Pharmacokinetics and absolute bioavailability of diltiazem in humans

Summary Six healthy male volunteers received single doses of diltiazem hydrochloride on three occasions separated by at least 10 days. Modes of administration were: 10-minute intravenous infusion of a 20-mg dose; oral administration of 120 mg in solution form; and oral administration of 120 mg as two 60-mg sustained-release tablets. Diltiazem concentrations were measured by electroncapture gas chromatography in multiple plasma samples drawn during the 36 hours after dosage. Following intravenous administration, mean (±S.E.) pharmacokinetic variables were: elimination half-life, 11.2 (±2.1) hours; volume of distribution, 11.1 (±3.0) liters/kg; and total clearance, 11.5 (±0.7) ml/min/kg. Oral diltiazem in solution form was rapidly absorbed, with peak plasma levels attained at 38 (±6) minutes after the dose. Absolute systemic availability averaged 44% (±4%). Oral administration of sustained-release tablets yielded, as predicted, slower absorption, with peak plasma concentrations attained at an average of 165 (±22) minutes after dosage. Thus, oral diltiazem is incompletely bioavailable after oral administration, mainly because of first-pass hepatic extraction.Supported in part by Grant Oc 10/6-3 from Deutsche Forschungsgemeinschaft, Bonn-Bad Godesberg, and by a Grant from Gödecke AG, Freiburg, West GermanyIn part presented at Frühjahrstagung der Deutschen Gesellschaft für Herz- und Kreislaufforschung, Bad Nauheim 1982 [7]     

Kinetics of 1,2-dinitroglycerin following sustained release nitroglycerin: Influence of propranolol and metoprolol

Summary Ten healthy volunteers ingested a single 18-mg oral dose of sustained release nitroglycerin (TNG) (Giulini-Pharma) on three occasions: once in the control state, once during coadministration of propranolol (80-mg three times daily), and once during coadministration of metoprolol (100-mg twice daily). The degree of beta adrenergic blockade was evaluated by the metaproterenol infusion test. Plasma concentration of TNG and its major metabolite, 1,2-dinitroglycerin (DNG), during 12 h after each dose were measured by gas chromatography-mass spectrometry. Intact TNG was not detected in the plasma of any patient. The major metabolite, DNG, was easily measurable in blood, and had a biphasic plasma concentration profile. Coadministration of the beta-blockers had no influence on any of the kinetic variables for DNG. The mean values during control, propranolol, and metoprolol trials of DNG elimination half-life were: 1.35, 1.10, and 1.09 h; total area under the curve: 42, 38, and 42 ng/ml × h; oral clearance: 6.6, 7.2, and 6.4 liters/min. Thus TNG when administered as a sustained release oral preparation is rapidly and completely transformed to DNG. There was no pharmacokinetic interaction between sustained release TNG and two commonly used beta-blocking agents, suggesting that any clinical interaction that may-occur between sustained release nitroglycerin and beta-blocking agents is pharmacodynamic rather than pharmacokinetic in nature.Abbreviations AUC Area under curve - DNG 1,2 Dinitroglycerin - h hour - min Minute - ml Milliliter - ng Nanogram - ns not significant - TNG Nitroglycerin Supported in part by Grant OC 10/6-4 from Deutsche Forschungsgemeinschaft and by Grant MH-34223 from the United States Public Health Service.Dedicated to Prof. Dr. H.J. Dengler's 60th year     

Desmethyldiazepam kinetics after intravenous,intramuscular, and oral administration of clorazepate dipotassium

Summary The pharmacokinetics and bioavailability of desmethyldiazepam (DMDZ), formed from its precursor clorazepate (CZP) dipotassium, were assessed in a series of 17 healthy volunteers aged 21–66 years. After a single 20-mg intravenous dose of CZP, mean kinetic variables for DMDZ were: volume of distribution, 1.24 l/kg; elimination half-life, 65 h; total clearance, 0.24 ml/min/kg. Among males, DMDZ half-life tended to be prolonged and clearance reduced with age, but this was not true for females. After oral administration of 20 mg CZP, appearance of DMDZ in the circulation was rapid; the mean peak plasma level was 356 ng/ml, reached an average of 0.9 h after dosage. Based on comparison with IV dosage, systemic availability of DMDZ was complete (100% absorption). Ten of the subjects also received a single 20-mg intramuscular dose of CZP. Mean peak DMDZ levels were 290 ng/ml, reaching an average of 2.7 h after dosage. Systemic availability of DMDZ was complete. Elimination half-life of DMDZ for a given individual was highly replicable from trial to trial regardless of the route of CZP administration.Part of doctoral thesis E. Steinhaus, University of Bonn 1982     

Elevation of Transforming Growth Factor-β1 Is Associated with Recurrent Miscarriage

To investigate the significance of transforming growth factor-1 (TGF-1) in reproduction we have compared plasma levels in normal pregnant women and patients suffering miscarriages. We examined 188 normal pregnant women and 12 pregnant women with miscarriages. Eight women with severe recurrent miscarriages (mean ± SD of previous number of miscarriages; 10.4 ± 2.4 times) were also examined before conception; 34 nonpregnant women served as controls. Plasma TGF-1 level increased with the gestational week and returned within the normal range 1 month after delivery. The levels among pregnant women with miscarriages (mean ± SD; 2.44 ± 0.83 ng/ml) were significantly higher than those of pregnant controls (1.74 ± 0.95 ng/ml) of matched gestational weeks; levels among nonpregnant women with severe recurrent miscarriages were extremely elevated (4.1 ± 3.04 ng/ml) compared to the control value (1.34 ± 0.59 ng/ml). These data suggest that TGF-1 may be necessary to maintain pregnancy but also may be a risk factor for recurrent miscarriages.     

Loxosceles Spider Venom Induces the Production of α and β Chemokines: Implications for the Pathogenesis of Dermonecrotic Arachnidism

Bites from the brown recluse spider and other Loxosceles arachnids result in dermonecrotic skin lesions. Neutrophils (PMN) are essential to the development of Loxosceles-induced skin lesions, but paradoxically, in vitro PMN activation is inhibited by direct exposure to Loxosceles venom. Neutrophil activation occurs in response to a myriad of soluble mediators that include members of both the and chemokine families. Because arachnid envenomation results in the exposure of several different cell types to venom, we investigated venom-induced expression of and chemokines in both endothelial cells (human umbilical vein; HUVEC) and epithelial cells (A549 pneumocytes). Chemokine-specific capture enzyme immunoassays (EIA) were used to measure Loxosceles deserta venom-induced chemokines: interleukin-8 (IL-8), growth-related oncogene-alpha (GRO-), and chemokines: monocyte chemoattractant protein-1 (MCP-1), and regulated on activation, normal T cell expressed and secreted (RANTES) in cell-free conditioned media from HUVEC and A549 cell monolayers. Exposure of HUVECs (8 h) to Loxosceles venom resulted in the production of IL-8 (5.2 ± 1.30 ng/ml), MCP-1 (1.44 ± 0.11 ng/ml) and GRO- (1.97 ± 0.15 ng/ml) in a dose and time-dependent manner. Exposure of A549 cell monolayers to venom resulted in IL-8 (7.74 ± 0.30 ng/ml), and MCP-1 (2.61 ± 0.31 ng/ml), but neither GRO- nor RANTES accumulated during an 8-hour incubation period. Chemokines accumulated in a venom dose and time-dependent manner. Neither cell type secreted RANTES in response to Loxosceles venom. These data indicate that Loxosceles spider venom is a potent inducer of and chemokines in both endothelial and epithelial cell types. Based on the established roles of IL-8, MCP-1, and GRO-, in inflammation, these observations have relevance to the pathophysiology of Loxosceles-Induced dermonecrosis.     

Pharmacokinetics of ciprofloxacin in healthy volunteers after oral and intravenous administration

The pharmacokinetics of ciprofloxacin was studied in three groups of healthy volunteers comprising a total of 16 males and 16 females (age 21–35 years; body weight 52–80 kg). Single oral doses of 50, 100, 250, 500 and 750 mg were given to fasting subjects. The 250 mg dose was repeated after a breakfast. Intravenous doses of 50, 100 and 200 mg were given by short infusion in a randomized cross-over sequence. Concentrations of the drug in serum and urine were determined by high-performance liquid chromatography and by a microbiological assay. Mean peak concentrations between 0.37±0.49 mg/l (100 mg dose) and 1.97±0.50 (750 mg dose) were measured 60–75 min after oral administration. Twelve hours after 750 mg ciprofloxacin, serum concentrations were 0.15±0.05 mg/l. Taking a breakfast reduced absorption by 15–20% compared to the fasting state, as judged by peak concentrations, AUC and renal excretion. After 200 mg i. v. (20 min infusion period), initial serum concentrations of 4.0±1.2 mg/l were observed which declined 12 h later to 0.070±0.025 mg/l. Mean cumulated recovery of ciprofloxacin from urine over 24 h varied between 25.5% and 33.6% of oral doses and between 53.2% and 57.4% of intravenous doses. Two of the three metabolites seen in the chromatograms were identified as M1 and M3 (oxo-ciprofloxacin). Cumulated renal excretion after an oral 250 mg dose was 1.2±0.4% of M1 and 5.5±1.6% of M3. Bioavailability of oral doses varied from 0.64±0.16 (100 mg) to 0.52±0.11 (500 mg). The AUC was linearly proportional to a single dose of up to 250 mg. Ciprofloxacin was rapidly absorbed and distributed. High distribution volumes were calculated (mean VD_area 186–217 1). The terminal half-life (t₁/2) was 3.1 to 5.4 h. Mean total body clearance was also high (600 to 693 ml/min · 70 kg)). Tolerance of ciprofloxacin was good for all oral doses and for intravenous administration up to 100 mg per dose. Intravenous infusion of 200 mg ciprofloxacin caused transient local irritation.     

Disposition of oxazepam in relation to age,sex, and cigarette smoking

Summary The kinetics of single 30-mg oral doses of oxazepam were determined in 22 male and nine female volunteers aged 20–86 years. Oxazepam plasma concentrations were measured in multiple plasma samples drawn during 36 h after each dose. Mean kinetic variables in males and females, respectively, were: elimination half-life, 7.5 and 8.5 h; volume of distribution, 0.96 and 1.17 l/kg; clearance, 1.48 and 1.70 ml/min/kg. Sex differences were not significant, nor were any of the kinetic variables significantly related to age. However, oxazepam clerance increased significantly with heavier cigarette smoking (r=0.48,p<0.01). Mean clearance in smokers (1.98 ml/min/kg) was significantly higher than in non-smokers (1.23 ml/min/kg,p<0.01). Thus, smoking is a more important determinant of oxazepam clearance than age or sex.Supported in part by Grant Oc 10/4 from the Deutsche Forschungsgemeinschaft, Bonn-Bad Godesberg, Federal Republic of Germany; and Grant MH-34223 from the United States Public Health Service     

Enhanced drug metabolism after sulfinpyrazone treatment in patients aged 50 to 60 years

Summary The induction of liver drug metabolism was investigated in five patients before and after the administration of 800 mg sulfinpyrazone daily for 4 weeks, by using antipyrine plasma-pharmacokinetics and by determining urinary excretion of 6--OH-cortisol and serum gamma-glutamyl-transpeptidase (GGT) activity. Antipyrine half-life was shortened in all patients from a mean value of 12.3±3.9 h to 7.8±2.0 h and antipyrine clearance was increased from 39.0±16.0 ml/min to 57.6±13.7 ml/min. In contrast the volume of distribution of antipyrine was unaffected; the values being 38.0±8.6 liters and 37.4±5.7 liters, respectively. In all patients the excretion of 6--OH-cortisol in the urine went up from 65.0±25.7 µg/24 h to 346.8±193.4 µg/24 h. The ratio 6--OH-cortisol/free cortisol changed from 4.1 to 15.8. After 21 days of treatment the GGT increased from 17.4±4.9 units/liter to 32.6±12.5 units/liter The data presented confirm that sulfinpyrazone induces drug metabolism in patients of the older age group. Interactions between sulfinpyrazone and other drugs given simultaneously must be borne in mind.     

Pharmacokinetics and pharmacodynamics of intravenous digoxin and digitoxin

Summary Healthy volunteers received single 1.0-mg doses of intravenous digoxin (n=10) or digitoxin (n=12). Glycoside pharmacokinetics were determined from multiple plasma samples drawn over the 48 hours (for digoxin) or 14 days (for digitoxin) after the dose. Electrocardiogram, echocardiogram, and blood pressure were recorded at multiple time points 24 h after the dose. To control for nonspecific cardiovascular changes, pharmacodynamic measurements were repeated on a second occasion for 8 hours after an intravenous injection of saline. Mean (±S.E.) kinetic variables for digoxin were: volume of distribution (Vd), 8.3 (±0.6) l/kg; elimination half-life (t1/2), 49 (±5) h; clearance 2.1 (±0.2) ml/min/kg. Changes in blood pressure, ventricular rate, and corrected QT-interval attributable to digoxin were small. However, echocardiographically-determined mean rate of circumferential fibre shortening (mVcf) and ejection fraction (EF) increased significantly following digoxin when compared to saline infusion. Changes were maximal at 4–6 h after dosage, and were highly correlated with plasma digoxin concentration. mVcf and EF returned to baseline by 24 h post-dosage. Mean kinetic variables for digitoxin were: Vd, 0.63 (±0.03) l/kg; t1/2, 7.3 (±0.4) days; clearance, 0.043 (±0.003) ml/min/kg. Like digoxin, digitoxin infusion produced minimal change in blood pressure, ventricular rate, or QT-interval. However, mVcf and EF increased significantly when compared to saline control. Changes were maximal at 4–8 h after infusion, and were correlated with plasma digitoxin concentration; at 24 h post-dosage, mVcf and EF were still increased over baseline. Thus, digoxin and digitoxin significantly increase myocardial contractility in healthy humans, but without important change in heart rate and blood pressure. Changes in contractility are of slow onset, probably due to slow distribution of glycoside to sites of pharmacologic activity.Supported in part by Grant Oc 10/4 from Deutsche Forschungsgemeinschaft, Bonn-Bad Godesberg, FRG; and by Grant MH-12279 from the United States Public Health Service     

Influence of propranolol coadministration or cigarette smoking on the kinetics of desmethyldiazepam following intravenous clorazepate

Summary The influence of propranolol coadministration or of cigarette smoking on the kinetics of desmethyldiazepam following a single 20-mg intravenous dose of clorazepate dipotassium was evaluated in healthy volunteers. In Study One, intravenous clorazepate was given once in the control condition, and again during coadministration of propranolol, 80 mg twice daily. Compliance with the prescribed propranolol regimen was verified by measurement of serum propranolol concentrations (mean, 37 ng/ml). In control vs propranolol treatment conditions, there was no significant difference in desmethyldiazepam volume of distribution (1.27 vs 1.23 liters/kg) or in free fraction in serum (1.83 vs 1.80% unbound). There was a small although statistically significant prolongation of desmethyldiazepam half-life (55 vs 61 h,P<0.05) and reduction in clearance (0.281 vs 0.247 ml/min/kg,P<0.02) attributable to propranolol. In Study Two, desmethyldiazepam kinetics were compared in eight cigarette smokers (mean, 19 cigarettes/day) and in 11 nonsmoking controls matched for age, sex, and body weight. There was no significant difference between controls and cigarette smokers in desmethyldiazepam volume of distribution (1.29 vs 1.34 liters/kg), elimination half-life (55 vs 59 h), clearance (0.284 vs 0.276 ml/min/kg), or free fraction in serum (1.96 vs 1.92% unbound). Thus, propranolol slightly although significantly impairs the clearance of desmethyldiazepam and prolongs its halflife. Cigarette smoking has no apparent influence on desmethyldiazepam kinetics.Supported in part by grants Oc 10/6–4 from the Deutsche Forschungsgemeinschaft and grants MH-34223 and AG-00106 from the United States Public Health ServicePart of doctoral thesis J. Weinbrenner, Bonn 1986     

Decreased serum levels of TGF-β in patients with acutePlasmodium falciparum malaria

Apart from cellular immunity and immunopathology, various cytokines have been implicated in malaria-associated immunosuppression. In this study, serum levels of transforming growth factor- (TGF-) were determined with an enzyme-linked immunosorbent assay in 37 patients with acutePlasmodium falciparum malaria prior to, during, and after therapy and in 17 healthy controls in Bangkok, Thailand. Patients were treated with artesunate and mefloquine. TGF- serum levels were found decreased prior to treatment (14±11 pg/ml versus 63±15 pg/ml in healthy controls;P<0.05). The serum concentrations of TGF- increased after initiation of treatment and were within normal range on day 21. Serum levels of both tumor necrosis factor-ga (TNF-) and soluble TNF-receptor 55 kDa were inversely correlated to serum levels of TGF- (r= –0.667 andr=}-0.592, n=37; respectively,P < 0.05 for both). No correlation between parasitemia and serum levels of TGF- could be found. The results are compatible with a decreased production and release, an enhanced clearance or utilization, or tissue accumulation of TGF- in acuteP. falciparum malaria.     

Kein Einfluß von Digitalis auf Sexual-und Nebennierenrindenhormone bei gesunden Probanden und bei Patienten mit Herzinsuffizienz

Summary Digoxin was studied to see whether it impairs adrenal function and feminizes male subjects by changing plasma sexual hormones; both have been reported on previously. In eight healthy male subjects neither estrone (38.7±7.7 vs 35.4±3.2 pg/ml) nor estradiol (35.8±6.4 vs 32.2±3.9 pg/ml) nor testosterone (6.32±0.74 vs 6.45±0.73 ng/ml) were found to be altered by digoxin administration (plasma levels 1.55±0.27 ng/ml) lasting 35 days. The same was true of free testosterone (147±24 vs 142±19 pg/ml) and free estradiol (657±77 vs 615±78 fg/ml). Even maximal stimulation of the adrenal and gonadal glands by adrenocorticotropic hormone (ACTH) and human chorionic gonadotropin (hCG) did not exhibit any digoxin-induced alterations in the synthesizing capacity of steroid hormones, as shown by plasma cortisol (increase from 128±18 to 389±18 ng/ml) and testosterone (from 5.96±0.90 to 10.33±1.19 ng/ml). Furthermore, seven subjects on digoxin were observed over a period of 150–210 days; they did not show any increase of estrogens. This was also found in three subjects when estrogen levels were elevated initially due to extreme obesity. Also, 35 patients who took -methyldigoxin (n=8), -acetyldigoxin (n=20) and digitoxin (n=7) from 1 to 9 (x:1.9) years demonstrated normal plasma concentrations of gonadal and adrenal steroids, irrespective of duration of application or the digitalis compound. However, our studies showed that sexual hormones are correlated to cardiac performance: with decreasing cardiac index, testosterone (r: 0.86;P<0.01) and estradiol (r: 0.68;P<0.05) decreased significantly. We conclude that digoxin does not exert any influence on plasma sexual steroids. Since no competition between digoxin and estradiol receptors was found, it may even be the digitalis compound of choice when feminization is expected due to other complications. Furthermore, on digoxin the adrenal gland is capable of synthesizing cortisol sufficiently.

Unterstützt durch die Deutsche Forschungsgemeinschaft (Kl 346)     

Caffeine elimination: A test of liver function

Summary Fasting plasma caffeine concentration and various parameters of caffeine elimination from plasma obtained after a standardized oral dose of 140 mg caffeine have been compared in nine patients with liver cirrhosis, eight patients with non-cirrhotic liver disease and ten healthy volunteers with regard to their ability to discriminate between the different groups. Fasting plasma caffeine concentrations were significantly higher in cirrhotics (11.1±10.5 mol/l) than in healthy volunteers (1.5±0.8 mol/l). The respective values measured in patients with non-cirrhotic liver disease (3.1±3.1 mol/l) did not differ significantly from the controls. Plasma disappearance rate and clearance of caffeine were significantly decreased in cirrhotics (0.11±0.02 h^–1; 1.0±0.3 ml/min per kg) and in patients with non-cirrhotic liver disease (0.18±0.04 h^–1; 2.2±0.7 ml/min per kg) as compared to healthy volunteers (0.23±0.04 h^–1; 3.1±0.9 ml/min per kg). Plasma caffeine concentration determined 12 h after administration of the test dosage discriminated best between patients with cirrhosis (5.4±1.6 mol/l), patients with noncirrhotic liver disease (2.0±1.4 mol/l) and healthy volunteers (0.8±0.2 mol/l). These results, the safety of the test compound and the simplicity of a single caffeine determination in plasma 12 h after a standardized dose of caffeine make this test attractive for evaluation of liver function.     

Hepatobiliary elimination of trovafloxacin and metabolites following single oral doses in healthy volunteers

Trovafloxacin, a fluoronaphthyridone derivative related to fluoroquinolones, has significant activity against gram-negative and gram-positive pathogens, including penicillin-resistantStreptococcus pneumoniae, anaerobes and atypical organisms, good tissue penetration and a long elimination half-life. Following oral administration, less than 10% of the dose is renally eliminated as unchanged drug. Hepatobiliary elimination of trovafloxacin was examined by comparing the time course and bile and serum concentrations of trovafloxacin and its metabolites following oral administration to three patients with in-dwelling nasobiliary catheters or T-tubes. Following a single 200 mg oral dose, the mean maximum plasma trovafloxacin concentration was 2.0±0.4mg/l, the area under the concentration-time curve 22.0±5.5 mg·h/l and the elimination half-life 8.5 h. Values in bile for the same subjects were 27.8±9.6 mg/l, 327.7±142.9 mg·h/l and 10.7 h. Corresponding values for the N-acetyl metabolite in bile were 3.8±3.4 mg/l, 35.3±29.8 mg·h/l and 8.3 h. The mean bile : serum ratio of trovafloxacin was 149 and consistent with biliary elimination. Serum concentrations of trovafloxacin in this study were similar to those reported in healthy volunteers. Bile concentrations of trovafloxacin substantially exceeded those of theN-acetyl metabolite, suggesting efficient clearance of the metabolite or that hepatic metabolism of trovafloxacin is not extensive.     

Glykosidkonzentration im Serum und Urin bei Herzgesunden nach Gabe von Beta-Methyl-Digoxin

Zusammenfassung 6 gesunde Probanden unterzogen sich einer oralen Sättigungsbehandlung mit -Methyl-Digoxin. Am Ende der Sättigungsbehandlung betrug die radioimmunologisch bestimmte Serumkonzentration 1,2±0,22 ng/ml; innerhalb von 24 Std wurden 55,9% der täglich zugeführten Glykosidmenge renal eliminiert. Die renale Clearance von -Methyl-Digoxin betrug 63±8,1 ml/min bzw. 57,5±8,3 ml/min/1,73 m². Nach Absetzen des Glykosids wurde die Serumeliminationshalbwertzeit mit 54 h ermittelt. Während der Sättigungsbehandlung ließ sich die Glykosidwirkung mit Hilfe des EKG's insbesondere durch Verkürzung der QT-Zeit sowie durch Verkürzung der frequenzkorrigierten Anspannungs- und Austreibungszeit nachweisen.     

Thrombolytic therapy with urokinase reduces increased circulating endothelial adhesion molecules in acute myocardial infarction

The aim was to investigate circulating E-selectin and Intercellular Adhesion Molecule-1 (ICAM-1) in acute myocardial infarction. Our study was carried out in 80 patients, 40 hospitalized for acute myocardial infarction (AMI), 20 suffering from chronic stable angina and 20 healthy control subjects. Samples of venous blood were taken from all patients at the moment of hospitalization and after 2, 4, 6, 8, 10, 12 and 24 hours from the thrombolytic treatment (AMI+urokinase) or conventional therapy (AMI+nitroglycerin), for the dosage of creatinine kinase (CK) and adhesion molecules. The CK was determined by means of a Hitachi 901 automatic analyser using an enzymatic method (reagents Boheringer-Biochemia, Germany). Soluble E-selectin (sE-selectin) and soluble ICAM-1 (sICAM-1) were measured in the serum using a specific immunoassay (British Biotechnology Products). The serum levels of Tumor Necrosis Factor (TNF-) were evaluated using an immunoenzymatic assay to quantitate the serum levels of the cytokine British Biotechnology Products). Patients with acute myocardial infarction (AMI) had increased serum levels of soluble E-selectin (sE-selectin; AMI+urokinase= 312±20 ng/ml; AMI+nitroglycerin=334±15 ng/ml) and soluble ICAM-1 (sICAM-1; AMI+urokinase= 629±30ng/ml; AMI+nitroglycerin=655±25 ng/ml) compared to both patients with chronic angina (sE-selectin =67±10 ng/ml; sICAM-1=230±20 ng/ml) and healthy control subjects (sE-selectin=53±15 ng/ml; sICAM-1 200±16 ng/ml). Furthermore patients with acute myocardial infarction also had increased serum levels of Tumor Necrosis Factor (TNF-=309±10 pg/ml; control subjects=13±5 pg/ml). Thrombolytic therapy with urokinase (1,000,000 IU as an intravenous bolus for 5 minutes, followed by an infusion of an additional 1,000,000 IU for the following two hours) succeeded in producing reperfusion and reduced the serum levels of sE-selectin (52±13 ng/ml) and sICAM-1 (202±31 ng/ml). In contrast patients not eligible for thrombolytic therapy and therefore treated with conventional therapy (a continuous i.v. infusion of nitroglycerin at the dose of 50 mg/die) did not show any significant reduction in both sE-selectin and sICAM-1 throughout the study. Our results confirm previous experimental data and indicate that adhesion mechanisms supporting leukocyte-endothelium interaction may also be operative in human acute myocardial infarction.accepted by I. Ahnfelt-Rønne     

Pharmacokinetic studies of high-dose metoclopramide with and without forced diuresis

Summary The pharmacokinetics of high-dose metoclopramide (10 mg/kg body wt. in five infusions of 2 mg/kg body wt. each) was studied in 11 patients (5 females, 6 males) in two groups: group A with and group B (consisting of five patients) without forced diuresis. When the drug was infused, forced diuresis had no influence on the pharmacokinetics of metoclopramide (serum level after the 1st infusion was 851±361 ng/ml in group A versus 840±348 ng/ml in group B; after the 5th infusion it was 2,005±588 ng/ml in group A versus 2,463±1,350 ng/ml in group B). There were significant differences in the 24-h serum levels (582±308 ng/ml in group A versus 379±170 ng/ml in group B;P<0.05) and in the elimination half life (8.5±2.6 h in group A versus 6.1±1.1 h in group B;P<0.05). The results demonstrate that the dosage regimen originally suggested by Gralla for cytostatic drugs, with forced diuresis for high-dose metoclopramide therapy, may also be applied, with no dosage reduction, with to other cytostatic drugs which do not require forced diuresis.     

GM-CSF counteracts hemorrhage-induced suppression of cytokine-producing capacity

Objective and design: To study whether a treatment with the hematopoietic growth factor GM-CSF restores the attenuated ex-vivo cytokine-producing capacity of macrophages after sublethal hemorrhagic shock.Subjects: Male Sprague-Dawley rats.Treatment: 20 g/animal of recombinant murine GM-CSF after shock via arterial line.Methods: Hemorrhagic shock was established by pressure-controlled bleeding to a mean arterial pressure of 50 mm Hg for 35–40 min and consecutive resuscitation. 24 h after hemorrhage, lipopolysaccharide (LPS)-induced cytokine production of isolated macrophages derived from different compartments was measured.Results: A significant reduction of LPS-induced TNF production was found in whole blood cultures (1.0 ± 0.7 ng/ml after sham vs. 0.23 ± 0.08 ng/ml after shock operation), macrophages derived from spleen (0.88 ± 0.23 ng/ml after sham vs. 0.03 ± 0.1 ng/ml after shock operation), peritoneum (2.2 ± 0.7 ng/ml after sham vs. 0.29 ± 0.4 ng/ml after shock operation) and bronchoalveolar fluid (0.65 ± 0.13 ng/ml after sham vs. 0.003 ± 0.027 ng/ml after shock operation, mean ± S.D.). In cells from animals treated with GM-CSF a significantly enhanced LPS-induced TNF production in splenic, alveolar and peritoneal macrophages was found after shock compared to the cells derived from untreated animals (peritoneum: 289 ± 366 ng/ml TNF after shock vs. 2066 ± 94 ng/ml TNF after shock and GM-CSF; lung: 9 ± 12 ng/ml TNF after shock vs. 64 ± 17 ng/ml TNF after shock and GM-CSF; spleen: 58 ± 96 ng/ml TNF after shock vs. 548 ± 47 ng/ml TNF after shock and GM-CSF). Blood cultures collected from rats after hemorrhagic shock did not show a significant increase of TNF-production after GM-CSF treatment.Conclusion: Hemorrhagic shock caused a depression of the TNFa response to LPS which was partly counteracted by treatment with GM-CSF. Therefore, GM-CSF represents a promising approach to normalise trauma- and shock-induced immune dysfunction.Received 4 April 2003; returned for revision 3 July 2003; accepted by A. Falus 25 August 2003     

Naloxone in treatment of circulatory shock resistant to conventional therapy

Summary The effect of naloxone (4.4–5.9 mg i.v.) was evaluated in 10 patients with circulatory shock (sepsis,n=7; intoxication,n=1; cardiogenic shock,n=2) not responding to full conventional therapy. In addition, we measured plasma ACTH and immunoreactive -endorphin before and 60 min after administration of naloxone and compared the results with hormone concentrations in 10 intensive care patients without shock. Only in two patient with septic shock a transient increase (duration 15 min and 60 min, respectively) of systolic blood pressure was observed, while naloxone was ineffective in the remaining eight patients. No adverse effects of naloxone were found. Plasma ACTH and immunoreactive -endorphin concentrations in patients with shock were not different from those in controls (ACTH, 79±28 vs 120±60 pg/ml; immunoreactive -endorphin, 952±262 vs 1,070±378 pg/ml).Our findings suggest that naloxone in a single dose of 4.4–5.9 mg i.v. does not improve the management of circulatory shock unresponsive to conventional treatment. -endorphin seems to play no major role in the hypotension of shock.Abbreviations ACTH Adrenocorticotrophic hormone - HD intermittent hemodialysis - HF heart rate - ir immunoreactive - RR_syst systolic blood pressure Supported by Landesamt für Forschung, NRW     

The source of urinary epidermal growth factor in humans

Summary To clarify the source of human urine EGF, we studied EGF renal clearance in 20 healthy, young adult subjects. Immunoreactive EGF was measured hourly in EDTA plasma, heparin plasma, serum and urine of 12 males and 8 females during a 3 h study period. Plasma and urine creatinine and creatinine clearance were measured and calculated hourly. Mean (and SEM) creatinine clearance was similar in males and females (118±12 vs 105±6 ml/min). EGF was not detectable in plasma, whereas relatively high levels were measured in serum (2.5±0.25 vs 1.5±0.18 ng/ml in males and females respectivelyp<0.05). Urine EGF excretion averaged 1641±233 ng/h in males and 1507±191 ng/h in females (p>0.05). A significant correlation was observed between urine creatinine and urine EGF concentrations in both male (r = 0.98,p<0.01) and female (r=0.94,p< 0.01) subjects. EGF immunoreactivity in urine and serum eluted from G-75 sephadex columns similarly to recombinant 6000 Mr hEGF. Urine excretion of EGF approximated 1.5 g/h or 25 ng/mg creatine. The high concentrations of EGF found in urine in the face of non-detectable levels of EGF in plasma favor the hypothesis that EGF in urine is derived from kidney synthesis and secretion. The significant positive correlation between urine creatinine and urine EGF suggests a functional correlation between glomerular filtration and the process of tubular EGF excretion.Abbreviations EGF epidermal growth factor - hEGF human epidermal growth factor - IGF insulin-like growth factor - TGF alpha transforming growth factor - TGF beta transforming growth factor - NGF nerve growth factor - PDGF platelet derived growth factor - CPDA citrate phosphate dextrose adenine buffer - EDTA ethylenedinitrilotetraacetic acid - PBS phosphate saline buffer