Nutzen und Risiko von hochdosiertem Metoclopramid im Vergleich zu hochdosiertem Haloperidol oder Triflupromazin bei cisplatin-induziertem Erbrechen

Summary The antiemetic efficacy of metoclopramide (MCL, Paspertin®, loading infusion 0.5 mg/kg body wt./h over 2 h, maintenance infusion 0.25 mg/kg/h over 24 h) has been compared with haloperidol (HAL, Haldol®, 1/10 of MCL dosage) and with triflupromazine (TFP, Psyquil®, 1/2 of MCL dosage) in two sequential analyses, against the emetic effects of cisplatin (60–90 mg/m²).After treating 14 and 8 pairs of patients respectively, MCL was significantly (=0.05) more effective than HAL or TFP. Only 1 of the 14 patients in the HAL group and 0 of 8 in the TFP group were totally protected against emesis, in contrast to 6 of 14 patients and 3 of 8 in the MCL groups. In order to quantify the benefit/risk relationship of the antiemetic drugs studied the number of prevented emetic episodes (in comparison to previous insufficient treatment) was related to the incidence of major undesired effects (i.e. dystonia and/or akathisia). This relationship was 17.8 and 12.1 for the two MCL groups; for HAL and TFP it was only 5.8 and 4.6, respectively.The high antiemetic selectivity of MCL against cisplatin-induced emesis is probably related to the still unknown action of MCL on the gastrointestinal motility. A high neuroleptic potency, with or without additional anticholinergic activity, is apparently not essential for high antiemetic protection against cisplatin.

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Abkürzungen HAL Haloperidol - MCL Metoclopramid - TFP Triflupromazin     

Concentration effect relationships of infused histamine in normal volunteers

Histamine was infused in six normal volunteers at rates of 16, 32, 64 and 96 ng/kg/min increasing at 5-min intervals followed by 128 ng/kg/min for 45 min. Heart rate increased, diastolic blood pressure decreased and skin temperature increased in a dose-dependent fashion. Mean heart rate increased by 15.6±5.7 beats/min, mean diastolic pressure fell by 8.8±3.2 mmHg and mean skin temperature increased by 1.2±0.3°C at the highest infusion rate. Mean plasma histamine rose from a basal level of 0.20±0.03 ng/ml to 1.97±0.25 ng/ml at the end of the highest infusion rate. The threshold infusion rate for physiological effects was 64–96 ng/kg/min corresponding to 0.77–0.97 ng/ml. Salivary flow was stimulated by 21% after 30 min at the highest dose infusion (P=0.05). Plasma adrenaline increased 132% but plasma noradrenaline was unchanged.There was a linear decline in heart rate after terminating the histamine infusion with a half time of 82 sec. The half life of infused histamine in the plasma was 102 sec. The clearance of histamine from the plasma was 6.1±0.2 l/min or 83 ml/kg/min.These concentration effect relationships in normals throw doubt on some of the high endogenous plasma histamine values in the literature.     

Action du clopamide et de l'acide ethacrynique sur la sécrétion de rénine chez le chien

Summary Renin secretion was studied in anesthetized dogs (Pentobarbital), after an injection of 5 mg/kg i.v. clopamide (10 animals) or ethacrynic acid (10 animals). Renin activity in venous renal blood (Boucher's method), renal blood flow (electromagnetic flowmeter), blood pressure, diuresis and natriuresis have been measured simultaneously. Basic renin secretion was 22,4±8,2 ng/g of kidney/min. During the 8 min following the ethacrynic acid injection renin secretion increased to 74,4±41,1 ng/g of kidney/min (p<0.005). Within the same time it dropped to 11.1±6.8 ng/g of kidney/min (p<0.005) after clopamide.These variations of renin secretion are related to the diuretic's action on the nephron, and depend on an endorenal mechanism. Ethacrynic acid suppresses the corticopapillary gradient while clopamide does not. We have not found any correlation between renin secretion and either natriuresis (mg/min) or diuresis (ml/min). But there is a connection (r=0.7367) between renin secretion after ethacrynic acid injection and sodium concentration in urine.

     

Plasma histamine and clinical tolerance to infused histamine in normal,atopic and urticarial subjects

Five subjects with a recent history of urticaria (U), five atopic (A) subjects and a non-atopic (NA) control group were given intravenous infusions of histamine starting at 0.05 g/kg/min, increasing by 0.05 g/kg/min every 30 minutes to a maximum of 0.35 g/kg/min. Plasma histamine levels were monitored every 15 minutes. The infusion was stopped when an objective clinical endpoint was reached, involving either evidence of peripheral vasodilatation (rise of skin temperature by at least 1 °C) or a 20% fall of peak expiratory flow rate.There were no significant differences in resting plasma histamine in the three groups. Those with urticaria reached the clinical endpoint at a lower infusion rate than non-atopic subjects (U 0.22±0.02 g/kg/min; A 0.26±0.02 g/kg/min; NA 0.32±0.2 g/kg/min.p<0.008) they also received a lower total histamine dose (U 1.12±0.33 mg; A 1.42±0.38 mg, NA 2.2±0.51 mg,p<0.008). Atopic subjects with a history of asthma, eczema or rhinitis also tolerated histamine poorly, some subjects reaching a clinical endpoint while the plasma histamine level was still relatively low (U 1.52±0.4 ng/ml, A 0.85±0.19 ng/ml, NA 1.4±0.44 ng/ml,p=0.05). After the histamine infusion was stopped, the fall in the blood level of histamine was slower in urticarial subjects than in the other two groups, with a half-life of 6.2±1.3 min (A 3.0±1.2 min, NA 4.0±0.7 min,p<0.02). There were thus differences in the metabolism of histamine in our non-atopic urticarial subjects and increased histamine sensitivity in atopic subjects which require further study.     

Verhalten der renalen Funktionsreserve von Typ I Diabetikern: Einfluß der Konversionshemmung

Summary Renal functional reserve capacity was evaluated in 19 normotensive type I diabetics without microalbuminuria. All patients had normal basal renal function as assessed by 24-hour creatinine clearances higher than 120 ml/min. PAH, inulin, and creatinine clearances were carried out every hour before, during, and after infusion of an amino acid (AA) solution. The same experiment was repeated after ACE inhibition with captopril (25 mg). Two groups of patients were found: Group A (responders) showed a significant rise in GFR after AA infusion (inulin clearances from 117±8 to 138±10 ml/min) (p<0.05), whereas in Group B (non-responders) no significant change in GFR was observed. Groups were comparable in age, duration of diabetes, metabolic control, and mean arterial blood pressure.Group B, however, had a significantly higher basal inulin clearance (167±17 ml/min) than Group A (117±8 ml/min).In Group A ACE inhibition completely blocked the AA-induced rise in GFR, while basal GFR in Group B was significantly reduced (167±17 to 148±8 ml/min) after captopril administration. In both groups renal plasma flow was enhanced by ACE inhibition.A rise in glucagon was observed in all patients during AA infusion.It is concluded that type I diabetics with normal basal renal function already have reduced (Group A) renal functional reserve capacity, which is completely abolished (Group B) when concomitant hyperfiltration occurs. ACE inhibition reduces hyperfiltration and is capable of blocking the AA-induced rise in GFR in these patients.

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Abkürzungsverzeichnis ACE Angiotensin converting enzyme - ANP Atriales natriuretisches Peptid - AS Aminosäuren - BE Broteinheit - GFR Glomeruläre Filtrationsrate - PAH Paraaminohippursäure Herrn Prof. Dr. med. F. Scheler zum 65. Geburtstag gewidmet.     

Blood transfusion requirements in coronary artery surgery with and without the activated clotting time (ACT) technique

Summary Control of anticoagulation during cardiopulmonary bypass (CPB) with the automated activated whole blood clotting time (ACT) and reversal of heparin after CPB using a computerized ACT dose-response curve method resulted in significant reductions of blood transfusion requirements, surgical time, and protamine doses in 150 patients undergoing coronary artery bypass grafting procedures (ACT group) as compared to 200 patients for whom a standard fixed dose protocol for heparin and protamine was used (control patients). Mean transfusion requirements were 1,938±60 SEM ml whole blood and 853±48.3 SEM ml red blood cells for control patients and 1,397±59 SEM ml whole blood (P<0.001) and 695±34 SEM ml red blood cells (P<0.01) in the ACT group. ACT group patients also required less protamine with 26.2±0.60 SEM ml Protamine 1,000 (Roche) as compared to 33.9±0.49 SEM ml for control patients (P<0.001) but more heparin with 31,440±783 SEM I.U. versus 26,760±263 SEM I.U. (P<0.001). Surgical time decreased from 321±5.5 SEM min for control patients to 289±5.4 SEM min for ACT group patients (P<0.001).Abbreviations AB autologous blood - ACD right coronary artery - ACT activated clotting time - ACT_o ACT — before heparin administration - ACT₃₆₀ ACT — 5 min. after 360 I.U. heparin/kg body wt. - CPB cardiopulmonary bypass - Cx circumflex branch of the left coronary artery - DIAG diagonal branch of the left coronary artery - ECC extracorporeal circulation - FB fresh blood - FFP fresh frozen plasma - POD postoperative day - RBC red blood cells - RIA descending branch of the left coronary artery - RIP posterior descending branch of the right coronary artery - WB whole blood     

Systemic inflammatory mediators and cystic fibrosis genotype

Abstract. Morbidity and mortality in cystic fibrosis patients is mainly attributed to pulmonary infection and inflammation. Chemokines play a pivotal role in the inflammatory process. Although genotype-phenotype correlation in cystic fibrosis patients has been defined, a clear relationship between the defect in the cystic fibrosis transmembrane regulator (CFTR) gene and pulmonary inflammation has not been established. The aim of this study was to assess whether serum chemokines levels in cystic fibrosis patients correlate with genotype and pulmonary function tests, as well as with other clinical characteristics. Serum levels of interleukin-8, RANTES, and monocyte chemoattractant protein-1 were measured in 36 cystic fibrosis patients grouped according to their genotype. Group A included 25 patients who carried two mutations associated with a pathological sweat test and pancreatic insufficiency (F508, W1282X, G542X, N1303K, S549R). Group B included 11 compound heterozygote patients who carried one mutation known to cause mild disease with borderline or normal sweat test and pancreatic sufficiency (3849+10kb C to T, 5T). Associations between chemokine levels, genotype, pulmonary function, Pseudomonas aeruginosa colonization, age, sweat chloride level, and pancreatic and nutritional status were examined. Mean interleukin-8 and monocyte chemoattractant protein-1 levels were significantly higher in group A than group B (11.4±2.1 pg/ml vs. 5±0.9 pg/ml and 157±16 pg/ml vs. 88.8±16.4 pg/ml, respectively) (P<0.01). No difference in RANTES levels were found between groups. interleukin-8 levels were inversely related to forced expiratory volume in 1 s (r=-0.37, P<0.02), while there was no association between the latter and RANTES and monocyte chemoattractant protein-1 levels. The Pseudomonas colonization rate was higher among group A patients than group B (88% vs. 40%, P<0.01). No relationship was found between measured chemokines and age, sweat chloride levels, and pancreatic and nutritional status. Our study demonstrates an association between interleukin- 8, forced expiratory volume, and cystic fibrosis genotype. Hence, elevated interleukin-8 serum levels could serve as an indicator of an early inflammatory process and encourage the initiation of anti-inflammatory treatment.     

Kinetics and cardiac effects of propranolol in humans

Summary Six healthy volunteers received single 20-mg intravenous (IV) and 80-mg oral doses of propranolol on two occasions in random sequence. Serum propranolol concentrations were determined by gas chromatography in multiple samples drawn during 24 h after each dose. Mean (±SE) kinetic variables for IV propranolol were: elimination half-life (t1/2), 5.3 (±0.6) h; volume of distribution, 2.3 (±0.3) l/kg; total clearance, 4.9 (±0.3) ml/min/kg; predicted extraction ratio, 0.23 (±0.02). After single oral doses, t1/2 (3.8±0.2 h) tended to be smaller than after the IV dose, and actual systemic availability (0.60±0.07) was less than that based on the predicted extraction ratio. During multiple oral dosage (80 mg every 12 h), observed steady state serum levels (47±5 ng/ml) tended to be less than those predicted based on the single oral dose (61±5 ng/ml), thus providing no evidence for reduced propranolol clearance at steady-state. Echocardiographic measurements of left ventricular performance (posterior wall velocity, diastolic dimensions) made during the single-dose oral study indicated significant impairment of function; impairment was maximal at 3 h post-dosage, and corresponded to the time of the peak serum propranolol concentration (341 ng/ml).Supported in part by Grant Oc 10/6-3 from Deutsche Forschungsgemeinschaft, Bonn-Bad Godesberg, FRG; and by Grant MH-34223 from the United States Public Health Service     

Effect of H1- and H2-receptor antagonists on the hemodynamic changes induced by the intravenous administration of ketamine in sevoflurane-anesthetized cats

Objective: The anesthetic ketamine has been reported to cause both an increase of the plasma histamine concentration, notably in cats, and a cardiovascular depression. The latter has been described in humans and in other species. However the relevance of the histamine fluctuation for the ketamine-induced hemodynamic changes has not been determined.Subjects and treatment: We studied the contribution of histamine to the hemodynamic effects induced by IV ketamine (7 mg/kg) in 12 sevoflurane anesthetized cats, of which half had been pre-treated with combined H₁- and H₂ -receptor antagonists.Methods: The mean arterial pressure (MAP) and the heart rate (HR) from both untreated (group C) and pre-treated (group AH) cats were recorded before and after the ketamine administration. The plasma histamine concentration was also measured.Results: Plasma histamine fluctuations in the control and the antihistamine-treated group followed a similar pattern (no statistical differences); an initial rise that peaked 2 min after ketamine injection (from 0.63 ± 0.11 ng/ml to 2.22 ± 0.69 ng/ml in the C group, and from 0.71 ± 0.10 ng/ml to 1.09 ± 0.28 ng/ml in the AH group) followed by an immediate decrease in plasma concentrations. As for the hemodynamic variables under analysis, in the control group ketamine administration was followed by an early 30.3 ± 8.1% reduction (p < 0.005) in the MAP with no associated changes in the HR. In the antihistamine pre-treated group, ketamine caused a further decrease of the MAP (41.7 ± 2.3%), and a significant (p < 0.01) 11.6 ± 2.9% reduction of the HR.Conclusion: Ketamine in anesthetized cats triggers histamine release and induces cardiovascular depression. The depression is more pronounced under the blockade of histamine activity through histamine receptor antagonists.Received 22 October 2004; returned for revision 5 January 2005; accepted by A. Falus 14 February 2005     

Changes in “Active” and “Inactive” renin in the juxtaglomerular apparatuses of rat nephrons and plasma induced by different salt intake

The juxtaglomerular apparatuses (JGA) of deep and superficial nephrons were isolated by microbiopsy or by microdissection. Inactive renin content was determined by acidification of JGA or plasma to pH 3.0.In rats with low salt intake the renin content of superficial JGA was 13.4±3.0 ng AI/JGA/h before and 20.4±3.4 ng AI/JGA/h (n=9,P<0.05) after acidification. The corresponding values for deep JGA were 9.1±1.2 ng AI/JGA/h and 12.7±2.7 ng AI/JGA/h (n=9,P<0.01). The plasma renin concentration was 54.1±15.0 ng AI/ml/h before and 56.0±10.6 ng AI/JGA/h (n=7, N.S.) after acidification.In rats with a normal salt intake the superficial renin JGA renin content was 11.6±2.3 ng AI/JGA/h before and 11.0 ±2.7 ng AI/JGA/h (n=9, N.S.) after acidification. The renin content of deep JGA was 4.6±0.6 ng AI/JGA/h before and 8.6±3.1 ng AI/JGA/h (n=9,P<0.005) after acidification. Plasma renin concentration was 34.5±4.7 ng AI/ml/h and did not change after acidification.In rats with a high salt intake superficial JGA content was 6.8±1.7 ng AI/JGA/h before and 8.4±2.1 ng AI/JGA/h (n=9, N.S.) after acidification. The corresponding values for deep JGA were 5.7±1.6 ng AI/JGA/h and 6.9±1.6 ng AI/JGA/h (n=9, N.S.) respectively. Plasma renin concentration was 13.1±1.1 ng AI/ml/h and this to 21.8±2.9 ng AI/ml/h (n=8,P<0.01) after acidification.These results suggest that although the synthesis of active and inactive renin is linked, the secretion of the two forms may be independent.     

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     

Zinc supplementation stimulates tetanus antibody formation and soluble interleukin-2 receptor levels in chronic hemodialysis patients

Summary Immunodepression in end-stage renal disease has been associated with zinc deficiency. In a controlled study serum zinc levels, serum concentrations of soluble interleukin-2 receptor (sIL-2R), and tetanus IgG antibody titers were measured in 65 hemodialysis patients before and after intravenous zinc supplementation for 2 months. The hemodialysis patients had significantly lower predialysis serum zinc concentrations compared to healthy controls (63 ± 1.65 versus 126 ± 4.6 g/dl, P < 0.001). Serum zinc concentrations increased to the normal range in the zinc-treated patients. After zinc substitution tetanus antibody titers rose significantly (0.81 ± 0.12 versus 1.22 ± 0.12U/ml, P < 0.01). Pretreatment sIL-2R levels were elevated in 95% of examined patients. A further increase in sIL-2R was observed after zinc supplementation (234 ± 14 versus 285 ± 21 U/ml, P<0.05). The results suggest that zinc induces the activation of T lymphocytes and T-cell dependent B lymphocytes in chronic uremic patients in vivo.Abbreviations IL-2 interleukin-2 - sIL-2R soluble interleukin-2 receptor     

Vascular Endothelial Growth Factor Is Increased in Patients With Preeclampsia

PROBLEM: This study was conducted to determine whether altered levels of vascular endothelial growth factor (VEGF) may play a role in the pathogenesis of preeclampsia. METHOD OF STUDY: Maternal plasma samples were collected from 19 patients with preeclampsia (group A) either before the onset of labor, or before induction of labor or medical intervention. Plasma samples were also obtained from 19 normotensive patients with uncomplicated pregnancies (group B), who were matched with the patients with preeclampsia for gestational age and parity. Samples were frozen at ?70°C until assayed for VEGF by a specific enzyme-linked immunoassay. RESULTS: The mean maternal age was similar in groups A and B. For both groups the VEGF was detectable in all plasma samples. However, the plasma concentrations of VEGF were significantly increased in the group A patients, compared with those in group B (median, 47ng/ml; range, 10.6–72 ng/ml versus median, 13.6 ng/ml; range, 0.66-20 ng/ml; P < 0.001). In group A, a positive correlation was noted between VEGF concentrations and the systolic and diastolic blood pressure (r = 0.56; P = 0.01 and r = 0.48; P = 0.037, respectively). CONCLUSIONS: Maternal plasma VEGF levels were elevated in the patients with preeclampsia and correlated with the severity of hypertension, suggesting a role for VEGF in the pathogenesis of preeclampsia.     

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     

Cardiovascular and adrenal sensitivity to angiotensin II in essential hypertension

Summary Regulation of aldosterone secretion by sodium chloride is impaired in a group of essential hypertensives: high-salt diet fails to suppress aldosterone in these patients despite low renin values. The mechanism of this impaired regulation of aldosterone has not been clarified so far. We tested the sensitivity of aldosterone secretion and blood pressure to A II in 20 normotensive controls (aged 20–60, MAP 92±3 mm Hg), in ten normotensives with one or two parents with hypertension, and in 21 patients with essential hypertension (aged 17–65, MAP 119±4 mm Hg). After a period of 6 days on high-salt intake (300–320 mEq Na⁺/day), A II (0.1, 0.5, 1.0 and 2.0 ng/kg/min) was infused, each concentration for 30 min. According to aldosterone excretion during sodium loading, patients were divided into group A with complete suppression (n=12, aldosterone excretion 3.6±0.4 µg/day) and in group B with insufficient suppression (n=9, aldosterone excretion 15.5±2.3 µg/day). Despite similarly low plasma renins, rise of serum aldosterone levels during A II infusion was significantly higher in group B patients than in group A patients and normotensive controls. Rise in mean arterial blood pressure, however, brought about by graded A II infusion was similar in both groups of hypertensives and in normotensive controls. The results demonstrate an increased adrenal sensitivity to A II in a subgroup of essential hypertensives only. A similar adrenal hypersensitivity to A II found by others in patients with hyperaldosteronism due to adrenal hyperplasia supports the hypothesis that the same mechanism underlies both disorders.Abbreviations MAP mean arterial blood pressure - A II Angiotensin II Dedicated to Prof. Dr. W. Kaufmann on the occasion of his 60^th birthday     

Pharmakokinetik und kardiale Wirksamkeit von β-Acetyldigoxin und Digitoxin unter einer Kombinationstherapie mit Nifedipin

Summary The effect of nifedipine (N) on the pharmacokinetics and pharmacodynamics of -acetyldigoxin (AD;n=11) and digitoxin (DGT;n=10) was studied in 21 patients with cardiac insufficiency stage II–III NYHA. Glycoside plasma concentration and renal excretion as well as electrocardiogram heart rate, atrioventricular transconduction time (PQ), duration of electrical systole corrected for heart rate (QT_c), mean amplitude of T waves in leads V₂ to V₆ (T_V2–6) and systolic time intervals total electromechanical systole index (QS_2I), left ventricular ejection time index (LVET_I), pre-ejection period index (PEP_I), PEP/LVET-ratio were recorded repeatedly before and during coadministration of 40–60 mg/day N. Plasma AD concentrations were 0.64±0.22 ng/ml (mean±SD) before and 0.61±0.21 ng/ml during co-administration of N over 10–14 days, plasma DGT concentrations 13.9±4.1 ng/ml before and 13.7±4.5 ng/ml during co-administration of N over 4–6 weeks. Daily glycoside excretion was not affected by treatment with N. Heart rate and PQ-interval were not significantly changed during co-administration of N whereas T-wave flattening was intensified and QT-duration was lengthened. Concomitant treatment of AD and N led to an increase of PEP_I and PEP/LVET compared to AD alone in ten patients whereas the systolic time intervals after concomitant treatment of DGT and N in most patients did not differ from those after DGT alone. From our findings we conclude that N had no clinically significant effect on pharmacokinetics and pharmacodynamics of AD or DGT.

     

Nierenfunktion nach Infusionspyelographie

Zusammenfassung Glomeruläre Filtrationsrate (GFR=Inulin-Clearance), effektiver Nierenplasmastrom (RPF=PAH-Clearance), Diurese, osmolare Clearance und Natriumausscheidung wurden bei 25 Patienten mit normaler und unterschiedlich eingeschränkter Nierenfunktion infolge beidseitiger parenchymatöser Nierenerkrankungen nach Infusionspyelographie (Methylglucamin-Iothalamat) untersucht. Die Patienten wurden nach der Größe der GFR vor der Kontrastmittel (KM-) Infusion in Gruppen mit normaler (113,8±18,9 ml/min/1,73 m²), eingeschränkter (36,9±5,9 ml/min/1,73 m²) und stark eingeschränkter (11,1±4,2 ml/min/1,73 m²) Nierenfunktion eingeteilt.Die GFR änderte sich innerhalb von 2 Std nach Kontrastmittelinfusion bei den einzelnen Gruppen zwischen +2,4% und –12,4% des Kontrollwertes, wobei nur der Abfall bei eingeschränkter Nierenfunktion signifikant war. Der RPF fiel nicht signifikant zwischen 13,2% und 20,5%. Das Verhalten von GFR und RPF der einzelnen Gruppen wich statistisch nicht vom gemeinsamen Verlauf nach KM-Infusion ab. Die beobachteten Änderungen lagen in der methodischen und physiologischen Streubreite.Diurese, osmolare Clearance und Natriumausscheidung stiegen nach KM-Infusion bei normaler und eingeschränkter Nierenfunktion signifikant an. Das Ausmaß des Anstiegs war abhängig von der GFR. Es handelte sich um eine osmotische Diurese mit einer signifikanten Korrelation zwischen Urinfluß und osmolarer Clearance. Die Natriumausscheidung stieg infolge Abnahme der Natriumrückresorption signifikant an. Bei stark eingeschränkter Nierenfunktion kam es nicht mehr zu einer signifikanten osmotischen Diurese und Zunahme der Natriumausscheidung.

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Renal function after infusion pyelography

Summary The effect of infusion pyelography (meglumine iothalamate) on glomerular filtration rate (GFR), effective renal plasma flow (RPF), diuresis, osmolar clearance and sodium excretion was investigated in 25 patients with normal and reduced renal function. GFR was normal in 11 patients (113.8±18.9 ml/min/1.73 m²), moderately reduced (36.9±5.9 ml/min/1.73 m²) and severely reduced (11.1±4.2 ml/min/1.73 m²) in 7 patients, respectively.GFR was between mean +2.4% and –12.4% of control within 2 hours after infusion pyelography. The fall became significant only in patients with moderately reduced renal function. The decrease of RPF in the three groups was not significant between 13.2 and 20.5% of control. Changes of GFR and RPF in single groups did not differ statistically from the overall trend. The changes observed were within physiological variation range.Diuresis, osmolar clearance and sodium excretion increased significantly after infusion pyelography in patients with normal and moderately reduced renal function. The increase was in correlation with the GFR. The diuresis was osmotic, characterized by a significant correlation between urine flow and osmolar clearance. Tubular sodium rejection and urinary sodium excretion increased significantly. After infusion pyelography no significant osmotic diuresis and increase of sodium excretion occured in severely reduced GFR.

     

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     

The role of bactericidal/permeability-increasing protein in the treatment of primate bacteremia and septic shock

Human neutrophil azurophilic granules contain an 55-kDa protein, known as bactericidal/permeabilityincreasing protein (BPI), which possesses a high-affinity binding domain for the lipid A component of lipopolysaccharide (LPS). Thein vivo LPS neutralizing activity of exogenous BPI was studied in a model of lethalEscherichia coli bacteremia. Five baboons were treated with BPI (5 mg/kg bolus injection followed by a 95 g/kg/min BPI infusion over 4 hr), while four additional animals received a genetically engineered variant of BPI (NCY103). Five animals received a placebo treatment and served as controls. Both wild-type rhBPI and NCY103 significantly (P<0.05) decreased blood levels of LPS throughout an 8-hr evaluation period following live bacterial challenge. Two hours followingE. coli administration, LPS levels peaked in the controls, at 6.86±3.22 ng/ml, whereas LPS levels were 3.39±2.1 ng/ml in the BPI group and 2.04±1.18 ng/ml in the NCY103 group. Tumor necrosis factor-alpha (TNF-) and interleukin-6 levels likewise were attenuated in the treatment groups, whereas circulating sTNFR I was significantly (P<0.05) reduced only in the BPI group. Leukocytopenia and granulocytopenia were significantly (P<0.02) lessened in the BPI group, by an average of 59% leukocytopenia and 65% granulocytopenia, respectively. This study supports the concept ofE. coli LPS neutralization by BPIin vivo and demonstrates that a moderate (70%) reduction in peak LPS-LAL activity is sufficient to alter some hematologic and cytokine manifestations of bacteremia.     

Usefulness of low-priming-volume cardiopulmonary bypass circuits and dilutional ultrafiltration in neonatal open-heart surgery

In neonate open-heart surgery, cardiopulmonary bypass (CPB) with extreme hemodilution induces an increased capillary permeability and accumulation of extravascular fluid, resulting in organ dysfunction. We evaluated the effects of a reduced priming volume for CPB and dilutional ultrafiltration (DUF) during neonatal open-heart surgery. Nineteen consecutive neonates with complete transposition of the great arteries who underwent an arterial switch operation were retrospectively assigned into two groups: the high-priming-volume circuit group (group A, n = 9) and the low-priming-volume circuit group (group B, n = 10). Patients in group B underwent surgery with a miniaturized CPB circuit and using the DUF technique. The priming volume of group B was nearly two-thirds that of group A. The water balance value after CPB and surgery was significantly lower in group B (–126 ± 118ml, –116 ± 116ml) than in group A (88 ± 218ml, 83 ± 165ml). Systolic blood pressure just after CPB was higher in group B (67.9 ± 9.1mmHg) than in group A (55.4 ± 10.3mmHg). Postoperative ventilatory support was shorter in group B (45 ± 19h) than in group A (68 ± 27h). In neonatal cardiac surgery, low-priming-volume CPB circuits and DUF improve the water balance during surgery and may attenuate any inflammatory reaction, which would help preserve postoperative organ function.