European Journal of Clinical Pharmacology

Scherberich, J.; Wolf, G.; Schoeppe, W.

doi: 10.1007/BF01428390pmid: 8486145

228 44 44 1 1 J. E. Scherberich G. Wolf W. Schoeppe MD Abteilung Nephrologie Zentrum Innere Medizin Haus 23B Theodor Stern Kai 7 W-6000 Frankfurt/Main 70 Germany Summary Nephrotoxic drugs may account for approximately at least 20 % of clinically observed cases of acute renal failure in whom tubular lethal or sublethal damage is a predominant finding. Acute toxic tubular cell injury is characterized by loss of cellular polarization, intrinsic energy deficiency, calcium overload, release of toxic proteases and free oxygen radicals, derangement of the cytoskeleton, and vacuolar transformation of brush border microvilli. These events may finally lead to irreversible cell death. Shedding of membrane enzymes and cytoskeletal components in urine (kidney tissue proteinuria) may serve as a noninvasive early marker for assessing tubular cell injury. Successful recovery of renal function depends on early repair of lethally or sublethally damaged nephrons, in which intrinsic nephrogenic adaptive and proliferative responses cooperate in concert with auto/para/-juxtacrine growth promoting factors and cytokines. Exogenously administered growth factors may enhance renal cell recovery, as shown in animal models. Increased expression of immediate early genes in tubular cells after renal injury reflects the ongoing mitogenic activity necessary for reepithelialization and remodeling (new, polarized, differentiated cells). Further progress in understanding the molecular mechanisms of renal tubular injury will probably influence the diagnostic modalities and therapeutic approaches to acute drug induced renal failure.

Wolter, K.; Fritschka, E.

doi: 10.1007/BF01428395pmid: 8387427

228 44 44 1 1 K. Wolter PD Dr. E. Fritschka Abteilung für Nieren- und Hochdruckkranke Medizinische Klinik Universitätsklinikum Essen Hufelandstrasse 55 W-4300 Essen 1 Germany Summary The pharmacokinetics and pharmacodynamics of the ACE inhibitor quinaprilat have been studied in six chronic haemodialysis (HD) patients and in six patients undergoing continuous ambulatory peritoneal dialysis (CAPD) after a single oral dose of 2.5 mg quinapril. Mean t max and C max values (SEM) for quinaprilat in interdialytic HD patients were 4.0 (0) h and 84 (8.4) ng · ml −1 respectively, and they did not differ significantly from those in CAPD patients (4.7 (0.7) h and 64 (5.7) ng · ml −1 ). Elimination half lives were 30 (10.1) h (HD) and 34 (7.3) h (CAPD). C max , t max , t /12 , and AUC were increased and CL was decreased compared to data reported previously after giving 2.5 mg to healthy subjects. Peritoneal clearance was calculated as 0.1 (0.1) ml · min −1 , thus less than 0.5 % of the dose were removed within 24 h by CAPD. ACE activity was suppressed by more than 93 % between 4 and 24 h postdose ( P < 0.001). It decreased in both groups with increasing plasma quinaprilat levels. Angiotensin II concentration compared to baseline was significantly decreased at 4 hours (−30.4±10 %) and 24 h (−30±9.9 %) ( P < 0.05, n =11), while active plasma renin concentration was still significantly increased at 48 h postdose (+60.2±14.5 %, P < 0.01). Mean arterial pressure 24 h postdose was significantly ( P < 0.05) decreased in HD (−12 mm Hg) and CAPD patients (− 20 mm Hg). Only two patients reported unwanted effects (fatigue, dizziness, nausea, and weakness). In conclusion, due to its long lasting effect on ACE activity and on blood pressure in terminal renal failure a starting dose of quinapril 2.5 mg o. d. may be used in hypertensive HD and CAPD patients.

Vanholder, R.; Smet, R.; Ringoir, S.

doi: 10.1007/BF01428386pmid: 8486140

228 44 44 1 1 R. Vanholder R. De Smet S. Ringoir Nephrology Department University Hospital De Pintelaa, 185 B-9000 Ghent Belgium Summary Investigations were undertaken to evaluate which uraemic solutes decrease drug protein binding. This was done by performing HPLC-fractionation of uraemic biological fluids and studying the effect of addition of a lyophilisate of each fraction to normal plasma containing standard quantities of radiolabelled drugs. From a first study, based only on fractionation of uraemic ultrafiltrate with an HPLC-gradient mainly aimed at elution of hydrophilic compounds, hippuric acid appeared to be a major protein binding inhibitor for theophylline and phenytoin. The problem with this approach was that it did not include the compounds with the most substantial protein binding. Therefore, studies were planned to fractionate deproteinized uraemic sera, but first it was necessary to define which deproteinisation methods gave the highest yields of protein bound ligand. Heat denaturation was found to be one of the most effective deproteinisation methods. When a lyophilisate of uraemic serum, deproteinised by this method, was added to normal plasma, a higher capacity to displace theophylline from protein binding sites was found compared to the effect of an identical volume of an ultrafiltrate of the same samples. Fractionation of the deproteinised sample by HPLC revealed a larger number of fractions able to inhibit drug protein binding.

Böhler, J.; Becker, A.; Reetze-Bonorden, P.; Woitas, R.; Keller, E.; Schollmeyer, P.

doi: 10.1007/BF01428396pmid: 8486148

228 44 44 1 1 Dr. J. Böhler A. Becker P. Reetze-Bonorden R. Woitas E. Keller P. Schollmeyer Department of Nephrology University of Freiburg Hugstetter Straße 55 W-7800 Freiburgi. Br. Germany Summary Glomerular hyperfiltration and hypertension may contribute to the progression of chronic renal insufficiency regardless of the underlying disease. Protein restriction and antihypertensive treatment are used to slow the decline in renal function. However, little is known about the interaction of protein loading and antihypertensive treatment on glomerular haemodynamics in humans. This paper compares the renal haemodynamic effects of β -adrenoceptor blockers with those of the calcium channel antagonist nifedipine and the ACE inhibitor captopril on resting glomerular filtration and during glomerular hyperfiltration. In two separate studies the effects of nifedipine, captopril, metoprolol, and celiprolol on renal haemodynamics have been investigated. In two groups of healthy volunteers ( n =13) inulin and PAH clearances were measured, first under fasting conditions and afterwards during aminoacid infusion. In fasting subjects nifedipine and metoprolol induced glomerular hyperfiltration, while celiprolol and captopril did not significantly affect GFR. Without premedication, and also after nifedipine, metoprolol and celiprolol, the aminoacid infusion significantly increased the GFR. After premedication with captopril, however, aminoacid-induced hyperfiltration was prevented. In fasting subjects captopril, celiprolol and metoprolol elevated PAH clearance. With our without premedication aminoacid infusion increased renal plasma flow compared to baseline on the control day. We conclude that in healthy subjects, acute administration of antihypertensive drugs results in different renal haemodynamic responses. In contrast to captopril and celiprolol, nifedipine and metoprolol induce glomerular hyperfiltration like protein loading. Thus, they may counteract the renal haemodynamic effects of protein restriction. Celiprolol behaves similarly to captopril, since it increases renal perfusion without inducing glomerular hyperfiltration, a pattern which might reflect lower glomerular pressure. Only captopril, however, was able to prevent glomerular hyperfiltration induced by aminoacids. If these observations are confirmed during chronic treatment of patients with impaired renal function, they may suggest that certain antihypertensive drugs reverse, while others seem more likely to support the effect of protein restriction on renal haemodynamics and on the progression of renal disease.

Pfeilschifter, J.; Mühl, H.; Pignat, W.; Märki, F.; Bosch, H.

doi: 10.1007/BF01428384pmid: 8387428

228 44 44 1 1 Prof. J. Pfeilschifter H. Mühl W. Pignat F. Märki H. van den Bosch Department of Pharmacology, Biocenter University of Basle Klingelbergstrasse 70 CH-4056 Basel Switzerland Pharmaceuticals Division Research Department Giba-Geigy, Basle Switzerland Centre for Biomembranes and Lipid Enzymology Utrecht The Netherlands Summary Phospholipase A 2 (PLA 2 ) is believed to play an essential role in inflammatory processes by releasing arachidonic acid from membrane phospholipids for synthesis of important lipid mediators, such as prostaglandins, leukotrienes and platelet activating factor. We have used glomerular mesangial cells as a model system to study the regulation of PLA 2 under inflammatory conditions. Potent pro-inflammatory cytokines, such as interleukin 1 (IL-1) and tumour necrosis factor α (TNFα), as well as agents that increase cellular cAMP levels have been found to increase Group II PLA 2 gene expression in a time- and dose-dependent manner. In all cases cytokine-induced synthesis of PLA 2 occurred in parallel with cytokine-stimulated prostaglandin (PG) E 2 synthesis. Three important classes of compounds that potently antagonise the stimulatory effect of IL-1, TNFα and cAMP on Group II PLA 2 expression in mesangial cells have been identified, namely, glucocorticoids, transforming growth factors (TGF) type- β and platelet-derived growth factor (PDGF). Those agents may act sequentially to protect the kidney from damage resulting from cytokine-stimulated mediator release and the subsequent inflammatory reactions.

Radeke, H.; Kuster, S.; Kaever, V.; Resch, K.

doi: 10.1007/BF01428385pmid: 7683610

228 44 44 1 1 Dr. H. H. Radeke S. Kuster V. Kaever K. Resch Institut für Molekularpharmakologie Medizinische Hochschule Hannover Konstanty-Gutschow-Strasse 8 W-3000 Hannover Germany Summary The cellular sources or molecular mechanisms responsible for the derangement of vasoactive prostanoid levels during immunosuppressive cyclosporin (CSA) therapy have not been defined. Using cultured rat glomerular mesangial cells (MC), the cytostatic, cytotoxic and prostanoid synthesis modulating effects of CSA and FK-506 have been measured and compared with the immunosuppressive action of these drugs. Both, CSA and FK-506 inhibited proliferation of MC at similar doses (IC 50 ≈ 1 μg·ml −1 ). Lymphoproliferation was suppressed with IC 50 s of 50 ng·ml −1 and < 1 ng·ml −1 , respectively. In contrast, and unlike FK-506, CSA caused mesangiolysis (IC 50 = 4.5 μg·ml −1 and concentration dependently inhibited the interleukin-1 β (IL-1- β ) stimulated mesangial cell release of TXB 2 at nanomolar doses (IC 50 = 50 ng·ml −1 ). In kinetic experiments (6–48h), CSA 1 ng·ml −1 partially and 1 μg·ml −1 completely abolished the IL-1 β augmented mesangial secretion TXB 2 at all the time points tested. Both, low and high doses of CSA reduced PGE 2 release by only 20–40% and then not until at least 24 h of incubation. Measuring enzymatic capacity of membrane fractions of MC to generate TXB 2 or PGE 2 from added arachidonic acid (10 −5 M), CSA (0.1–1000 ng·ml −1 caused a dose dependent reduction in cyclooxygenase (COX)/thromboxane synthase activity up to 76%, while PGE 2 synthesis (COX/prostaglandin synthase) was decreased by 34%. Immunoblots with a specific COX-1 antiserum revealed that COX-1 protein expression of MC was not affected by CSA. The in vitro data suggest that, unlike FK-506, CSA has a specific and direct effects on the cytochrome P-450 III enzyme, thromboxane synthase, at concentrations in the range of these producing immunosuppressive effects.

Giebisch, G.

doi: 10.1007/BF01428383pmid: 8486143

228 44 44 1 1 Dr. G. Giebisch Department of Cellular and Molecular Physiology Yale University School of Medicine 06510 8036 New Haven Conn. USA Summary The availability of specific potassium channel blockers has made it possible to examine their effects along the nephron on fluid and electrolyte excretion. Recent experiments indicate that they modulate transepithelial sodium and potassium transport. In the thick ascending limb, potassium channel blockers, by interfering with potassium recycling across the apical cell membrane, reduce the activity of the sodium-2chloride-potassium cotransporter. In the initial and cortical collecting duct their inhibitory action on ATP-sensitive potassium channels reduces potassium secretion. Accordingly, tissue-specific potassium channel blockers are promising diuretic agents that may induce diuresis by inhibiting tubular sodium transport with only minimal loss of potassium.

Keller, E.

doi: 10.1007/BF01428382pmid: 8486139

Weber, W.; Kewitz, G.; Rost, K.; Looby, M.; Nitz, M.; Harnisch, L.

doi: 10.1007/BF01428387pmid: 8486141

228 44 44 1 1 Dr. W. Weber G. Kewitz K. L. Rost M. Looby M. Nitz L. Harnisch Central Clinical Research and Clinical Pharmacology Hocchst AG P.O. Box 80 0320 W-6230 Frankfurt/Main 80 Germany Neonatology Clinic Free University of Berlin, Klinikum Steglitz Berlin Germany Summary A population kinetic analysis was carried out on sparse plasma gentamicin (GE) concentration data from 469 neonates obtained as part of a routine therapeutic drug monitoring (TDM) programme in the hospital neonatology unit. The best predictors of the kinetic parameters of the monoexponential model, volume of distribution (Vd) and clearance (CL), were the weight (WT) and gestational age (GA). Vd of the neonates was only related to WT, whereas the half-life was only related to the GA. The clinical implications of the findings are that the initial dose per WT administered to premature infants should be larger than that for term infants, because of a larger Vd per unit WT, and the intervals between maintenance doses should extended due to the prolonged half-life. Apart from these general guidelines, specific dose recommendations are also given.

Rump, L.; Schwertfeger, E.; Schaible, U.; Schuster, M.; Frankenschmidt, A.; Schollmeyer, P.

doi: 10.1007/BF01428393pmid: 8097997

228 44 44 1 1 Dr. L. C. Rump E. Schwertfeger U. Schaible M. J. Schuster A. Frankenschmidt P. Schollmeyer Innere Medizin IV Universitätsklinik Freiburg Hugstetter Strasse 55 W-7800 Freiburg i. Br. Germany Summary The effect of the dopamine D 2 -receptor agonist carmoxirole on noradrenaline release was investigated in human and rat cortical kidney slices. After preincubation with 3 H-noradrenaline, the slices were electrically stimulated at 5 Hz in superfusion chambers, and the stimulation-induced (S-I) outflow of radioactivity was taken as the index of noradrenaline release. In human but not in rat cortical kidney slice, carmoxi-role (0.03 μM) inhibited the S-I outflow of radioactivity. Carmoxirole (0.3 μM) also failed to inhibit the S-I outflow of radioactivity from human kidney slices. When α-adrenoceptors were blocked by the non-selective α-adrenoceptor antagonist phentolamine (1 μM), carmoxirole (0.03 μM, 0.3 μM) inhibited S-I outflow to a similar extent. The inhibitory effect of carmoxirole (0.03 μM) was prevented by the D 2 -receptor antagonist (−)-sulpiride (10 μM) but not by the D 1 -receptor antagonist SCH 23390 (1μM) in human kidney slices. Phentolamine (1 μM) by itself induced a five-fold greater enhancement of the S-I outflow of radioactivity in rat than in human cortical kidney slices. The data suggest that activation of prejunctional D 2 -re-ceptors by carmoxirole inhibits noradrenaline release from human renal sympathetic nerves. Carmoxirole in higher concentrations (0.3 μM) blocks inhibitory prejunctional α-autoreceptors, which seems to mask the inhibitory D 2 -receptor mediated effect. The different effects of phentolamine and carmoxirole in human and rat kidney may indicate a difference of the prejunctional α-autoreceptor mechanism in the two species.