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.
The behaviour of human platelets was studied by mechanical induced platelet aggregation under inhibition of different enzymes of the arachidonic acid metabolism. Platelet aggregation was followed by the release of thromboxane B2 (TXB2) and prostaglan
Abstract. 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‐PGF 1α 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 PGE 2 (142 ng (6 h) ‐1 , SEM 26, n = 8), PGF 2α (162ng(6h) ‐1 , SEM 27, n = 8) and TXB 2 (59 ng (6 h) ‐1 , SEM 5, n = 8). During peritonitis a significant increase of all prostaglandins and TXB 2 occurred ( P < 0·001). The ratio of the vasodilating prostaglandins and their metabolites (PGE 2 and 6‐keto‐PGF 1α ) to the vasoconstrictors and their metabolites (PGF 2α and TXB 2 ) 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 adequated 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.
8029 Background: Interval reduction from 3 (CHOP-21) to 2 wks (CHOP-14) and the addition of R to CHOP-21 (R-CHOP-21) improved outcome in elderly pts with DLBCL to a similar extent compared to CHOP-21. Methods: In the RICOVER-60 trial, elderly pts.(61-80 yrs) were randomized to receive 6 or 8 cy CHOP-14 with or without 8 cy R. RX was planned to sites of initial bulk and/or extranodal inv. The primary endpoint was EFS, secondary endpoints were PFS and OS. Results:Between 07/2000 and 06/2005, 1,222 pts with CD20+ DLBCL were recruited and are evaluable (med age 68 yrs; IPI=1: 30%, IPI=2: 28%, IPI=3: 26%, IPI=4,5: 16%). There was no difference between the 4 arms with respect to long-term tox and 2nd neoplasms. As by intention to treat, the 7-yr EFS rate was 33% after 6xCHOP-14 (n=307), 40% after 8xCHOP-14 (n=305), 50% after 6xR-CHOP-14 (n=306), and 52% after 8xR-CHOP-14 (n=306). After a median obs time of 82 mo, the estimated 7-yr OS rates were 50% for 6xCHOP-14, 52% for 8xCHOP-14, 62% for 6xR-CHOP-14, and 60% for 8xR-CHOP-14. In a multivariate analysis using 6xR-CHOP-14 without R as the reference and adjusting for the stratification variables elevated LDH, stage III&IV, ECOG ps>1, bulky dis, >1 extranodal site, and age >70, both R arms had a significantly improved EFS (6xR-CHOP-14: RR=0.5, p<0.001; 8xR-CHOP-14: RR=0.5, p<0.001), PFS (6xR-CHOP-14: RR=0.5, p<0.001; 8xR-CHOP-14: RR=0.5; p<0.001) and OS (6xR-CHOP-14: RR=0.6; p<0.001; 8xR-CHOP-14: RR=0.7; p=0.004). 6xR-CHOP-14 was slightly better than 8-R-CHOP-14 with respect to all endpoints and had a significantly better OS in pts with bulky dis (p=0.005). Conclusions: In contrast to the 3-yr FU, not only 6xR-CHOP-14, but also 8xR-CHOP-14 achieved a significantly better OS compared to 6xCHOP-14 after a med obs time of 82 mo. Due to its lower tox and shorter time under CTX (6xCHOP-14: 10 wks, 8xCHOP-14: 15 wks, and 8x-CHOP-21 even 21 wks, each plus 1 d), 6xCHOP-14 in comb with 8 app of R is the preferred regimen for elderly patients with CD20+ DLBCL. The significant superiority of 6xR-CHOP-14 over 8xR-CHOP-21 in pts with bulky dis, who received RX to the resp areas, suggests that RX to bulky dis is more effective when given after 6 than after 8 cy of R-CHOP-14.
The purpose of this study was to investigate the therapeutic potential of prolonged inhibition of atrial natriuretic factor (ANF) degradation in patients with severe chronic heart failure.The effects of repeated doses of the endopeptidase inhibitor candoxatrilat (150 mg i.v.) were examined over a 24-hour period in patients with severe chronic heart failure (New York Heart Association class III-IV). Plasma alpha-hANF(99-126) was elevated at baseline (235 +/- 59 pg/ml), increased 2.5-fold at 2 hours after the first dose, and remained significantly elevated throughout the 24-hour protocol. In contrast, pro-hANF(31-67) decreased from 3,151 +/- 616 to 2,072 +/- 362 pg/ml (p less than 0.05). Cardiac index (CI) increased only transiently after the first dose of candoxatrilat (CI, 2.11 +/- 0.2 to 2.67 +/- 0.28 l/min/m2, p less than 0.05). Sodium excretion increased sixfold (p less than 0.05) 2 hours after the first dose of candoxatrilat and remained significantly elevated throughout the protocol. Degree of natriuresis and diuresis in response to candoxatrilat was closely related to baseline cardiac output. Glomerular filtration rate and volume excretion did not change significantly. Pulmonary capillary wedge pressure fell from 23 +/- 3 to 18 +/- 3 mm Hg (p less than 0.05) and remained below baseline throughout the 24 hours. Arterial pressure, heart rate, and total peripheral resistance did not change significantly during the 24-hour period. Urinary cGMP excretion increased fivefold (p less than 0.05), whereas urinary ANF immunoreactivity and plasma cGMP levels remained unchanged. Excretion of prostacyclin metabolite 6-keto-PGF-1 alpha increased 3.3-fold (p less than 0.05). Plasma norepinephrine and epinephrine levels decreased significantly after candoxatrilat and remained suppressed over the 24-hour period. There was also a transient reduction in plasma vasopressin, aldosterone levels, and plasma renin activity. Hematocrit, total protein content, and plasma albumin concentrations did not change, indicating that no fluid shift into the extravascular space had occurred.1) The inhibition of ANF degradation causes sustained drop in left and right atrial pressures that appears to be mediated by an inhibition of neurohumoral activity; 2) concomitant inhibition of bradykinin breakdown (which in turn stimulates renal prostacyclin synthesis) contributes to natriuresis; 3) the close correlation between renal response and baseline cardiac index indicates that an inadequate renal perfusion secondary to low cardiac output diminishes the efficacy of this treatment modality. This spectrum of action would be advantageous for a first-line diuretic agent early in the course of disease rather than in patients with advanced chronic heart failure.
