Flat panel detectors--closing the (digital) gap in chest and skeletal radiology.

In the radiological department today the majority of all X-ray procedures on chest and skeletal radiography is performed with classical film-screen-systems. Using digital luminescence radiography (DLR or CR, which stands for Computed Radiography) as a technique has shown a way to replace this 100-year-old procedure of doing general radiography work by acquiring the X-rays digitally via phosphor screens, but this approach has faced criticism from lots of radiologists world wide and therefore has not been widely accepted except in the intensive care environment. A new technology is now rising based on the use of so called flat panel X-ray (FD) detectors. Semi-conducting material detects the X-rays in digital form directly and creates an instantaneous image for display, distribution and diagnosis. This ability combined with a large field of view and compared to existing methods--excellent detective quantum efficiency represents a revolutionary step for chest and skeletal radiography and will put basic X-ray-work back into the focus of radiological solutions. This paper will explain the basic technology of flat panel detectors, possible system solutions based on this new technology, aspects of the user interface influencing the system utilization and versatility as well as the possibility to redefine the patient examination process for chest and skeletal radiography. Furthermore the author discusses limitations for the first released systems, upgrades for the installed base and possible scenarios for the future, e.g. fluoroscopy or angiography application.

Aminoguanidine inhibits albuminuria, but not the formation of advanced glycation end-products in skin collagen of diabetic rats.

Aminoguanidine, an inhibitor of advanced glycation reactions in vitro, inhibits the development of diabetic complications in animal models of diabetes, suggesting that it acts by inhibition of advanced glycation reactions in vivo. However, effects of aminoguanidine on the formation of specific advanced glycation end-products (AGEs) in vivo have not been rigorously examined. Therefore, we studied the effects of aminoguanidine on the formation of pentosidine and N(epsilon)-(carboxymethyl)lysine (CML), measured by analytical chemical methods, in collagen of streptozotocin-diabetic Lewis rats at doses which ameliorated urinary albumin excretion, an index of diabetic nephropathy. At 12 weeks, diabetic animals had fivefold higher blood glucose, threefold higher glycated hemoglobin and fivefold higher collagen glycation, compared to metabolically healthy controls; pentosidine and CML in skin collagen were increased by approximately 30 and 150%, respectively. Administration of aminoguanidine, 50 mg/kg by daily intraperitoneal injection, significantly inhibited the development of albuminuria (approximately 60%, P < 0.01) in diabetic rats, without an effect on blood glucose or glycation of hemoglobin or collagen. Surprisingly, aminoguanidine failed to inhibit the increase in pentosidine and CML in diabetic rat skin collagen. Similar results were obtained in an independent experiment in which aminoguanidine was administered in drinking water at a dose of 0.5 g/l. We conclude that the therapeutic benefits of aminoguanidine on albuminuria may not be the result of inhibition of AGE formation.

Effect of 17beta-estradiol-bisphosphonate conjugates, potential bone-seeking estrogen pro-drugs, on 17beta-estradiol serum kinetics and bone mass in rats.

In order to target 17beta-estradiol directly at bone we synthesized three 17beta-estradiol-bisphosphonate conjugates (E2-BPs) with different esterase-sensitive linkers between both molecular moieties. The systemic administration of these compounds should result primarily in local estrogenic effects on bone with no or negligible systemic hormonal effects. Only if a considerable margin exists between the doses required for inhibition of bone loss and those for systemic hormonal effects can such a pro-drug be considered acceptable for patients refusing systemic estrogen replacement therapy for several reasons. The conjugates were tested in vitro for their 17beta-estradiol release in rat serum and in vivo for their local and systemic effects in rats: in vitro, the conjugates expressed cleavage resistance, low cleavage (4.8%), or high cleavage (33.1%) within 48 hours of incubation. The conjugate with the low-cleavage doubled 17beta-estradiol serum half-life (3.78 hours) whereas the high-cleavage conjugate resulted in approximately four times higher serum half-life (8.36 hours) when compared with free 17beta-estradiol. In ovariectomized rats, bone loss was optimally prevented by 50 nmol/kg/day of 17beta-estradiol when administered S. C. over a period of 5 weeks, and protection against uterine atrophy was achieved at doses as low as 5 nmol/kg/day. The cleavage-resistant conjugate was ineffective in preserving bone and uterus in doses ranging from 5 to 150 nmol/kg/day. The other two E2-BPs revealed a dose-dependent inhibition of bone loss which was paralleled by the respective uterus weight with a dose range of 1.5-150 nmol/kg/day being fully effective in a range similar to 17beta-estradiol alone. The higher sensitivity of the uterus versus bone to protective estrogenic effects (1:10) was abolished by the conjugates. We conclude that E2-BPs containing esterase-sensitive linkers failed to act as bone-seeking pro-drugs expressing primarily local effects on bone without systemic effects.

Dose proportionality studies of novel thiazolidinedione derivatives as potent antidiabetic agents in mice.

The determination of the plasma concentrations of the new oral antidiabetic agents BM 13.1246 ((+/-)-5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy] benzyl]-2,4-thiazolidinedione), [sequence: see text] BM 13.1215 ((+/-)-5-[(5-methyl-2-phenyl-4-oxazolyl)-methyl-2- benzofuranyl-5-methyl]-2,4-oxazolidinedione), [sequence: see text] and BM 50.1050 ((+/-)-5[4-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy] naphthalyl]methyl-2,4-thiazolidinedione) [sequence: see text] in ob/ob mice plasma was performed by using liquid-liquid extraction and high-performance liquid chromatography with ultraviolet (270 nm) detection. The analytical procedures have recoveries of more than 80%, and a between-run precision of less than 4% for all analysed compounds. The pharmacokinetic behaviour, especially the dose proportionality, was investigated in ob/ob mice after repeated oral doses of 1 and 10 mg/kg, respectively. All compounds were absorbed quickly and attained maximum plasma concentrations within 2-5 h after administration. In the examined interval of dosing, an approximately proportional increase of the plasma levels for BM 13.1246 and BM 50.1050 was observed. After repeated oral doses the terminal half-lives are about 4 h for BM 13.1246, 8 h for BM 13.1215, and 6 h for BM 50.1050.

Pharmacokinetics of some new oral blood glucose-lowering agents in dogs.

The determination of the plasma concentrations of the new oral antidiabetic agents BM 17.0505 (2-(4-cyclopentylphenoxy)-7- (4-chlorphenyl)-heptanic acid), BM 13.1196 (2-(4-chlorphenyl)- heptanic acid), BM 13.1196 (2-(4-cyclopentylphenoxy)-7-(2-methoxy- phenyl)-heptanic acid: BM 13.1188 (2-(4-benzylphenoxy)-7-(2-methoxy- phenyl)-heptanic acid) and BM 13.1180 (2-(4-butylphenoxy)-5- (4-chlorphenyl)-pentanic acid) in dog plasma were performed by using liquid-liquid extraction and high-performance liquid chromatography with ultraviolet (220 nm) detection. The analytical procedures have recoveries of more than 90%, and a between-run precision of less than 5% for all analysed compounds. The pharmacokinetic behaviour, especially the dose proportionality, was investigated in dogs after a single oral dose of 5 and 50 mg/kg and repeated oral doses of 5 and 50 mg/kg, respectively. All compounds were absorbed quickly and attained maximum plasma concentrations within 1-3 h after administration. In the examined interval of dosing, a clear non proportional increase of the plasma levels was observed. After repeated oral doses the terminal half-lives are about 60-70 h (BM 17.0505), 80 h (BM 13.1196), 30 h (BM 13.1180) and 100-140 h (BM 13.1180).

[Which factors determine the critical hematocrit as an indication for transfusion?]. / Welche Faktoren bestimmen den Kritischen Hämatokrit bei der Indikationsstellung zur Transfusion?

The question as to what extent the hematocrit (Hct) is a strong indicator for or against the need for transfusion of whole blood or blood products is still controversial. In order to enable the clinician to make a definite decision, a number of aspects have to be taken into consideration. The human organism has only limited oxygen reserves, and these are even more limited under pathological conditions. Oxygen flux - the amount of oxygen transported by the blood in 1 min - is a critical factor in the oxygenation of the human body. Another critical factor is oxygen consumption, which is highly variable depending on the presence of conditions such as rest, shivering, seizures, hypothermia, etc. Furthermore, different organ systems have different oxygen consumption rates. The ratio of oxygen consumption to oxygen flux is referred to as the oxygen extraction rate or oxygen utilization. Under normal conditions oxygen uptake is independent of oxygen flux, and thus independent of blood flow. Under conditions of organ dysfunction, however, oxygen deficiency may be present without being recognized on standard clinical diagnostic parameters. The normal human organism has a number of possibilities to compensate for acute or chronic anemia, i.e., increases in cardiac output, organ perfusion, 2,3-DPG content, a shift in the oxygen dissociation curve, etc. These compensatory mechanisms may, however, be restricted or cease to function under conditions of acute or chronic disease. Arterial and mixed-venous PO2 and oxygen content are some of the parameters used to assess the oxygen reserves available to the organism even under critical conditions. Although oxygen content is the most significant of these parameters, accurate measurement of this parameter remains a problem of laboratory medicine. PVO2 is of only limited importance under conditions of anemia. Minimum oxygen content or minimum oxygen flux values should under no conditions be approximated during anesthesia or intensive care. The critical Hct as an indicator for or against transfusion of blood or blood products is considerably modified by restricted organ function, anesthesia, intensive care treatment, resuscitation, etc.(ABSTRACT TRUNCATED AT 400 WORDS)

Disposition of carvedilol enantiomers in patients with liver cirrhosis: evidence for disappearance of stereoselective first-pass extraction.

The racemic drug carvedilol exerts its antihypertensive action through vasodilation and nonselective beta-blockade. The R(+)-enantiomer has twice (31.1%) the absolute bioavailability than the S(-) form (15.1%). The pharmacokinetics of the enantiomers were investigated after intravenous (i.v.) (12.5 mg in 1 h) and p.o. (25 mg) administration of racemic carvedilol in six patients with cirrhosis of the liver according to a randomized crossover design. Although the difference between areas under the curve of R(+) and S(-) were of borderline significance after i.v. administration but significant after oral administration, no difference existed between the absolute bioavailabilities of R(+) (83.7%) and S(-) (71.3%). The enantiomer ratio is similar after i.v. (1.3) and p.o. administration (1.6). In contrast to healthy subjects, the apparent volume of distribution of S(-) is about 90% greater than that of R(+) in patients. The renal excretion of carvedilol and of one of its major metabolites, carvedilol glucuronide, also exhibited stereoselective behavior, but in opposite directions. In patients with liver cirrhosis, stereoselective metabolism of carvedilol is still operative. However, probably because of portocaval shunts, the hepatic first-pass extraction is markedly reduced, eliminating the difference in bioavailability between the two enantiomers.

Stereoselective disposition of carvedilol in man after intravenous and oral administration of the racemic compound.

The racemic compound carvedilol is a multiple-action oral antihypertensive drug that exhibits both vasodilator and non-selective beta-adrenergic blocking activities. The effects of the levorotatory S-enantiomer [S(-)-CARV] are vasodilatation and beta-blockade. The R(+)-enantiomer [R(+)-CARV] is a pure vasodilating agent. Quantitative determination of the enantiomers in human plasma by HPLC was carried out after formation of diastereoisomers with the chiral reagent 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl isothiocyanate (GITC). The pharmacokinetics of the enantiomers were studied following i.v. (12.5 mg in 1 h) and p.o. (50 mg) administration of racemic carvedilol in ten healthy male subjects according to a randomized crossover design. The AUCs of S(-)-CARV were significantly lower than those of R(+)-CARV after both i.v. and p.o. administration. The systemic clearance of the two enantiomers was significantly different, whereas half-lives and apparent distribution volumes were comparable. Following p.o. administration, the absolute bioavailability (31.1% and 15.1%, respectively) and maximal plasma concentrations of R(+)-CARV were twice those of S(-)-CARV. A similar difference was found in the half-lives. A close correlation existed between enantiomeric ratios after i.v. and after p.o. administration, demonstrating slight intraindividual variability. The preferential systemic clearance of the S(-)-enantiomer suggests stereoselective hepatic metabolism of carvedilol, becoming especially apparent after p.o. administration. The small intrasubject variability in enantiomer ratios indicates a relatively constant relation of beta-blockade to vasodilation during chronic treatment.

Pharmacokinetics and bioavailability of carvedilol, a vasodilating beta-blocker.

The pharmacokinetics and absolute bioavailability of carvedilol have been studied in 20 male healthy volunteers in a randomised 4-period, cross-over trial. Carvedilol 12.5 mg was given i.v., 50 mg was administered p.o. as a suspension and 25 and 50 mg were given in a capsule formulation. For the 50 mg capsule Cmax was 66 micrograms.l-1, tmax 1.2 h, t1/2 6.4 h. The t1/2 after i.v. administration was 2.4 h, CL 589 ml/min and VZ 132 l. The absolute bioavailability was 24% (50 mg capsule). The kinetics after the 25 and 50 mg capsules were consistent with dose linearity.

Pharmacokinetics and disposition of carvedilol in humans.

Pharmacokinetics of carvedilol (C) have been studied in healthy volunteers after a single i.v. and oral administration, and the metabolic disposition after oral administration of 14C-labeled drug. C demonstrates dose-linear behavior. The absolute bioavailability reaches 24% probably due to a first-pass effect. After a 50 mg oral dose, maximum concentrations of 66 micrograms/l are achieved within 1.2 h. C is extensively distributed to the tissues (Vz = 132 l) and eliminated primarily by hepatic metabolism (total clearance 590 ml/min, renal clearance 4 ml/min). Because of the longer half-life of 6.4 h after oral administration in contrast to 2.4 h after i.v. administration, C is assumed to be absorption dependent since no sustained-release formulation was used. The half-life of radioactivity in plasma is 39 h; 16% of C is excreted in urine in the form of metabolites and only 0.3% unchanged. The urinary metabolites consist of carvedilol glucuronide (5.2% of the dose), cleavage products of the beta-blocking side chain (2.1%), and ring-hydroxylated forms (2.9%). Sixty percent of the dose is recovered in the feces. A demethylated product of C exhibits only minor beta-blocking activity. This metabolite is detected in plasma in concentrations ten times lower than the parent compound.