Inhibition of GATA2 in prostate cancer by a clinically available small molecule.

Castration-resistant prostate cancer (CRPC) remains highly lethal and in need of novel, actionable therapeutic targets. The pioneer factor GATA2 is a significant prostate cancer (PC) driver and is linked to poor prognosis. GATA2 directly promotes androgen receptor (AR) gene expression (both full-length and splice-variant) and facilitates AR binding to chromatin, recruitment of coregulators, and target gene transcription. Unfortunately, there is no clinically applicable GATA2 inhibitor available at the moment. Using a bioinformatics algorithm, we screened in silico 2650 clinically relevant drugs for a potential GATA2 inhibitor. Validation studies used cytotoxicity and proliferation assays, global gene expression analysis, RT-qPCR, reporter assay, reverse phase protein array analysis (RPPA), and immunoblotting. We examined target engagement via cellular thermal shift assay (CETSA), ChIP-qPCR, and GATA2 DNA-binding assay. We identified the vasodilator dilazep as a potential GATA2 inhibitor and confirmed on-target activity via CETSA. Dilazep exerted anticancer activity across a broad panel of GATA2-dependent PC cell lines in vitro and in a PDX model in vivo. Dilazep inhibited GATA2 recruitment to chromatin and suppressed the cell-cycle program, transcriptional programs driven by GATA2, AR, and c-MYC, and the expression of several oncogenic drivers, including AR, c-MYC, FOXM1, CENPF, EZH2, UBE2C, and RRM2, as well as of several mediators of metastasis, DNA damage repair, and stemness. In conclusion, we provide, via an extensive compendium of methodologies, proof-of-principle that a small molecule can inhibit GATA2 function and suppress its downstream AR, c-MYC, and other PC-driving effectors. We propose GATA2 as a therapeutic target in CRPC.

Behçet's disease complicated by IgA nephropathy with nephrotic syndrome.

A 65-year-old woman with a 48-year history of Behçet's disease associated with nephrotic syndrome is described. Immunofluorescence study revealed IgA nephropathy. Following treatment with an angiotensin II type-I receptor-blocker, an anti-platelet drug, and an HMG-CoA reductase inhibitor, accompanied by dietary restrictions of protein and sodium, proteinuria was markedly decreased. This report describes our experience with a rare entity of Behçet's disease complicated by nephrotic syndrome due to IgA nephropathy. Routine urine examination and renal biopsy are needed for the detection and diagnosis of renal problems with Behçet's disease.

Meta-analysis of antiplatelet therapy for IgA nephropathy.

BACKGROUND: Antiplatelet agents have been widely used in the management of immunoglobulin A (IgA) nephropathy in the Japanese population. To systematically evaluate the effects of antiplatelet agents for IgA nephropathy, we conducted a meta-analysis of the published studies. METHODS: Data sources consisted of MEDLINE, EMBASE, the Cochrane Library, Ityu-shi (Japanese medical database), and bibliographies from the studies. The quality of the studies was evaluated from the intention to treat analysis and allocation concealment, as well as by the Jadad method. Meta-analyses were performed on the outcomes of proteinuria and renal function. RESULTS: Seven articles met the predetermined inclusion criteria. The use of antiplatelet agents showed statistically significant effects on proteinuria and renal function. The pooled risk ratio for proteinuria was 0.61 (95% confidence intervals (CI) 0.39-0.94) and for renal function it was 0.74 (95% CI 0.63-0.87). CONCLUSIONS: Antiplatelet agents resulted in reduced proteinuria and protected renal function in patients with IgA nephropathy. However, studies of high-quality design were rare, and most studies assessed surrogate outcomes. More properly designed studies are needed to reach a definitive assessment of this matter.

Immunotactoid glomerulopathy with microtubular deposits, with reference to the characteristics of Japanese cases.

We present the case of a 69-year-old man with nephrotic syndrome and renal insufficiency, who developed lobular glomerulonephritis. An electron microscopy examination of a renal biopsy showed microtubular structures of 24 nm in diameter in the subendothelial space and the paramesangial area. These deposits were PAS-positive and Congo red-negative, and revealed predominantly positive staining for kappa light chain. There was no evidence of diseases with highly organized glomerular deposits, such as amyloidosis, cryoglobulinemia, systemic lupus erythematosus or paraproteinemia. Therefore, the patient was diagnosed to have immunotactoid glomerulopathy (ITG). During a seven-year course he has not developed any disease known to be associated with organized glomerular immune deposits. Hence, we believe ITG occurred as a primary glomerular disease in this case. We also highlight cases of ITG with microtubular deposits that have been reported in Japan, compare these cases to previous reports, and show that the characteristics of the Japanese cases are male predominance; a high incidence of membranoproliferative glomerulonephritis (MPGN); a low incidence of monoclonal gammopathy and hematological malignancies and a higher incidence of hypocomplementemia.

Silent cerebral infarction in patients with type 2 diabetic nephropathy. Effects of antiplatelet drug dilazep dihydrochloride.

BACKGROUND: To determine whether diabetic nephropathy is a risk factor for silent cerebral infarction and whether antiplatelet drug dilazep dihydrochloride decreases the occurrence of silent cerebral infarction in type 2 diabetes patients with microalbuminuria. METHODS: Two hundred four type 2 diabetes patients (124 men, 80 women; age, median 56 years, range 42-74 years) and 60 healthy age-matched subjects (no diabetes, normal renal function) were recruited for brain magnetic resonance imaging. The diabetes patients included 40 without nephropathy (group A), 42 with microalbuminuria (20-200 microg/min) (group B), 44 with macroalbuminuria (>200 microg/min) and normal renal function (blood creatinine <132.7 micromol/L) (group C), 33 with chronic renal failure but not undergoing haemodialysis (blood creatinine >132.7 micromol/L; mean creatinine 335.9 micromol/L) (group D) and 45 undergoing haemodialysis (duration; median 4 years, range 3-6 years) (group E). RESULTS: Silent cerebral infarction was found in 20, 29, 34, 45, 53 and 8% of group A, B, C, D, E and control patients respectively. The incidence of silent cerebral infarction was increased with diabetic nephropathy. Thirty group B patients with no silent cerebral infarction were divided into two groups: (B1) 15 treated with dilazep dihydrochloride and (B2) 15 not treated with dilazep dihydrochloride. Treatment continued for 24 months. The incidence of silent cerebral infarction was significantly lower in the dilazep-treated patients (6.7%) than in the untreated patients (33.3%) (p < 0.01). CONCLUSIONS: These data suggest that diabetic renal dysfunction increases the risk of silent cerebral infarction and that dilazep dihydrochloride prevents its onset in early type 2 diabetic nephropathy patients.

Efficacy of prednisolone and mizoribine therapy for diffuse IgA nephropathy.

OBJECTIVE: There have been only a few studies concerning oral prednisolone and mizoribine therapy for diffuse IgA nephritis (IgAN). We evaluated the efficacy of prednisolone and mizoribine therapy for diffuse IgAN. METHODS: We enrolled 34 patients who had been diagnosed as having diffuse IgAN with severe proteinuria during the period from 1992 to 1999. Following diagnostic renal biopsy, the patients were treated with prednisolone, mizoribine, warfarin and dilazep dihydrochloride. The clinical features, laboratory data and pathological findings between pre- and post-therapy were investigated. RESULTS: The mean urinary protein excretion after 6 months of treatment had decreased significantly compared to pre-therapy. The incidence of hematuria in post-therapy was lower than that of pre-therapy. The grading index decreased significantly from 4.8 +/- 2.1 at the first biopsy to 2.3 +/- 1.7 at the second biopsy (p < 0.001) and the staging index decreased significantly from 4.1 +/- 1.9 at the first biopsy to 2.7 +/- 2.4 at the second biopsy (p < 0.05). Macrophage infiltration and alpha-smooth muscle actin-positive cells in the glomerulus and interstitial region decreased significantly in post-therapy compared with pre-therapy. At the most recent follow-up, none of the 34 patients had renal insufficiency. CONCLUSIONS: Our study suggested that prednisolone and mizoribine therapy is effective for those patients with the risk of progression of IgAN.

Combination AST-120 and dilazep dihydrochloride therapy reduced urinary protein excretion and serum creatinine levels in patients with chronic renal failure.

The effect of AST-120 and dilazep dihydrochloride on serum creatinine levels and urinary protein excretion was assessed in patients with chronic renal failure. We found that both drugs in combination provide an additive renoprotective effect over each drug in some chronic renal failure patients.

Effect of dilazep dihydrochloride on serum cardiac troponin T levels in hemodialysis patients.

BACKGROUND/AIM: Cardiac troponin T is a highly sensitive marker for the detection of myocardial injury. We studied whether dilazep dihydrochloride affects cardiac troponin T levels in hemodialysis patients. METHODS: Our study included 60 hemodialysis patients without symptoms of acute myocardial ischemia. We measured serum cardiac troponin T levels by the Elecsys troponin T assay and randomized 40 hemodialysis patients with left ventricular hypertrophy (LVH) into two treatment groups: a dilazep dihydrochloride group (300 mg/day, n = 20) and a placebo group (n = 20). Treatment was continued for 12 months. RESULTS: There were no significant differences between pre- and postdialysis cardiac troponin T levels before treatment. LVH was noted in 40 patients out of 60 hemodialysis patients (67%). Cardiac troponin T levels were significantly higher in these patients (0.23 +/- 0.08 microg/l) than in hemodialysis patients without LVH (0.09 +/- 0.03 microg/l). Cardiac troponin T levels were reduced from 0.24 +/- 0.08 to 0.12 +/- 0.06 microg/l (p < 0.01) in patients treated with dilazep dihydrochloride. There were no change in cardiac troponin T levels in patients receiving placebo (from 0.21 +/- 0.08 at baseline to 0.20 +/- 0.07 microg/l). CONCLUSION: Dilazep dihydrochloride may be effective in ameliorating myocardial damage in hemodialysis patients.

Dilazep hydrochloride, an antiplatelet drug, prevents progression of diabetic nephropathy in Otsuka Long-Evans Tokushima fatty rats.

Diabetic nephropathy is a leading cause of end-stage renal disease in industrialized countries. Although the mechanisms for the development and progression of diabetic nephropathy are not fully understood, platelet activation may participate in its pathogenesis by promoting microthrombus formation. In this study, we investigated the effects of dilazep hydrochloride, an antiplatelet agent, on the development and progression of diabetic nephropathy in Otsuka Long-Evans Tokushima fatty (OLETF) rats, a type 2 diabetes mellitus animal model. Administration of dilazep hydrochloride significantly reduced the increase of urinary protein excretions and N-acetyl-beta-D-glucosaminidase (NAG) activity in OLETF rats. Furthermore, dilazep hydrochloride treatment prevented glomerulosclerosis and tubular atrophy and reduced positive staining for type IV collagen in the glomeruli of diabetic rats. These results indicate that platelet activation plays a dominant role in the development and progression of diabetic nephropathy. Our study suggests that dilazep hydrochloride is a valuable new drug for the treatment of diabetic patients with nephropathy.

Steroid therapy and urinary transforming growth factor-beta1 in IgA nephropathy.

Transforming growth factor-beta1 (TGF-beta1) has an important role in the pathogenesis of glomerular damage by influencing matrix metabolism. An association of TGF-beta1 with glomerulosclerosis and interstitial fibrosis has been shown in various renal diseases, suggesting that TGF-beta1 may serve as a diagnostic marker of glomerular diseases. The aim of this study is to determine the usefulness of urinary TGF-beta1 values to monitor therapeutic effects of steroids in patients with immunoglobulin A (IgA) nephropathy. Concentrations and activation rates of TGF-beta1 (mature/total) were determined in urine of patients with renal diseases by means of a double-antibody enzyme immunoassay. The urinary TGF-beta1 level before steroid therapy was compared with renal histological characteristics, creatinine clearance, and proteinuria in patients with a variety of renal diseases. Urinary excretion of total and mature TGF-beta1 was significantly greater in patients with crescentic glomerulonephritis and IgA nephropathy than in healthy controls, whereas the activation rate of urinary TGF-beta1 was similar among patients with other renal diseases. Urinary TGF-beta1 excretion at the time of renal biopsy significantly correlated with the degree of crescent formation in patients with IgA nephropathy, but not in those with glomerular sclerosis or tubulointerstitial fibrosis. Urinary excretion of total and mature TGF-beta1 was reduced in patients with IgA nephropathy after treatment with prednisolone (0.8 mg/kg/d) for 1 month. The activation rate of urinary TGF-beta1 also decreased significantly after steroid therapy. Urinary TGF-beta1 values therefore may be useful to assess disease activity or the effects of steroid therapy in patients with IgA nephropathy.

Effect of the antiplatelet drug dilazep dihydrochloride on urinary podocytes in patients in the early stage of diabetic nephropathy.

OBJECTIVE: To determine whether the antiplatelet drug dilazep dihydrochloride affects the number of urinary podocytes in diabetic patients with microalbuminuria. RESEARCH DESIGN AND METHODS: Fifty patients with type 2 diabetes and microalbuminuria (30 men and 20 women, mean age 48.6 years) and 30 age-matched control subjects (18 men and 12 women, mean age 49.2 years) were included in the study. No patients showed serum creatinine levels in excess of 2.0 mg/dl. Urinary podocytes were examined by immunofluorescence microscopy with monoclonal antibodies against podocalyxin. RESULTS: Urinary podocytes were detected in 18 of the 50 microalbuminuric diabetic patients (mean, 1.3 cells/ml). Urinary podocytes were not detected in the remaining 32 patients or in the 30 healthy control subjects. Diabetic patients positive for urinary podocytes were divided into 2 treatment groups: a dilazep dihydrochloride treatment group (300 mg/day; n = 9, group A) and a placebo group (n = 9, group B). Treatments were continued for 6 months. In group A, microalbuminuria decreased significantly from 146 +/- 42 to 86 +/- 28 microg/min (P < 0.01) and urinary podocytes also decreased from 1.3 +/- 0.8 to 0.4 +/- 0.2 cells/ml (P < 0.01). However, in group B, microalbuminuria and urinary podocytes changed little over the study period. CONCLUSIONS: Podocyte injury may occur in patients with early diabetic nephropathy, and dilazep dihydrochloride may be useful for preventing glomerular injury.

Hyperimmunoglobulin E syndrome associated with nephrotic syndrome.

A 21-year-old man was admitted to Kure National Hospital with nephrotic syndrome in September 1996. He had suffered from an intractable pruritic skin rash and recurrent subcutaneous abscesses caused by the hyperimmunoglobulin E syndrome since the age of 18 months. Renal biopsy gave a diagnosis of membranoproliferative glomerulonephritis. Steroid therapy decreased urinary protein loss and hypoproteinemia, and his pruritic skin rash was improved. Patients with hyperimmunoglobulin E syndrome have a defective immune response, especially to Staphylococcus aureus infection. Continuous antigen stimulation may have caused this patient's renal histological damage as in immune complex glomerulonephritis.

Antiplatelet therapy decreases the incidence of erythropoietin-induced hypertension in predialysis patients.

The observation that antiplatelet therapy may decrease the incidence of Epo-induced hypertension in dialysis patients remains a subject of particular interest. The aim of the present study was to test this hypothesis in patients at the predialysis stage. Predialysis patients with renal anemia were treated with EPO (6000 IU/week) for 6-12 months. Patients were divided into two groups, one of which received antiplatelet therapy and the other did not, and a comparison was made between them with respect to the incidence of EPO-induced hypertension. Logistic regression analysis was used to determine the risk factors for developing hypertension during the EPO therapy. Such predictors included age, gender, antecedent of hypertension, antiplatelet drugs and diabetes mellitus. Overall, 66 patients were enrolled in the study and 18 developed hypertension (27%). Out of the 35 patients not receiving antiplatelet therapy, 15 developed hypertension (43%). In contrast, out of the 31 patients receiving antiplatelet therapy, only 3 (10%) developed hypertension (p=0.003 by Chi square test). Multiple regression analysis showed that the best predictive variables for the development of hypertension were antecedent of hypertension (odds ratio: 0.064, p=0.0118), and use of antiplatelet drugs (odds ratio: 5.081, p=0.0295). The present data provide evidence that antiplatelet therapy may prevent EPO-induced hypertension in predialysis patients. However, the mechanism to explain such an effect still remains to be elucidated.

Cross over placebo control trial of dilazep in beta-thalassemia/hemoglobin E patients.

An attempt was made to find better symptomatic treatment for beta-thalassemia/hemoglobin E (beta-thal/Hb E) patients in order to reduce their blood demand. Oral administration of dilazep was prescribed for these patients and a clinical trial was conducted over a 2-year period as a cross over placebo control study. Seventeen beta-thal/Hb E patients were enrolled in the study. All of them received dilazep and placebo for 10 months at different periods of time and were taken care of by the same doctor throughout the study. The blood demand of the same patients during the period of receiving dilazep with the period of receiving placebo, was 1.5 +/- 1.8 U/10 months versus 2.2 +/- 2.6 U/10 months, respectively. Thus dilazep showed a benefit in decreasing the blood demand by about 50% although the results did not reach statistical significance (p = 0.1). There was a statistical difference in hemoglobin concentration of the patients receiving dilazep compared with placebo (p = 0.038). While receiving dilazep the mean +/- SD hemoglobin level was 5.82 +/- 0.8 g/dl, significantly higher than while receiving placebo (5.66 +/- 0.9 g/dl) (p = 0.038). The liver, and renal function tests, and cardiac enzyme levels of the patients showed no significant changes throughout the study. However, one case had a problem with bleeding following tooth extraction whilst receiving dilazep and needed 1 unit of blood transfusion. In conclusion, administration of dilazep to patients with beta-thal/Hb E increased the patients' hemoglobin and reduced their blood demand with few side effects.

Elevation of plasma adenosine levels may attenuate the severity of chronic heart failure.

Adenosine is known to be an endogenous cardioprotective substance. Since we have reported that adenosine levels increase in patients with chronic heart failure, we tested whether further elevation of the adenosine levels due to dipyridamole or dilazep for 6 months modulates the pathophysiology of chronic heart failure. In patients with chronic heart failure, either dipyridamole (300 mg/d n = 17) or dilazep (300 mg/d n = 5) were administered for 6 months. Twenty-two patients (mean +/- SE age 58 +/- 4 years old) attending a specialized chronic heart failure (CHF) clinic over 6 months and judged as in New York Heart Association (NYHA) function class II or III were examined. The other drugs used for the treatment of CHF were not altered during the study. There were 5 patients with CHF caused by ischemic heart diseases, and 17 patients with either valvular heart diseases or dilated cardiomyopathy. We found that increases in the plasma adenosine levels (202 +/- 34 and 372 +/- 74) nmol/L before and after dipyridamole administration, P < 0.005 ameliorate the severity of CHF (NYHA: 2.1 +/- 0.5 to 1.7 +/- 0.2). Both ejection fraction and maximal oxygen consumption increased. These improvements in the severity of chronic heart failure returned to baseline levels 6 months after discontinuation of dipyridamole. Comparable results were obtained in the dilazep protocol. We suggest that the elevation of plasma adenosine levels improves the pathophysiology of CHF.

Cardioprotective effect of K-7259, a novel dilazep derivative, against ischemia-reperfusion damage in isolated, working rat hearts.

Global ischemia (15 min) followed by reperfusion (10, 20 or 30 min) was performed in isolated, working rat hearts. Ischemia depressed mechanical function, which was not restored by reperfusion of 20 min. Preischemic administration of K-7259 (N,N'-bis[4-(3,4,5-trimethoxyphenyl)butyl]homopiperazine dihydrochloride) (1, 5 or 10 microM) decreased the function before ischemia, but it attenuated the ischemia-induced dysfunction during reperfusion (20 min). Postischemic administration of K-7259 (10 microM) or dilazep (20 microM) also attenuated the ischemia-induced dysfunction during reperfusion (30 min). Ischemia-reperfusion (10 min) increased the tissue malondialdehyde level, and postischemic administration of K-7259 (10 microM) or dilazep (20 microM) attenuated the malondialdehyde accumulation. K-7259 has a cardioprotective effect when given either before or after ischemia.

A double-blind placebo control trial of dilazep in beta-thalassemia/hemoglobin E patients.

Since the obtained results from the pilot study indicated that dilazep which was a membrane stabilizer would be benefit to treatment and prevention of anemia and chronic leg ulcer in beta-thalassemia/hemoglobin E (beta-thal/HbE) patients, the authors had continued the study in a second phase, ie a double blind placebo control trial. Twenty-seven beta-thal/HbE patients were recruited in the study. Eight patients who suffered from chronic leg ulcer were given dilazep. The rest of patients were given dilazep or placebo according to a randomized table. Hence, 16 patients received dilazep and 11 received placebo. When we compared the number of unit of blood transfusion, hemoglobin level, 2-3 DPG and P50 value between the dilazep and placebo groups using unpaired t-test, we found that there were no statistical differences in any of the parameters. However, when we compared the data within the group using paired t-test, there was statistical decrease in blood requirement after treatment in the dilazep group (p < 0.05). Concerning with the treatment of chronic leg ulcer, 3 in 8 patients were completely healed within 3 months, 4 in 8 patients were improved and 1 in 8 patients was not improved. There were complaints of skin itching and mild epigastric pain in placebo group but the liver function tests, kidney function tests and cardiac enzyme did not significantly change during the medication.

A study on dilazep: I. Mechanism of anti-ischemic action of dilazep is not coronary vasodilation but decreased cardiac mechanical function in the isolated, working rat heart.

In the isolated, perfused working rat heart, ischemia (15 min) decreased the mechanical function and the tissue levels of adenosine triphosphate and creatine phosphate and increased the levels of lactate and free fatty acids. Reperfusion (20 min) did not restore the mechanical function, but restored incompletely the levels of metabolites, with the exception of free fatty acids, which increased further during reperfusion. Dilazep was given 5 min before starting ischemia until the end of ischemia. Dilazep at 5 or 10 microM decreased the cardiac mechanical function, but did not affect coronary flow in the pre-ischemic heart. Dilazep at 5 or 10 microM accelerated the recovery of mechanical function and coronary flow during reperfusion, and it attenuated metabolic changes induced by ischemia and reperfusion. Dilazep at 1 microM neither decreased the pre-ischemic mechanical function nor restored the mechanical function during reperfusion, although it attenuated the accumulation of free fatty acids during reperfusion. These results suggest that dilazep attenuates both ischemia- and reperfusion-induced myocardial damage and that the anti-ischemic action of dilazep is not due to coronary vasodilation but probably due to an energy-sparing effect and other effects that remain to be studied.

Nucleoside transport inhibitors enhance the infarct size-limiting effect of ischemic preconditioning.

We recently observed that dipyridamole pretreatment significantly enhanced the infarct size (IS)-limiting effect of preconditioning (PC), which was attenuated by adenosine receptor antagonist. This potentiation of PC was interpreted to result from inhibition of nucleoside transport by dipyridamole, but contribution of other pharmacologic actions of dipyridamole could not be excluded. To confirm that inhibition of nucleoside transport leads to PC enhancement, we assessed alteration of mild PC by two different nucleoside transport inhibitors, dilazep and R75231, which, unlike dipyridamole, lack action on phosphodiesterase (PDE) and prostacyclin. Myocardial infarction was induced in rabbits by 30-min coronary occlusion and 72-h reperfusion. IS and area at risk (AAR) were determined by histology and fluorescent particles, respectively. Rabbits either were untreated or received dilazep (0.34 mg/kg intravenously, i.v.) or R75231 (0.05 mg/kg i.v.) before coronary occlusion. In other groups of rabbits, PC was conducted with 2-min ischemia and 5-min reperfusion with or without injection of the nucleoside transport inhibitor (0.34 or 0.10 mg/kg dilazep or 0.05 mg/kg of R75231) before PC. IS expressed as percentage of AAR (%IS/AAR) was 43.9 +/- 2.3% (SE) in untreated controls; dilazep (0.34 mg/kg) and R75231 alone did not modify IS (%IS/AAR = 50.6 +/- 4.7 and 42.7 +/- 11.9%, respectively). PC tended to reduce IS (%IS/AAR = 33.3 +/- 3.5%), but the combination of dilazep or R75231 with PC significantly limited %IS/AAR (%IS/AAR = 22.5 +/- 5.0% after low-dose dilazep plus PC, 27.6 +/- 4.9% after high-dose dilazep plus PC, and 19.9 +/- 3.6%, after R75231 plus PC).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of pancreatic elastase on diabetic nephropathy.

Pancreatic elastase has been shown to inhibit the thickening of glomerular basement membranes in experimental diabetic animals. We explored the clinical significance of the prolonged administration of pancreatic elastase on diabetic nephropathy, in patients whose blood glucose levels and blood pressure were controlled. Pancreatic elastase was administered for 12 months. Body weight levels, blood glucose levels, HbA1c values and blood pressure remained unchanged. Administration of 10,800 U of pancreatic elastase caused a significant decrease in albuminuria (before administration, 512.4 +/- 79.8 mg/g creatinine vs. 12 months after administration, 284.1 +/- 61.9 mg/g creatinine, P < 0.01, n = 28). In the contrast group (n = 18), no significant changes in albuminuria were observed after administration of 300 mg of dilazep dihydrochloride. Serum levels of creatinine and urinary levels of NAG and beta 2 MG were not affected by pancreatic elastase. The present study indicates a significant inhibitory effect of pancreatic elastase on increased albuminuria in diabetic patients.