Effects of renal dysfunction on the pharmacokinetics of loracarbef.

Loracarbef, the first carbacephem antibiotic to undergo clinical development, is excreted primarily unchanged in the urine (> 90%). Data analyzed from subjects with various degrees of renal dysfunction who were given single oral doses of loracarbef indicated a linear relationship between creatinine clearance (CLCR) and plasma clearance [CLP (L/hr) = 0.106.CLCR (ml/min/1.73 m2)]. The mean area under the plasma concentration-time curve in normal subjects and in patients with severe renal insufficiency (no dialysis/receiving dialysis) was 32 micrograms.hr/ml and 1085 micrograms.hr/ml/103 micrograms.hr/ml, respectively. Therefore, for individuals with moderate renal insufficiency (CLCR, 10 to 49 ml/min/1.73 m2), the dose should be halved or the dosing interval doubled; patients with severe renal insufficiency who are not receiving dialysis should be treated with the normal dose given once every 3 to 5 days. Loracarbef is readily cleared from plasma by hemodialysis; dosing should be repeated after a hemodialysis treatment.

Factors influencing endothelial cell proliferation in vitro.

The relative roles of blood cell products and plasma factors on endothelial cell proliferation were evaluated by studying the proliferative response of human umbilical vein endothelial cells to cell free plasma derived serum (CFPDS), whole blood serum (WBS), platelet released factors, fibroblast growth factor and macrophage conditioned medium in vitro. Human adult arterial smooth muscle cells were treated in a similar manner for comparison. The rate of endothelial cell proliferation was directly related to the concentrations of both WBS and CFPDS. Grwoth rate in WBS was marginally greater than that observed in CFPDS during early culture, however, similar confluent densities were achieved. The addition of platelet released factors to CFPDS did not further stimulate endothelial cell proliferation. In contrast smooth muscle cells were quiescent in CFPDS despite increasing serum concentrations, but proliferated actively in response to platelet released factors. Both human macrophage conditioned medium and fibroblast growth factor increased endothelial cell proliferation significantly when compared with CFPDS alone. It is concluded that endothelial cell proliferation in preconfluent cultures is dependent on plasma factors while human vascular smooth muscle cells also require cell derived mitogens such as platelet growth factor to proliferate. The release of a substance by human macrophages mitogenic for endothelial cells may be involved in endothelial cell proliferation in vivo.

The effects of anti-lymphocyte globulin on lymphocyte subpopulations in recipients of kidney allografts.

During the first three weeks following transplantation kidney allograft recipients were treated with zero, 15 or 30 mg/day of anti-human-lymphocyte globulin (ALHG, Behringwerke). T-cells were determined as sheep erythrocyte rosette forming cells (E--RFC) and B cells were identified using the surface membrane immunoglobulin (SmIg) marker. The proportion of E--RFC decreased with increasing AHLG dose. The absolute number of E--RFC was lower in patients receiving 30 mg/kg AHLG compared to those not treated with AHLG. In patients receiving 30 mg/kg AHLG the mean number of lymphocytes covered with AHLG was 78 +/- 3%, detected by using a fluorescent anti-horse IG; significantly higher (p less than 0,001) than 31 +/- 3% in patients treated with 15 mg/kg AHLG. T cell function was measured as the mitogenic response to phytohemagglutinin (PHA) and Concanavalin A (Con A) and the B cell response was measured as the mitogenic response to anti-B2microglobulin (anti-B2m). No differences in response to Con A or anti-B2m were seen in lymphocytes from the various groups of patients. The response to PHA increased (p less than 0,05) in patients treated with the highest dose of AHLG.

The appearance of nonlinear deposits of immunoglobulins in Goodpasture's syndrome.

A twenty year old woman presented with pulmonary hemorrhage and glomerulonephritis with linear deposition of IgG on the glomerular capillary basement membrane, and high titer of antiglomerular basement membrane antibody in her serum. Without treatment, renal function, which was transiently impaired, has improved, pulmonary hemorrhage subsided, and repeat renal biopsies have revealed the appearance of nonlinear in addition to the linear deposition of IgG on the glomerular capillary basement membrane in the face of diminished serum antiglomerular basement membrane antibody titer.

The effect of uremia and transplantation on lymphocyte subpopulations.

The in vitro immune response of uremic and transplanted patients was studied by determining lymphocyte surface and functional markers. Because of lymphopenia, the absolute number of T and B cells are diminished in uremia and transplantation. The uremic state had a profound effect of T cell mitogenic response, while the relative number (%) of T cells was not reduced. B cell responses and relative numbers were significantly diminished. The early posttransplant period was associated with a significant reduction in both T and B cell response and relative numbers. All indexes returned toward normal late in the posttransplant course with reduction of immunosuppression and cessation of the uremic state. Horse anti-human lymphocyte globulin treatment caused a significant reduction in T cells and an increase in B cells. Prednisone therapy did not appear to influence the relative number of the lymphocyte subpopulation but did reduce the mitogenic responses. Changes in surface or functional markers did not prove useful in predicting rejection episodes in transplanted patients.

Renal microangiopathy of the hemolytic-uremic syndrome in childhood.

18 children with clinical and laboratory findings characteristic of the hemolytic uremic syndrome were retrospectively studied. Thrombocytopenia due to platelet destruction was accompanied by only minimal changes in fibrinogen turnover and fibrinolytic degradation products. The most consistent pathologic feature was severe renal endothelial cell injury, which was postulated to produce both platelet and red cell destruction. Despite initially severe renal damage, 90% of the patients ultimately recovered normal renal function if adequately supported during the acute phase of the disease.

The treatment of rejection. A trial of acetylsalicylic acid, dipyridamole, and heparin.

Serial studies of platelet and fibrinogen survival were performed in 26 nonimmunosuppressed dogs after allogenic renal transplant operations. Treatment with acetylsalicylic acid, dipyridamole, and heparin failed to improve the selective platelet destruction which occurred in untreated animals, and it did not improve postoperative longevity. There was a high incidence of postoperative wound and intrarenal hemorrhage after heparin treatment. These results are consistent with the hypothesis that platelet destruction is a consequence rather than the cause of acute graft rejection, and it is concluded that antithrombotic therapy is not of practical benefit in preventing acute rejection.