low molecular sacharide chains of the LMWH.
A 26-year-old female with a history of preterm labor and cerclage placement presented at 29 weeks gestation. Twin girls were delivered at 29 1 7 weeks. Twin A presented with clinical sepsis at birth. Twin A's blood cultures became positive for Actinomyces species on day of life 15. Despite aggressive medical management twin A died at 35 days of life.
Myelokathexis is a rare from of neutropenia that is probably congenital, characterized by severe noncyclic neutropenia, recurrent infections, granulocytic hyperplasia of the bone marrow, and degenerative changes in mature neutrophils. The cause remains uncertain. A case of myelokathexis was reported in a father and two daughters, and based on this, myelokathexis was given an autosomal-dominant inheritance in Mendelian Inheritance in Man (11th edition, 1994). We present the case of a 12-month-old male with chronic neutropenia and the morphologic features of myelokathexis whose mother carries the same diagnosis, providing additional evidence in favor of dominant transmission.
Nebulized amiloride has been proposed as therapy in cystic fibrosis to block Na+ hyperabsorption in airway epithelium and prevent dehydration of secretions. Patients with cystic fibrosis often have reactive airways. Bovine and canine trachea relax to amiloride in vitro, suggesting another benefit as a bronchodilator, whereas guinea pig trachea, a useful model of human airways, does not. We hypothesized that human airways would respond like guinea pig airways. Airway ring segments from guinea pigs, mice, and human fetuses were constricted with the concentration of acetylcholine producing 50–75% maximum contraction. Subsequent changes in isometric tension to cumulative additions of amiloride (10−8–10−4M) were measured. Guinea pig airways contracted 29 ± 5%, mouse airways contracted 23 ± 6%, and human fetal airways contracted 30 ± 8%. Contraction to amiloride was mimicked by dimethylamiloride, a more selective inhibitor of the Na+/H+antiporter, and was attenuated by protein kinase C (PKC) inhibition with GF109203X and staurosporine. The present study indicates that amiloride-induced airway contraction in guinea pigs and mice closely parallels the response in isolated human airways and that the mechanism may involve the Na+/H+antiporter and PKC.
Airway hyperresponsiveness in neonatal chronic lung disease is treated with both furosemide, a diurectic that inhibits the Na-K-2Cl cotrasporter, and salbutamol, a β2-adrenoceptor agonist. Tachyphylaxis to both drugs in vitro has been described. This study was conducted to determine if the relaxation response in newborn guinea pig airways to furosemide and salbutamol can be cross-desensitized in vitro. Tracheal ring segments from 4- to 7-day-old guinea pigs were suspended in HEPES buffer for measurement of isometric tension. Segments were pre-treated with either furosemide (300 μM, 1 h) or salbutamol (10 μM, 30 min). After constriction with 3 μM acetylcholine, relaxation response to salbutamol or furosemide, respectively, was measured. Pretreatment with furosemide diminished relaxation response to salbutamol [87 ± 3% (n = 11) vs. 117 ± 8% (n = 10), p < 0.05], as compared to saline-treated controls. In addition, pretreatment with salbutamol diminished relaxation response to furosemide [53 ± 2% (n = 11) vs. saline-treated (83 ± 7%, n = 7, p < 0.05) and DMSO-treated controls (69 ± 5%, n = 5, p < 0.05)]. Measurements of 86Rb uptake, cyclic AMP levels and responses in the presence of charybdotoxin make it unlikely that Na-K-2Cl cotransporter activity, stimulation of cAMP, or opening of maxi-K+ channels are mechanisms involved in the cross-desensitization to furosemide and salbutamol in vitro.
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