ozagrel and Proteinuria

We used rats (the Otsuka Long-Evans Tokushima Fatty strain) as a model of type 2 diabetes to find whether thromboxane (TX) A2 is involved in diabetic nephropathy, and if so, to identify where it is synthesized. We measured urinary excretion of TXB2 and 2,3-dinor-TXB2 in rats up to 60 weeks of age as markers of renal and platelet synthesis of TXA2, respectively. Some diabetic rats were given daily oral doses of OKY-046 (100 mg/kg), a TXA2 synthase inhibitor, starting when they were 10 weeks of age. Healthy Long-Evans Tokushima Otsuka rats served as the controls. Urinary excretion of protein was greater in diabetic rats at 26 weeks than in controls, and the difference increased with age. Urinary excretion of TXB2 by diabetic rats was about 150% that of controls at 14 weeks, and remained at that level. In diabetic rats, urinary excretion of 2,3-dinor-TXB2 increased with age in parallel to increases in proteinuria, but in controls, excretion of these metabolites did not change with age. In diabetic rats, OKY-046 prevented the increase in urinary excretion of both metabolites, and decreased the proteinuria. Histologic examination at 60 weeks showed intraglomerular thrombi in diabetic rats but not in controls. OKY-046 reduced intraglomerular thrombi formation and the score for glomerulosclerosis. When platelet aggregation began, more TXA2 than before was released from the thrombi that formed, and the TXA2 contributed to the progress of nephropathy in this rat model of type 2 diabetes.

Topics: 6-Ketoprostaglandin F1 alpha; Aging; Animals; Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Enzyme Inhibitors; Glomerular Mesangium; Male; Methacrylates; Prostaglandins; Proteinuria; Rats; Rats, Inbred OLETF; Thrombosis; Thromboxane A2; Thromboxane-A Synthase

The antinephritic effect of DP-1904 [6-(1-imidazolylmethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid hydrochloride], a thromboxane A2 synthase inhibitor, was evaluated using an experimental model of membranous nephropathy, viz. accelerated passive Heymann nephritis in which the glomerular injury is mediated by immune complexes. DP-1904 markedly inhibited the develop-ent of glomerular alteration as well as the elevation of proteinuria and plasma creatinine. When the treatment was started from the 22nd day, at which time proteinuria is fully developed, DP-1904 showed beneficial effects on proteinuria and glomerular histopathological changes. DP-1904 apparently decreased the deposition of both rabbit immunoglobulin G and rat immunoglobulin G on glomerular basement membrane in nephritic rats. A single administration of DP-1904 restored the decreased renal tissue blood flow, inhibited glomerular thromboxane B2 production and increased glomerular prostaglandin E2 and 6-keto prostaglandin F1 alpha production in nephritic rats. These results suggest that DP-1904 may be an effective agent for the treatment of idiopathic membranous nephropathy and that the beneficial effect of this drug may be due to the elimination of glomerular immune deposits and to an increase in renal tissue blood flow related to amelioration of the abnormal metabolism of arachidonic acid.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antibodies; Azathioprine; Creatinine; Dinoprostone; Drug Interactions; Enzyme Inhibitors; Glomerulonephritis; Imidazoles; Immunoglobulin G; Immunosuppressive Agents; Kidney Glomerulus; Male; Methacrylates; Proteinuria; Rabbits; Rats; Rats, Sprague-Dawley; Renal Circulation; Tetrahydronaphthalenes; Thromboxane B2; Thromboxane-A Synthase

The antinephritic effect of DP-1904 [6-(1-imidazolylmethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid hydrochloride], a thromboxane (TX) A2 synthase inhibitor, was compared with that of OKY-046 and azathioprine, using an experimental model of nephritis, crescentic-type anti-glomerular basement membrane (GBM) nephritis. Test drugs were given p.o. once daily from an autologous phase in which proteinuria was already fully developed. DP-1904 (15 and 45 mg/kg per day) and OKY-046 (20 mg/kg per day), another TXA2 synthase inhibitor, significantly inhibited the development of glomerular alteration as well as the elevation of proteinuria. On the other hand, azathioprine (20 mg/kg per day), an immunosuppressive agent, failed to suppress the proteinuria. A single administration of DP-1904 or OKY-046 inhibited glomerular TXB2 production and increased glomerular prostaglandin (PG) E2 and 6-keto PGF1 alpha production in nephritic rats. Both drugs apparently decreased the depositions of both rabbit immunoglobulin (Ig) G and rat IgG on GBM in nephritic rats, but azathioprine inhibited only the deposition of rat IgG. These results suggest that DP-1904 may be an effective agent for the treatment of proliferative glomerulonephritis and its antinephritic effect may be due to the amelioration of abnormal metabolism of arachidonic acid.

Topics: Animals; Antimetabolites; Azathioprine; Creatinine; Enzyme Inhibitors; gamma-Globulins; Glomerulonephritis; Imidazoles; Immunoenzyme Techniques; Male; Methacrylates; Proteinuria; Rats; Rats, Sprague-Dawley; Tetrahydronaphthalenes; Thromboxane-A Synthase

The antinephritic effect of DP-1904 [6-(1-imidazolylmethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid hydrochloride], a thromboxane A2 synthetase inhibitor, was compared with that of OKY-046, using an experimental model of nephritis, crescentic-type anti-glomerular basement membrane nephritis. Test drugs were given p.o. once daily from the day after the the development of glomerular alteration as well as the elevation of proteinuria and plasma cholesterol. On the other hand, OKY-046 (20 mg/kg per day), a thromboxane A2 synthetase inhibitor, significantly inhibited only deterioration in the glomeruli. DP-1904 and OKY-046 inhibited glomerular thromboxane B2 production and increased glomerular prostaglandin E2 and 6-keto prostaglandin F1 alpha production in normal and nephritic rats. Both drugs inhibited the increase in platelet aggregability, restored decreased renal tissue blood flow to a near-normal level and decreased the deposition of rat immunoglobulin G on glomerular basement membrane in nephritic rats. These results suggest that DP-1904 may be an effective agent for the treatment of proliferative glomerulonephritis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Basement Membrane; Cholesterol; Dinoprostone; Fluorescent Antibody Technique; Imidazoles; Kidney Glomerulus; Male; Methacrylates; Nephritis, Interstitial; Platelet Aggregation; Proteinuria; Rats; Rats, Sprague-Dawley; Tetrahydronaphthalenes; Thromboxane B2; Thromboxane-A Synthase

To examine the effects of endogenous thromboxane A2 on the development of diabetic nephropathy, we administered OKY-046, an inhibitor of thromboxane synthesis, to streptozotocin-induced diabetic rats. Animals were divided into three groups; nondiabetic control, diabetic, and diabetic with OKY-046, and were sacrificed 16 weeks after experimental procedures. The chronic oral administration of OKY-046 to diabetic rats significantly decreased plasma and urinary thromboxane B2 levels. Urinary protein excretion and serum glucose levels were significantly lower in the OKY-046-treated diabetic rats than in the untreated diabetics (60.8 +/- 23.2 vs. 94.1 +/- 33.4 mg/day in the 16th week, p less than 0.05 and 424.4 +/- 93.3 vs. 614.4 +/- 102.3 mg/dl in the 16th week, p less than 0.01, respectively). Platelet aggregation was inhibited by OKY-046. Blood urea nitrogen was unaffected. Ultrastructural examination revealed that the thickness of glomerular basement membrane was markedly thinner in the OKY-046-treated diabetic rats than in the untreated diabetics (197.4 +/- 29.6 vs. 288.6 +/- 46.9 nm, p less than 0.01). These results suggest that thromboxane A2 may play an important role in the development and progression of diabetic nephropathy in rats.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Animals; Blood Glucose; Blood Pressure; Blood Urea Nitrogen; Body Weight; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Insulin; Kidney; Male; Methacrylates; Microscopy, Electron; Platelet Aggregation; Proteinuria; Rats; Rats, Inbred Strains; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

There has been no useful treatments for chronic vascular rejection (CVR) after kidney transplantation until now. Recently, however, some reports have suggested that the thromboxane A2 synthetase inhibitor, OKY-046, is useful in reducing proteinuria in nephrotic syndrome and preventing progression of CVR. Five patients with CVR (serum creatinine range: 1.7-2.6 mg/dl) were treated with OKY-046 for over one year and the effect of OKY-046 was evaluated. One patient developed acute rejection and another renal hypertension during this study. Except for the cases of acute rejection and renal hypertension, serum creatinine slightly decreased in 1 case and remained unchanged in 2 cases. Urinary excretion of protein and thromboxane B2 decreased significantly but prostaglandin E2 did not change in the treatment of the deterioration with OKY-046. We concluded that OKY-046 was effective in preventing graft function and decreasing urinary protein excretion in kidney transplant recipients with CVR.

Topics: Acrylates; Chronic Disease; Female; Graft Rejection; Humans; Kidney; Kidney Transplantation; Male; Methacrylates; Prostaglandins E; Proteinuria; Thromboxane B2; Thromboxane-A Synthase

To induce crescentic-type anti-glomerular basement membrane (anti-GBM) nephritis, male Sprague-Dawley rats were immunized with rabbit gamma-globulin in Freund's complete adjuvant following i.v. injection of anti-GBM serum. At the same time, original type anti-GBM nephritis was induced in other rats by anti-GBM serum only. The animals with crescentic-type anti-GBM nephritis showed significantly higher platelet aggregability than that in rats with original-type anti-GBM nephritis at days 5, 10 and 40 after anti-GBM serum administration, respectively. To estimate the antinephritic effect of OKY-046, a thromboxane A synthetase inhibitor, it was given orally to rats at doses of 0.5, 2.5 or 20 mg/kg for 39 days after anti-GBM serum. OKY-046 (20 mg/kg) significantly inhibited the increase in both urinary protein and plasma cholesterol levels (40% and 35% vs. control, respectively). Moreover, when examined by light microscopy, this drug remarkably prevented histological involvement of the glomeruli. OKY-046 at 20 mg/kg had suppressed the hyperaggregability of platelets by 77% by day 40 as compared with the control, but doses of 0.5 and 2.5 mg/kg did not. It is concluded from these data that OKY-046 has beneficial effects on crescentic-type anti-GBM nephritis and may act through inhibition of not only platelet TxA2 but also glomerular TxA2 in its action to prevent histological alterations.

Topics: Acrylates; Animals; Blood Urea Nitrogen; Body Weight; Cholesterol; Glomerulonephritis; Kidney; Kidney Glomerulus; Male; Methacrylates; Platelet Aggregation; Platelet Aggregation Inhibitors; Proteinuria; Rats; Rats, Inbred Strains; Thromboxane-A Synthase; Urodynamics

Recent studies have suggested a role for thromboxane in the progression of renal disease. The current study evaluated the role of this arachidonic acid metabolite in a model of renal disease which bears many biologic similarities to that in the kidneys of patients with chronic progressive renal failure. The model is that induced by ferritin-anti-ferritin immune complex nephritis in Dahl-salt sensitive rats rendered hypertensive by a high salt intake. Rats with this model of renal disease were chronically given a thromboxane synthetase antagonist OKY-046 or a placebo treatment from 16 to 29 weeks of age. Sequential observations of serum creatinine and 24-hour urinary protein excretion showed an ameliorating effect of OKY-046 on these renal parameters. Histologic examination of the kidneys also showed significantly less glomerular sclerosis in OKY-046 treated animals. The efficacy of OKY-046 was monitored by measurements of serum TXB2 levels and of glomerular production of TXB2 (and other prostaglandins); amounts of TXB2 were significantly reduced in the OKY-046 group. It is concluded that blockade of thromboxane generation has been successful in ameliorating the functional and structural lesions in this model of renal disease, providing further support to the thesis that thromboxane is an important mediator in events leading to eventual chronic renal failure and sclerosis.

Topics: Acrylates; Animals; Creatinine; Fatty Acids, Unsaturated; Immune Complex Diseases; In Vitro Techniques; Kidney Glomerulus; Male; Methacrylates; Nephritis; Proteinuria; Rats; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

Topics: Animals; Blood Pressure; Diabetes Mellitus, Experimental; Kidney; Male; Methacrylates; Proteinuria; Rats; Rats, Inbred Strains; Renin; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

To determine if a selective thromboxane (TX)A2 synthetase inhibitor is clinically effective for the treatment of nephrotic syndrome, 11 patients with nephrotic syndrome were treated only with OKY-046, (E)-3-4-(1-imidazolylmethyl)phenyl-2-propenoic acid hydrochloride monohydrate, for at least 8 weeks. Urinary excretion of protein, TXB2, 2,3-dinor-TXB2, and beta-N-acetyl-D-glucosaminidase decreased with OKY-046. Creatinine clearance value, and urinary excretion of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), however, did not show any significant change, while serum albumin level increased. Two patients with minimal change nephrotic syndrome showed complete remission only with OKY-046. These results demonstrate that the selective TXA2 synthetase inhibitor is an effective drug for the treatment of chronic glomerulonephritis accompanied by nephrotic syndrome.

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Adolescent; Adult; Aged; Female; Glomerulonephritis; Humans; Male; Methacrylates; Middle Aged; Nephrosis, Lipoid; Nephrotic Syndrome; Proteinuria; Thromboxane B2; Thromboxane-A Synthase

Topics: Acrylates; Animals; Male; Methacrylates; Nephrotic Syndrome; Proteinuria; Puromycin Aminonucleoside; Rats; Rats, Inbred Strains; Thromboxane-A Synthase

Repeated subcutaneous (SC) injections of mercuric chloride (MC) in Brown Norway (BN) rats induce an autoimmune glomerulonephritis (GN) due to antiglomerular basement membrane (BM) antibody deposition in the glomeruli. The aim of this study was to investigate the effects on MC-induced autoimmune GN of OKY-046, a selective TXA-synthetase inhibitor herring oil (HO), which is rich in eicosapentaenoic acid (EPA) (5.6%) precursor of the three series of prostaglandins (PGs) and of (inactive) thromboxane (TXA3), and evening primrose oil (EPO), which is rich in linoleic acid (LA) (72%) and gamma-linolenic acid (GLNA) (9%), precursors of the one series of PGs, mainly PGE1, and of (inactive) TXA1. The administration of OKY-046 significantly inhibited proteinuria, partially prevented fibrin thrombi (FT) formation in the glomeruli, decreased urinary TXB, enhanced 6ketoPGF excretion and, increased survival rate of the animals from 60% (group receiving only MC) to 86%. However, OKY-046 did not prevent body weight (BW) loss or the development and deposition of IgG in the glomeruli. Increased intake of HO (80 days prior and throughout the experiment) and avoidance of arachidonic acid (AA) intake produced an effect comparable to that of OKY-046 in the rats. Furthermore, HO significantly inhibited the deposition of IgG in the glomeruli, increased the survival rate of the animals to 100% and further enhanced the increased urinary PGE excretion induced by MC. However, HO did not prevent BW loss in the animals. Increased intake of EPO and avoidance of AA intake produced an effect comparable to that of HO. Additionally, EPO completely prevented BW loss induced by MC in these animals. These findings suggest that the metabolites of AA, EPA and GLNA play an important role either in the development or in the modulation of this model of MC induced GN.

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Animals; Autoimmune Diseases; Fatty Acids, Essential; Fatty Acids, Unsaturated; Fish Oils; gamma-Linolenic Acid; Glomerulonephritis; Hypolipidemic Agents; Immunoglobulin G; Linoleic Acids; Mercuric Chloride; Methacrylates; Oenothera biennis; Plant Oils; Prostaglandins E; Proteinuria; Rats; Thromboxane-A Synthase; Thromboxanes

Topics: Acrylates; Animals; Fatty Acids, Essential; Female; gamma-Linolenic Acid; Glomerulonephritis, IGA; Linoleic Acids; Mercuric Chloride; Methacrylates; Oenothera biennis; Plant Oils; Prostaglandins; Proteinuria; Rats; Rats, Inbred BN; Thromboxane-A Synthase