[High-dose chemotherapy with transplantation of autologous stem cells in advanced germ-cell poor-risk testicular tumors].

Testicular tumors illustrate curable cancer, but 25% patients are resistant to standard therapy. High-dose chemotherapy (HDC) is promising therapy for germ-cell tumors with poor prognosis. HDC and transplantation of autologous stem cells were performed in 13 patients with germ-cell testicular tumors (GTT). In 6 patients of group 1 HDC was first-line treatment in poor prognosis, in 7 patients (group 2) it was a salvage treatment after recurrences. Patients of group 1 had longer mean survival than those of group 2 (31.3 and 11 months, respectively; p = 0.136). Two patients died of HDC complications. Neurological, hematological and other complications occurred. In spite of 50-90% remission after HDC, multicenter prospective randomized trials will give final conclusion on effectiveness of HDC which must be performed in special clinics having many specialists in their staff (urologists, oncologists, chemotherapists, etc.).

Effect of a silver device in preventing catheter-related infections in peritoneal dialysis patients: silver ring prophylaxis at the catheter exit study.

Catheter-related infections remain a significant cause of method failure in chronic peritoneal dialysis (PD) therapy. Given the increasing antibiotic resistance, such nonpharmacological strategies as local silver devices attract more interest. To establish whether a silver ring device (designed by Grosse-Siestrup in 1992) mounted onto the PD catheter and placed at the exit site at skin level is effective in preventing exit-site and other catheter-related infections, a prospective 12-month, multicenter, controlled study stratified by diabetes status was conducted. The study subjects were assessed by an extensive structured inventory, including a broad spectrum of control variables, such as age, body mass index (BMI), Staphylococcus aureus carrier status, catheter features, mode and quality of PD therapy, comorbidity, and psychosocial rehabilitation. Ten experienced German outpatient dialysis centers (seven adult, three pediatric) participated in the trial. All eligible patients (n=195) from the study area without catheter-related infections during the ascertainment period were included (incidental subjects undergoing PD therapy for at least 3 months). The main outcome measures were the occurrence of first exit-site infections (primary study end point), sinus tract/tunnel infection, and peritonitis. Ninety-seven patients were assigned to the silver ring and 98 patients to the control group. Baseline characteristics of age, sex, proportion of pediatric and incidental patients, S aureus carrier status, and other variables were similar in both groups. The incidence of infections in the silver ring group versus the control group was as follows: 23 of 97 versus 16 of 98 patients had exit-site infections, 12 of 97 versus 12 of 98 patients had sinus tract/tunnel infections, 16 of 97 versus 18 of 98 patients had peritonitis, respectively. Kaplan-Meier analysis for the probability of an infection-free interval showed no statistical difference (log-rank test) between the two groups. Displacement of the silver ring contributed to study termination in 6% of the study group patients, including two patients with catheter loss. Univariate analysis and multiple logistic regression identified younger age (<50 years), low serum albumin level (<35 g/L), number of previously placed PD catheters, short cuff-exit distance (<2 cm), and S aureus nasal carriage as risk factors for the development of exit-site infections. In conclusion, our study does not show any benefit of the silver ring in preventing catheter-related infections in PD patients. Thus, prevention of infection-related method failure in PD still has to rely on conventional antibiotic treatment strategies and less so on alternative methods.

Lowering of the convulsive threshold by non-steroidal anti-inflammatory drugs.

Administration of convulsant doses of pentetrazole induced an increase of PGF2 alpha, PGE2 and TXB2 immuno-reactive material in mouse brain in vivo. The non-steroidal anti-inflammatory drugs indomethacin, flurbiprofen and diclofenac in equipotent doses inhibited the convulsion-induced increase of prostaglandins and thromboxane B2 (P less than 0.01). The same drugs also lowered the LD50 of pentetrazole (P less than 0.05) and accelerated the onset of tonic seizures evoked by pentetrazole (P less than 0.05). Ibuprofen in a submaximal centrally effective dose acted in the same way on cerebral PG and TXB2 synthesis and on the LD50 of pentetrazole but failed to influence significantly the latency time to the onset of pentetrazole-induced tonic seizures. Aspirin (100 mg/kg) and paracetamol (30 mg/kg), which were without effect on cerebral PG and TXB2 concentrations following pentetrazole-induced seizures, were also ineffective in lowering the convulsive threshold and the LD50 of pentetrazole. It is concluded that non-steroidal anti-inflammatory drugs act on the convulsive threshold by inhibition of cerebral prostaglandin and/or thromboxane synthesis.

Effect of prostaglandins D2, E2 and F2alpha on catecholamine release from slices of rat and rabbit brain.

Slices of rabbit or rat brain cortex were preincubated with [3H]noradrenaline, and slices of rabbit caudate nucleus or rat stratum with [3H]dopamine. The slices were then superfused and stimulated electrically. In rat cortex slices, PGE2 (0.01-1 millimicronmol/l) markedly reduced the stimulation-evoked overflow of tritium. PGF2alpha (1 millimicronmol/l) caused a slight decrease only after the formation of endogenous prostaglandins had been blocked by indomethacin. PGD2 (1 millimicronmol/l) had no effect. In slices of rabbit cortex and caudate nucleus as well as in rat striatal slices, none of the prostaglandins (1 millimicronmol/l) caused any change, irrespective of whether the production of endogenous prostaglandins was intact or blocked. The results show that, of three major prostaglandins that occur in the brain, only PGE2 is a potent presynaptic inhibitor of noradrenaline release in the rat. The catecholamine neurones of rabbit brain, and the dopamine neurones of rat striatum, are resistant to these prostaglandins.

The synthesis of prostaglandins and thromboxane in the mouse brain in vivo. Influence of drug induced convulsions, hypoxia and the anticonvulsants trimethadione and diazepam.

1. The i.v. administration of convulsant doses of penetrazole or picrotoxin induced an increase in PGF2 alpha, PGE2 and TXB2-like immunoreactive material in mouse brain tissue. The onset of increase coincided with the appearance of clonic seizures. 2. The anticonvulsant drugs trimethadione and diazepam reduced both convulsions and increase of the above arachidonic acid metabolites induced by pentetrazole or picrotoxin. 3. In synaptosomal preparations of the brain, neither pentetrazole (10(-3) mol 1(-1) picrotoxin (10(-4) mol 1(-1) nor trimethadione (5 x 10(-4) mol 1(-1)) had any influence on cyclooxygenase activity as indicated by the unimpaired PGF2 alpha-synthesis. 4. Under hypoxic conditions at equal durations as the seizures, the formation of PGF2 alpha and PGE2 was less than 10% of the amount occurring after penetrazole-induced convulsions. 5. It is concluded that the seizure-induced rise of PGF2 alpha, PGE2 and TXB2 is the result of increased central nervous activity.

Pharmacological manipulation of peritoneal transport in CAPD.

Various endogenous compounds and drugs influence different determinants of peritoneal transport. Catecholamines affect vascular diameter and mesenteric blood flow. Several gastrointestinal hormones were found to induce splanchnic vasodilation and to augment the effective vascular surface. Different prostanoids, histamine, and bradykinin influence peritoneal mass transfer by increasing vascular permeability. Vasodilative acting drugs, diuretics and surface active compounds were found to augment peritoneal solute clearances and water efflux by acting on peritoneal vessels or the serosal surface of the peritoneal membrane. Hyperosmolar dialysis solutions increase ultrafiltration and contribute to total peritoneal clearance by convective transport. The present paper aims to summarize the current knowledge on pharmacological and physiological manipulation of peritoneal transport function and to show some ways of its clinical use.

Studies on thromboxane B2 and prostaglandin E2 production in the course of murine autoimmune disease: inhibition by oral histidine and zinc supplementation.

Synthesis of both prostaglandin E2 and thromboxane B2 in liver and kidney tissue of NZB/W F1 hybrid mice was found to increase with advancing age. The rise in prostanoid generation coincided with the appearance and progression of the spontaneous systemic lupus erythematosus (SLE)-like disorders seen in these mice. Substitution of a diet supplemented with histidine (50 g kg-1 dry weight) and/or zinc (160 mg kg-1 dry weight) suppressed the autoimmune disease associated increase in prostanoid generation. The parent NZB and NZW strains also revealed an age-dependent increase in prostanoid synthesis whereas no age-related changes of tissue prostanoid generation were seen in healthy DBA-2 and C57-BL/6 control mice. In a previous study [Schwerdtfeger et al. 1980] a protective effect of histidine and/or zinc on the course of SLE-like disease in NZB/W F1 mice was reported. The current work suggests that this effect may in part have been mediated by the modulation of cellular arachidonic acid metabolism. The proposal that prostanoids are involved in the pathogenesis of autoimmune disease in NZB/W F1 mice is supported by these results.

Granulocyte activation during hemodialysis.

Plasma levels of granulocyte lactoferrin, myeloperoxidase, and elastase in complex with alpha 1-proteinase inhibitor (E-alpha 1PI) during hemodialysis were investigated in patients undergoing maintenance hemodialysis with dialyzers made from cellulose hydrate, polymethylmethacrylate, cuprophan, ethylene-vinyl alcohol copolymer, polycarbonate, polyacrylonitrile or polysulfone. Polymethylmethacrylate membrane caused markedly elevated plasma lactoferrin (712.5 +/- 165.9 ng/ml) and E-alpha 1PI (681.8 +/- 102.6 ng/ml). Lower levels were observed in patients dialyzed with cuprophan or polycarbonate dialyzers, while cellulose hydrate membrane caused a maximal increase of the E-alpha 1PI levels (1,6590 +/- 256.8 ng/ml). Polyacrylonitrile membrane provoked minimal E-alpha 1PI formation (267.6 +/- 79.6 ng/ml) but markedly elevated plasma levels of lactoferrin. However, polysulfone dialyzers displayed only very modest increases of the plasma E-alpha 1PI and lactoferrin levels. Plasma levels of myeloperoxidase were unchanged comparing the effects of the different dialyzers. We conclude that granulocyte activation during hemodialysis does not necessarily need anaphylatoxin formation.

One year experience with subcutaneous human erythropoietin in CAPD: correction of renal anemia and increased ultrafiltration.

After 6 months of (recombinant human erythropoietin) rHuEPO treatment we recently observed an increased peritoneal ultrafiltration (UF) (Nephron 53: 91, 1989). The aim of the present study was to investigate the long term effect of subcutaneous (SC) on dialysis efficiency in CAPD. Fourteen patients (11 female, 3 male, mean age 42.6, range 18-65 years) with renal anemia (HCT less than 28%) took part in the study. rHuEPO was administered s.c. twice weekly in an initial dose of 50 U/kg body weight. This dose was increased by 25 U/kg body weight every 4 weeks till the target HKT of 35% had been achieved. After 12 months of mean time of treatment (range 8-14 months) hematocrits had increased from 23.3 +/- 3.2 (x +/- SD) to 36.6 +/- 5.3% (p less than 0.005). UF improved from 0.70 +/- 0.22 to 1.03 +/- 0.47 ml/min (4 hr dwell time, 1.5% glucose monohydrate) (p less than 0.03). Increased UF resulted in an augmented creatinine clearance (p less than 0.05). No changes were observed in serum chemistries, body weight, pulse rate or cardiothoracic index. The observed increase in peritoneal ultrafiltration might be due to augmented mesenteric perfusion resulting from improved cardiac function. The sustained increase in UF after rHuEPO-induced correction of renal anemia may improve the fluid balance on CAPD patients.

Effect of CAPD dialysate on the release of eicosanoids and cytokines from human peritoneal macrophages.

The effect of fresh peritoneal dialysis (PD) solution and effluent on the generation of eicosanoids and cytokines by human peritoneal macrophages (PMO) was studied in vitro. PMO, isolated by density gradient separation from patients undergoing intermittent peritoneal dialysis (IPD), were incubated for 2 h with PD effluent after dwell periods of 5 to 240 min or fresh PD solution. Supplemented RPMI-1640 medium served as control. PMO were stimulated by calcium ionophore A23187 (10 M). PD solution significantly inhibited the release of prostanoids (PGE2, TXB2, 6-k-PGF1), leukotrienes (LTB4, LTC4), and cytokines (11-6, TNF) from PMO by 60 to 96% (p < 0.05). Addition of A23187 increased the generation of TXB2, LTB4, and LTC4 in PD solution adjusted to pH 7.4 to 2.7 up to 28.6 times the basal level, but was ineffective in PD fluid at pH 5.2. Incubation of PMO with PD effluent of varying dwell times resulted in a rise of all assayed mediators (p < 0.05). The release of IL-6 increased continuously from 80 +/- 10 pg/10(6) PMO (0 min dwell time) to 440 +/- 104 pg/10(6) PMO (4 h dwell time, mean +/- S.E.M.). TNF generation rose from 6.0 +/- 0.1 pg/10(6) PMO (0 min dwell time) to 162 +/- 54 pg/10(6) PMO after 5 min dwell time and remained constant with effluents of longer dwell times (15 to 240 min). Exposure of PMO to PD effluents after 240 min dwell time tended to decrease the median levels of PGE2, TXB2, and 6-k-PGF1.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of C5a-induced actin polymerization, chemotaxis, and phagocytosis of human polymorphonuclear neutrophils incubated in a glucose-based dialysis solution.

Chemotaxis and phagocytosis are important functions of phagocytic cells, which are closely related to cytoskeletal reorganization. These functions may be abnormal in phagocytes of uremic patients undergoing continuous ambulatory peritoneal dialysis (CAPD). In order to examine whether these abnormalities result from treatment, we studied actin polymerization (AP), as an index of cytoskeletal alterations, chemotaxis, and phagocytosis in polymorphonuclear neutrophils (PMNs) of healthy subjects. Polymorphonuclear neutrophils were exposed to either a hepes buffer or a glucose-based dialysis solution (GBDS) of different pH's (5.2, 7.4) and different glucose concentrations (1.36%, 2.27%, 3.86%). After incubation for 0, 5, or 20 minutes, cells were activated with 10 nmol/L C5a-complement. AP was measured as filamentous (F) actin content by NBD phallacidin staining and FACS analysis. Chemotaxis of PMNs was measured in Boyden chambers. In addition, phagocytosis of zymosan particles was assessed. Prior exposure to GBDS pH 5.2 of each glucose concentration immediately and completely inhibited AP in response to 10 nmol/L C5a-complement, reduced chemotaxis (> 95%), and completely inhibited phagocytosis. The inhibition was pH-dependent, since GBDS pH 7.4 caused less inhibition of these functions. We conclude that glucose-based dialysis solutions are cytotoxic towards neutrophils and completely inhibit their ability to display responses requiring cytoskeletal reorganization.

[Sclerosing peritonitis following continuous ambulatory peritoneal dialysis]. / Die sklerosierende Peritonitis nach kontinuierlicher ambulanter Peritoneal-Dialyse (CAPD).

Sclerosing peritonitis is a severe complication after CAPD treatment. The visceral peritoneum is thickened and interenteric adhesive parts are found. Myofibroblasts are proliferated and the collageneous tissue is hyperplastic. The mean clinical symptom is the mechanical obstruction of the small bowel. We observed this illness in three out of sixty patients under CAPD. These patients had higher incidence of bacterial peritonitis. In the ascites high concentrations of PG E2 and Thromboxan B2 were observed. After treatment of the infection the concentrations fell down to normal values. Electronoptical observations from peritoneal biopsies showed a proliferation of myofibroblasts and extracellular lysosomes. It is known from these lysosomes that they are able to set free proteasis. These lead to degredation of fibrin and fibrinogen. These splits are mitogen to myofibroblasts. release from HIT cells could also be evoked by the sulphonylureas glibenclamide and tolbutamide and by an increase in concentration of extracellular K+ to 40 mmol/l. The content of cyclic AMP in HIT cells was increased modestly by glucose but not by an increase in extracellular K+. Forskolin elicited a 4-fold increase in cyclic AMP content. We conclude that HIT cells retain the essential features of the insulin secretory response of normal B cells and represent an important tool for further biochemical characterisation of the secretory system.

[Comparative study of the pharmacokinetics of amitriptyline oxide and trimipramine after single administration in healthy male probands and patients with renal failure]. / Vergleichende Untersuchung zur Pharmakokinetik von Amitriptylinoxid und Trimipramin nach Einmalgabe bei gesunden männlichen Probanden und Patienten mit Niereninsuffizienz.

The pharmacokinetics of the antidepressants amitriptyline oxide and trimipramine and their major metabolites amitriptyline, nor-triptyline and desmethyltrimipramine, were studied in twelve healthy male subjects (aged from 22 to 62 years) and twelve patients (aged from 25 to 73 years) with severe renal impairment (glomerular filtration rate < 10 ml/min). Oral single doses of 60 mg amitriptyline oxide and 50 mg trimipramine, separated by a washout period, were administered to all study participants. Blood and urine samples were collected up to 120 hours after administration. For trimipramine and desmethyltrimipramine, a new HPLC method was developed. The "Fischer Somatic and Undesired Effects Check List" was used for the assessment of adverse events. The mean plasma half-life and AUC of amitriptyline oxide and its metabolites were significantly higher in patients than in healthy adults. For trimipramine the AUC was significantly higher in patients. The plasma half-life of trimipramine was longer in patients, but statistically not significant. The maximum plasma concentrations for both drugs and metabolites were at an average distinctly higher in patients. Clearance rate of amitroptylinoxide and trimipramine also differed between the two groups. Correlating with these results a high incidence and a longer persistence (in most cases > 12 hours) and more pronounced adverse effects were noted in the patient group, whereas in volunteers adverse events were only observed up to approximately eight hours.

Prostaglandin-mediated loss of proteins during peritonitis in continuous ambulatory peritoneal dialysis.

The loss of proteins into the dialysate and the peritoneal generation of the immunoreactive prostanoids PGE2, 6-keto-PGF1 alpha, PGF2 alpha, and TXB2 were studied in 12 patients undergoing continuous ambulatory peritoneal dialysis (CAPD) during 16 episodes of peritonitis and in inflammation-free periods. Protein permeability, defined as the ratio of dialysate/plasma protein (D/P), decreased with increasing molecular weight, independent of the condition of the peritoneum. With peritonitis a general rise of permeability was noticed for total protein (TP) and the individual proteins beta 2-microglobulin (beta MG), albumin (Alb), immunoglobulin G (IgG), and alpha 2-macroglobulin (alpha MG) (P less than 0.001). Simultaneously, an increase of dialysate prostanoids occurred with predominance of the vasodilative acting prostaglandins PGI2, determined as its metabolite 6-keto-PGF1 alpha, and PGE2 by factors of 8.4 and 9.7, respectively (P less than 0.001), in comparison to peritonitis-free control. In the early phase of peritonitis (0 to 12 hr after the onset of therapy) the augumented peritoneal prostaglandin synthesis correlated positively with the increased permeability of TP (r greater than or equal to 0.7446, P less than 0.01) and the individual proteins beta MG, Alb, IgG, and alpha MG (r greater than or equal to 0.5970, P less than 0.05). Inhibition of cyclo-oxigenase activity by local administration of indomethacin inhibited both the generation of 6-keto-PGF1 alpha and PGE2 by 39 and 42%, respectively (P less than 0.05), and the peritoneal loss of TP by 34% (P less than 0.05). In the absence of peritonitis indomethacin only diminished the synthesis of PGE2 whereas the generation of the other prostanoids remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Modification of prostaglandin generation by L-histidine--possible pathogenetic implication in rheumatoid arthritis.

The effect of l-histidine on arachidonic acid metabolism was studied in rabbit splenic fibroblast cultures and human platelets. The noradrenaline-stimulated generation of PGE2 in fibroblast cultures was inhibited by l-histidine dose dependently. In the same way l-histidine diminished the aggregation-induced synthesis of TXB2 in human platelets. In contrast to this, after incubation with l-histidine the generation of PGE2 in activated platelets increased in a dose dependent way up to 240% of pretreatment values. The further increase of l-histidine concentration resulted in an inhibition of platelet PGE2 synthesis. The present results demonstrate a differential influence of the amino acid l-histidine on cell arachidonic acid metabolism. It is concluded that the supposed anti-rheumatic property of l-histidine is caused by its effect on the synthesis of prostaglandins which are known to be mediators of inflammation.

Effect of L-histidine in vivo on human platelet function and arachidonic acid metabolism.

The effect of the amino acid l-histidine on human platelet function and arachidonic acid metabolism was studied in 18 healthy subjects with increased spontaneous platelet aggregation. The participants received placebo or l-histidine 3g/day for 7 days. The intake of l-histidine reduced the degree of spontaneous platelet aggregation (p less than 0.05) and inhibited the generation of platelet TXB2 by 47% (p less than 0.001) whereas platelet PGE2 synthesis was not affected. The mean l-histidine plasma concentration increased from 83.1 +/- 2.4 to 108 +/- 8.1 mumol/l (p less than 0.01) during the study. L-histidine was found to be an effective inhibitor of spontaneous platelet aggregation and platelet TXB2 generation. The present data verify interactions of histidine with human platelet function, probably mediated by arachidonic acid metabolites.

Stimulation of peritoneal synthesis of vasoactive prostaglandins during peritonitis in patients on continuous ambulatory peritoneal dialysis.

The peritoneal generation of arachidonic acid metabolites was studied in eight patients with end-stage renal disease undergoing continuous ambulatory peritoneal dialysis (CAPD) during infection-free periods and during bacterial peritonitis. The prostacyclin metabolite 6-keto-PGF1 alpha was found to be the major prostanoid generated by human peritoneal mesothelium (1090 ng (6h)-1, SEM 86, n = 8) followed by lesser amounts of PGE2 (142 ng (6 h)-1, SEM 26, n = 8), PGF2 alpha (162 ng (6 h)-1, SEM 27, n = 8) and TXB2 (59 ng (6 h)-1, SEM 5, n = 8). During peritonitis a significant increase of all prostaglandins and TXB2 occurred (P less than 0.001). The ratio of the vasodilating prostaglandins and their metabolites (PGE2 and 6-keto-PGF1 alpha) to the vasoconstrictors and their metabolites (PGF2 alpha and TXB2) increased from 6.6 to 10.5 during peritoneal inflammation. Augmented peritoneal clearances of creatinin and urea and increased losses of proteins during peritonitis as well as the enhanced peritoneal generation of prostanoids were reduced to basal values by adequate antibiotic therapy. The present results suggest that the increased peritoneal blood flow during peritonitis, probably responsible for the observed changes of peritoneal transport properties, may be induced by a change in the ratio of vasoactive prostaglandins generated by peritoneal mesothelial cells.