[Unusual forms of the course of giant-cell arteritis]. / Ungewöhnliche Verlaufsformen der Riesenzellarteriitis.

Giant cell arthritis may be combined with retroperitoneal fibrosis, or lesions of the brachial plexus. Horner's Syndrome may develop. Occult vascular disease of cranial arteries was established in the presence of generalized arthritis, including the vessels of an ovarian tumor. Giant cell arthritis may be generalized at the time of detection, especially in patients presenting unusual clinical courses.

Cimetidine kinetics in renal transplant recipients.

Single dose kinetics of cimetidine (Ci) were investigated in 10 patients with renal impairment of varying degrees after renal transplantation. Thirteen healthy subjects and 7 patients with stable renal insufficiency served for control. The studied groups showed no difference in the non-renal Ci-clearance (Clnr) and the volume of distribution at steady state (Vdss). The renal Ci-clearance (Clr) declined parallel to renal function, whereas the estimation of renal tubular transport capacity (Clr/endogenous creatinine-clearance) was independent of renal function in either group studied. The healthy subjects and the control-patients showed a significant correlation between the reduction of the total Ci-clearance (ClB) and the endogenous creatinine-clearance (Clcrea) (ClB = 192 +/- 3.8 Clcrea, p less than 0.001). The individual ClB-values of the patients after kidney transplantation were found within the 90% confidence intervals of this regression line. According to these findings, dosage adjustments of Ci on the basis of Clcrea measurements appear to be valid for renal transplant recipients.

Increased nonrenal clearance of cimetidine during antituberculous therapy.

To investigate the influence of antituberculous treatment on Cimetidin (Ci) disposition, 300 mg Ci were administered intravenously to 12 patients on triple drug therapy (Ethambutol 25 mg/kg/d, Isoniazid 8 mg/kg/d, Rifampicin (Rif) 8 mg/kg/d) and to 13 healthy subjects. Plasma levels and urinary recovery of Ci and its major metabolite Ci-Sulfoxide (CiS) were measured by HPLC. In patients on tuberculostatics nonrenal clearance (Clnr) increased by 52% (395 +/- 85 ml/min, controls 261 +/- 74 ml/min), while total clearance (ClB) (703 +/- 154 ml/min controls 632 +/- 118 ml/min) and volume of distribution (Vd beta) (1.35 +/- 0.33 l/kg, controls 1.6 +/- 0.37 l/kg) remained unchanged. The reduced renal clearance of Ci in the patients (308 +/- 125 ml/min, controls 371 +/- 115 ml/min) appeared to be mainly dependent on reduced renal function and not on antituberculous therapy. The CiS/Ci ratio in urine was unchanged in the patients (16 +/- 6.5, controls 20.5 +/- 10.6). The increased elimination of undegraded Ci via nonrenal pathways under tuberculostatic triple drug therapy may be a consequence of Rifampicin induced microsomal enzyme induction.

Intraperitoneal and intravenous cefoperazone kinetics during continuous ambulatory peritoneal dialysis.

Serum cefoperazone (CFP) kinetics after a 1-gm dose added to the peritoneal dialysate were followed in seven patients undergoing continuous ambulatory peritoneal dialysis (CAPD). In a randomized order five of the seven patients received 1 gm IV CFP. Serum samples were collected over 10 hr during one dialysate exchange interval. CFP concentrations were determined by HPLC. After intravenous dosing CFP mean peak and 6-hr serum concentrations were 104.2 +/- 29.1 micrograms X ml-1 and 8.5 +/- 3.8 micrograms X ml-1, mean body clearance was 80 +/- 20 ml X min-1, and mean apparent volume of distribution was 14.6 +/- 3.2 l. The elimination rate constant (kel) varied from 0.29 to 0.38 hr-1 and was almost identical to kel derived from intraperitoneal application (range 0.29 to 0.42 hr-1). Instillation of CFP with the peritoneal dialysate resulted in a rapid rise of serum levels (Tmax = 1.9 +/- 0.7 hr; absorption rate constant ka = 0.68 +/- 0.11 hr-1), and sufficient CFP concentrations (Cmax = 33.2 +/- 5.3 micrograms X ml-1), were maintained over 6 hr (C6 hr = 17.3 +/- 5.8 micrograms X ml-1). Mean systemic availability of intraperitoneal CFP was 95% +/- 12%. Intraperitoneal administration of CFP in patients undergoing CAPD resulted in serum levels of CFP adequate for systemic treatment of bacterial infections.

Single-dose ceftriaxone kinetics in functionally anephric patients.

The disposition profile of ceftriaxone was studied in 12 functionally anephric patients (creatinine clearance less than 10 ml/min) who received bolus injections of 150, 500, and 1500 mg IV in a noncrossover fashion. As in healthy subjects, the kinetics in uremic patients were nonlinear for total (bound plus unbound) and linear for free (unbound) drug. The plasma protein binding was reduced due to a decreased association constant, resulting in a doubling of the free fraction in plasma. Ten of 12 patients showed nonrenal clearance values of unbound drug (ClFNR) identical to those in healthy adults and only minor increases in their biologic t1/2(beta) compared to normal (12 and 8 hr). These patients would require no dose adjustments in their dosing regimen. Two of the patients exhibited decreased ClFNR values and increased t1/2(alpha) of 20 and 34 hr. Anephric patients with impaired nonrenal elimination would require minor dose adjustments.

Disposition and diuretic effect of furosemide in the nephrotic syndrome.

Plasma levels and diuretic response were determined in seven healthy subjects and six patients with severe nephrotic syndrome (NS) after 40 mg furosemide (Fu). Mean apparent volume of distribution and distribution volume at steady state of the groups did not differ. Total Fu clearance was higher in NS (251 +/- 54 ml/min) that in healthy subjects (174 +/- 32 ml/min) (P less than 0.01), a difference that correlated with the nonrenal clearance of 56 +/- 28 ml/min in healthy subjects and 154 +/- 45 ml/min in patients with NS (P less than 0.001). Normal beta-elimination half-life of 51 +/- 7.7 min was 37 +/- 6.2 min (P less than 0.001) in NS. Mean normal Fu protein binding pf 98.6 fell to 97.2%, with decreasing plasma albumin levels. After 40 mg IV Fu, sodium and volume excretion decreased in NS (P less than 0.001 and P less than 0.005). In patients Na+/Fu excretion rate ratios showed "tubular resistance" to Fu over the time when large amounts of Fu were excreted. The reduced diuretic response to Fu in NS is taken to be mainly a consequence of its impaired renal excretion.

Disposition of hydrochlorothiazide (Hct) during phenytoin (Ph) treatment.

Plasma levels and urinary recovery of Hct were determined in seven healthy male volunteers. 75 mg Hct were administered as a tablet in a randomised fashion with or without phenytoin pretreatment (300 mg/d). Bioavailability of Hct showed considerable intra- and interindividual variation (32--87% and 42--77% respectively), but phenytoin did not influence the disposition parameters of the diuretic.

Influence of hepatic cirrhosis and end-stage renal disease on pharmacokinetics and pharmacodynamics of furosemide.

After rapid intravenous injection of furosemide 40 mg (Fu), plasma levels were determined in 7 healthy volunteers, 8 patients with liver cirrhosis with ascites and 7 patients with end-stage renal disease (ESRD). The diuretic response was evaluated by measuring the urinary excretion of sodium and potassium and the urine volume. The mean elimination half life (t 1/2 beta) of Fu averaged 51 +/- 7.7 (+/- SD) min in healthy subjects, 52 +/- 7.7 min in cirrhosis and 200 +/- 57 min in ESRD. The non-renal clearance (Clnr) in healthy subjects (56 +/- 28 ml/min) corresponds to the total plasma clearance in functionally anephric patients (54 +/- 18 ml/min). In cirrhosis there was no significant change in the disposition parameters of Fu in comparison to the healthy volunteers, but there was a significant reduction in urine sodium and volume, whereas potassium excretion remained unchanged. Fu "excretion rate--response" curves showed diminished tubular sensitivity to Fu in cirrhosis.

[Toxicity of ammonium acetate in rats with acute and subacute galactosamine-induced hepatitis (author's transl)]. / Toxizität von Ammoniumacetat bei Ratten mit akuter und subakuter Galactosamin-Hepatitis.

Ammonia toxicity and the protective effect of arginine thereon were investigated in rats after single and repeated doses of galactosamine. Urea cycle enzymes and ornithine-oxo-acid transaminase activities were measured in rat liver homogenates. Ammonium acetate proved to be less toxic in rats treated with single or repeated doses of galactosamine than in untreated animals. Urea cycle enzyme activities of galactosamine-treated rats were clearly lowered. The protective effect of arginine against lethal ammonia intoxication was found in animals that had been treated with galactosamine as well as in untreated rats. Since the toxicity of ammonium acetate is lower in rats with galactosamine hepatitis, in which the activities of the liver urea cycle enzymes are reduced, it seems likely that ammonia detoxication in galactosamine-poisoned rat liver partly bypasses the urea cycle.

Possible sites of interaction of acute renal failure with amino acid utilization for gluconeogenesis in isolated perfused rat liver.

Experiments were performed to elucidate the mechanisms involved in the enhanced conversion of amino acids to glucose in acute uraemic rats. Increased gluconeogenesis from a mixture of serine, threonine, lysine, glutamate, ornithine and citrulline was confirmed using a non-recirculating perfusion system. Stimulation was concentration dependent, being most pronounced at physiological amino acid concentrations. Stimulation of glucose and urea formation could be mimicked by using serine alone whereas with lactate and pyruvate inhibition of gluconeogenesis was observed. Serine dehydratase activity was significantly elevated following nephrectomy. Further, the uptake of the non-metabolize amino acid alpha-aminoisobutyrate was considerably increased. It is concluded that serine may play a special role as substrate for the additional glucose formation in acute uraemic rats, probably mediated by an activation of serine dehydratase. Acceleration of amino acid transport seems to represent an additional component of stimulation of amino acid utilization in acute uraemia.

[Intracellular localisation of urea-cycle enzymes in liver (author's transl)]. / Intrazelluläre Lokalisation von Enzymen des Krebs-Henseleit-Cyclus in der Leber

Enzymes of the Krebs-Henseleit urea-cycle were localized by means of differential centrifugation and fractional tissue extraction in rat liver and in human liver. Argininosuccinatlyase (ASAL) and Argininosuccinatsynthetase (ASAS) represent enzymes of the soluble cytoplasmic fraction. Ornithine-ketoacid-transaminase(OKT), carbamyl-phosphate-synthetase (CPS) and ornithine-carbamyl-transferase (OCT) are localized in the mitochondrial and nuclei fractions of the liver cell. Most of the arginase activity is bound to subcellular structures (probably to nuclei). A small portion of arginase-activity was found in the soluble cytoplasmatic fraction. The enzymes of the Krebs-Henseleit urea-cycle are equally distributed in rat liver and in human liver. Differences in the subcellular localisation of (mitochondrial) enzymes in human liver could be attributed to mitochondrial breakage during tissue preparation and do not represent in-vivo conditions.

[Ultrastructural changes of the stria vaseularis and the spiral ligament in chronic uremic rats (author's transl)]. / Ultrastrukturelle Veränderungen an der Stria vascularis und dem Ligamentum spirale bei chronisch-urämischen Ratten

Looking for the morphological correlation of uremic inner ear damage a 5/6 resection of kidney parenchyma in rats was performed. A biochemically proven chronic uremia was so created. The ultrastructural examination of the stria vascularis showed a marked swelling of the intermediate cells, compressing occasionally stria vessels. The stria was enlarged and the mitochondria of the dark and light cells swollen. In the spiral ligament connective tissue cells were moderately swollen and blood vessels partially obstructed by swelling of the endothelium. These changes are proved not to be dependent on the urea. The pathophysiological significance for uremic inner ear damage can only be determined after further examination of cochlear tissue.

[Perimembranous glomerulonephritis after treatment with D-penicillamine. Report on 31 cases (author's transl)]. / Perimembranöse Glomerulonephritis nach Penicillamintherapie. Bericht über 31 Fälle

This report includes 31 patients who developed a perimembranous glomerulonephritis generally 7 months after the onset of the treatment of various illnesses with D-Penicillamine. In all cases the patients had a proteinuria, associated with a hematuria in 12 cases. After the treatment was stopped 8 patients rapidly developed a nephrotic syndrome, while its onset was more gradual in 12 other patients. 5 patients initially with a nephrotic syndrome had no proteinuria at the time of a second biopsy made up to 12 months later. In these 5 cases the typical changes of perimembranous glomerulonephritis observed on electron microscopy were much reduced in the second biopsy.