temocapril-hydrochloride and Diabetic-Nephropathies

We conducted a multicenter, randomized, open-label, ascending dose study to investigate the efficacy and safety of combination therapy using the calcium channel blocker azelnidipine and angiotensin-converting enzyme (ACE) inhibitor temocapril in hypertensive diabetics. Patients received monotherapy with 8 mg azelnidipine (group A, n=112) or 2 mg temocapril (group T, n=111) for 4 weeks. If the target blood pressure (<130/80 mmHg) was not achieved, doses were doubled. If it was still not achieved, both drugs were coadministered at week 8, and, if needed, another antihypertensive drug was added after week 16. The treatment period was 52 weeks. Blood pressure was decreased significantly beginning at week 8 (p<0.0001 in both groups), and the systolic and diastolic blood pressure at the end of the treatment period was 128.2+/-11.1/76.4+/-8.1 mmHg. Overall, 53.8% (113/210) of patients achieved the target blood pressure by the end of the study. The effect during the monotherapy period (through week 8) was greater in group A than in group T (systolic, p=0.0475; diastolic, p=0.0001). Laboratory tests showed significant decreases in the urine albumin:creatinine ratio (p=0.0006), high-sensitivity C-reactive protein concentration (p=0.0073), and urine 8-isoprostane concentration (p=0.0215) at the end of the treatment period, as compared with baseline values. No adverse events caused safety problems. In conclusion, combination therapy using azelnidipine and temocapril is an effective treatment for hypertensive diabetics.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Azetidinecarboxylic Acid; Blood Glucose; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Drug Therapy, Combination; Female; Heart Rate; Humans; Hypertension, Renal; Kidney Function Tests; Lipids; Male; Middle Aged; Thiazepines; Treatment Outcome

We examined the effects of increasing the recommended initial doses of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), or of switching to combination therapy with both drugs, on diabetic nephropathy. Hypertensive type 2 diabetic patients with urinary albumin excretion (ACR) between 100 and 300 mg/g creatinine (Cre) were assigned to the following five groups in which an antihypertensive drug was administered at a recommended initial dose for 48 weeks, and then either the dose was doubled or an additional drugs was added to regimen for the following 48 weeks: N, nifedipine-CR (N) 20 mg/day (initial dose); T, ACEI temocapril (T) 2 mg/day; C, ARB candesartan (C) 4 mg/day; T+C, T first and then addition of C; C+T, C first and then addition of C. ACR decreased in the T (n=34), C (n=40), T+C (n=37) and C+T (n=35) groups, but not in the N group (n=18). However, the anti-proteinuric effect was less in the T than in the C, T+C or C+T groups, while no differences existed among the latter three. In each group, there were significant linear relationships between attained BP and ACR; however, the regression lines were shifted toward lower ACR level in the renin-angiotensin system-inhibition groups compared with the N group. These results indicate that an ACEI and/or ARB is superior to a CCB in retarding diabetic nephropathy, while the combination of low doses of ACEI and ARB has effects similar to those of high-dose ARB. Even among patients treated with an ACEI and/or ARB, lowering BP is important.

Topics: Aged; Albuminuria; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Cost-Benefit Analysis; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Middle Aged; Tetrazoles; Thiazepines

Combined antihypertensive therapy plays a crucial role in achieving targeted blood pressure reductions and renoprotection. We therefore compared the antihypertensive and antiproteinuric effects of combined therapy with either a calcium channel blocker (CCB) plus an angiotensin II receptor blocker (ARB) or an angiotensin converting enzyme inhibitor (ACE-I) plus an ARB in patients with type 2 diabetes mellitus complicated by overt nephropathy and mild to moderate hypertension. After a 12-week dietary control period, diabetic patients with mildly to moderately impaired renal function were randomly assigned to either a CCB (amlodipine 5 mg once daily) or an ACE-I (temocapril 2 mg once daily) for 12 weeks (monotherapy period). Both groups then received add-on therapy with an ARB (candesartan 4 mg once daily) for an additional 12 weeks. During the monotherapy period, blood pressure was decreased equally well in both groups. Daily urinary protein excretion remained unchanged in the CCB-treated group (control period, 4.0 +/- 1.8 g/day vs. CCB period, 4.1 +/- 1.9 g/day; ns; n = 8), but decreased in the ACE-I-treated group (control period, 4.3 +/- 1.8 g/day vs. ACE-I period, 3.5 +/- 1.7 g/day; p < 0.05; n = 9). After the combined therapy period, blood pressure was decreased to the same degree in both groups. Although ARB plus CCB significantly reduced urinary protein excretion (to 3.5 +/- 1.5 g/day; p < 0.05 vs. control period; n = 8), a more profound reduction was achieved with ARB plus ACE-I (to 2.6 +/- 1.3 g/day; p < 0.01 vs. control period; n = 9). Monotherapy with the ACE-I increased the serum potassium concentration, and this elevation was sustained after addition of the ARB. In contrast, the serum potassium concentration was not influenced by monotherapy with the CCB, but was significantly increased after addition of the ARB. A decreased hematocrit was observed in the ARB plus ACE-I group. The present study suggests that combined antihypertensive therapy with either a CCB plus an ARB or an ACE-I plus an ARB exerts an antiproteinuric effect in patients with type 2 diabetic nephropathy with mildly impaired renal function. Although the latter combination had a more profound effect, it was associated with an increased serum potassium concentration and worsening of renal anemia. Thus, the combination of a CCB and an ARB should be the first line antihypertensive therapy in those with overt diabetic nephropathy. The long-term efficacy of these combined antihyperten

Topics: Aged; Amlodipine; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Middle Aged; Pilot Projects; Proteinuria; Tetrazoles; Thiazepines; Treatment Outcome

Whether temporary angiotensin II (AngII) blockade at the prediabetic stage attenuates renal injury in type 2 diabetic OLETF rats later in life was investigated. OLETF rats were treated with an AT(1) receptor antagonist (olmesartan, 0.01% in food), angiotensin-converting enzyme inhibitor (temocapril, 0.01% in food), a combination of the two, or hydralazine (25 mg/kg per d) at the prediabetic stage (4 to 11 wk of age) and then monitored without further treatment until 50 wk of age. At 11 wk of age, blood glucose levels and urinary protein excretion (U(protein)V) were similar between OLETF and control LETO rats. However, OLETF rats showed higher kidney AngII contents and type IV collagen mRNA expression than LETO rats at this age. These decreased with olmesartan, temocapril, and a combination of these but not with hydralazine. At 50 wk of age, diabetic OLETF rats showed higher BP, U(protein)V, and intrarenal AngII levels than LETO rats. Temporary AngII blockade did not affect glucose metabolism or the development of hypertension in OLETF rats but significantly suppressed proteinuria and ameliorated glomerular injury. However, no parameters were affected by temporary hydralazine treatment. The present study demonstrated that intrarenal AngII and type IV collagen expression are already augmented long before diabetes becomes apparent in OLETF rats. Furthermore, temporary AngII blockade at the prediabetic stage attenuates the progression of renal injury in these animals. These data suggest that early AngII blockade could be an effective strategy for preventing the development of type 2 diabetic renal injury later in life.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Glucose; Blood Pressure; Body Weight; Collagen; Connective Tissue Growth Factor; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Hydralazine; Imidazoles; Immediate-Early Proteins; Intercellular Signaling Peptides and Proteins; Male; NADPH Oxidases; Olmesartan Medoxomil; Prediabetic State; Rats; Rats, Inbred OLETF; Receptors, Angiotensin; Renin; Tetrazoles; Thiazepines; Thiobarbituric Acid Reactive Substances; Transforming Growth Factor beta

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Kidney Glomerulus; Male; Metabolic Clearance Rate; Proteinuria; Rats; Rats, Inbred OLETF; Thiazepines

Diabetic nephropathy is a leading cause of end-stage renal disease in industrialized countries. Previous studies have documented that angiotensin converting enzyme (ACE) inhibitors consistently reduce albuminuria and retard the progression of diabetic nephropathy. However, the involvement of angiotensin II in diabetic nephropathy is not fully understood.. In this study we compared the effects of CS-866, a new angiotensin II type 1 receptor antagonist, to that of an ACE inhibitor, temocapril hydrochloride, on the development and progression of diabetic nephropathy using Otsuka Long-Evans Tokushima fatty rats, a type II diabetes mellitus model animal.. High doses of CS-866 or temocapril treatment were found to significantly improve urinary protein and beta(2)-microglobulin excretions in diabetic rats. In electron microscopic analysis, loss of glomerular anionic sites, one of the causes of glomerular hyperpermeability in diabetic nephropathy, was found to be significantly prevented by CS-866 treatment. Light microscopic examinations revealed that both treatments ameliorated glomerular sclerosis and tubulointerstitial injury in diabetic rats. Furthermore, high doses of CS-866 or temocapril treatment significantly reduced the positive stainings for transforming growth factor-beta (TGF-beta), vascular endothelial growth factor, and type IV collagen in glomeruli of diabetic rats.. These results indicate that intrarenal angiotensin II type 1 receptor activation plays a dominant role in the development and progression of diabetic nephropathy. Our study suggests that CS-866 represents a valuable new drug for the treatment of diabetic patients with nephropathy.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Anions; Diabetic Nephropathies; Disease Models, Animal; Imidazoles; Immunohistochemistry; Kidney Glomerulus; Male; Olmesartan Medoxomil; Proteinuria; Rats; Rats, Inbred OLETF; Severity of Illness Index; Tetrazoles; Thiazepines; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Biopsy; Diabetic Nephropathies; Female; Humans; Kidney; Proteinuria; Remission Induction; Thiazepines

Renal excreted angiotensin converting enzyme (ACE) inhibitor captopril, and renal.hepatic bile excreted ACE inhibitor temocapril, were compared by monitoring serum ACE and renal ACE expression (protein and mRNA) in streptozotocin-induced diabetic rats. Serum ACE levels did not change in untreated diabetic rats or in those treated with temocapril, compared with normal control rats. However, serum ACE levels significantly increased in diabetic rats treated with captopril after 3 months (153.8 +/- 23.0 vs. 43.5 +/- 5.5 IU/l/37 degrees C, p < 0.01) and 6 months (113.6 +/- 9.3 vs. 36.9 +/- 2.9 IU/l/37 degrees C, p < 0.01) compared with normal control rats. Compared with normal control rats (3.6 +/- 0.4), proximal tubular ACE protein expression significantly (p < 0.01) decreased in untreated diabetic rats (1.6 +/- 1.1), but significantly (p < 0.01) increased in diabetic rats treated with captopril (3.7 +/- 0.3) and temocapril (3.5 +/- 0.4). Renal ACE mRNA levels decreased in untreated diabetic rats (125.5 +/- 20.3 vs. 313.3 +/- 53.4, p < 0.01) compared with normal control rats for 6 months. Renal ACE mRNA levels tended to increase in diabetic rats treated with captopril (184.4 +/- 51.2 vs. 125.5 +/- 20.3) and temocapril (165.4 +/- 43.2 vs. 125.5 +/- 20.3) compared with untreated diabetic rats for 6 months. In conclusion, diabetic rats had lower proximal tubular ACE protein expression and lower renal ACE mRNA levels compared with normal control rats. Furthermore, both ACE inhibitors increased renal ACE protein and mRNA expression, but differed in their effect on serum ACE levels.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Kidney; Male; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; RNA, Messenger; Thiazepines

Tempocapril is a novel angiotensin-converting enzyme (ACE) inhibitor which is preferentially eliminated via the biliary tract. To examine whether it has a protective effect in diabetic nephropathy like conventional ACE inhibitors which are eliminated via the kidney, a study was performed in streptozotocin-induced diabetic rats for 8 months. Male Wistar rats were divided into 4 groups (control rats, diabetic rats treated with temocapril at the doses of 5 mg/l or 15 mg/l of drinking water, and untreated diabetic rats). There was no significant difference in the blood glucose levels of the 3 diabetic groups. Administration of temocapril at both doses of 5 mg/l and 15 mg/l significantly reduced the blood pressure as well as the urinary excretion of albumin and N-acetyl-beta-D-glucosaminidase. However, significant suppression of glomerular basement membrane hypertrophy was only induced by treatment with temocapril at the dose of 15 mg/l. Elevated glomerular filtration rate and filtration fraction in diabetic rats were decreased by tempocapril at the dose of 15 mg/l, but not significantly. These results indicate that tempocapril has a protective effect on diabetic nephropathy like conventional ACE inhibitors.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Basement Membrane; Biliary Tract; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Glomerular Filtration Rate; Kidney Glomerulus; Male; Rats; Rats, Wistar; Streptozocin; Thiazepines