temocapril-hydrochloride and Diabetes-Mellitus--Type-2

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

The effects of angiotensin antagonists on coronary circulation in type 2 diabetes are unclear. We aimed to assess whether 4 weeks of treatment with angiotensin-converting enzyme inhibitor or angiotensin II type 1 receptor antagonist improves coronary flow velocity reserve (CFVR) in patients with type 2 diabetes.. Twenty-four asymptomatic patients with type 2 diabetes were randomly assigned to temocapril (2 mg/d) or candesartan (8 mg/d). Coronary flow velocity reserve, calculated as the ratio of adenosine-induced hyperemic to basal coronary flow velocity, was measured with transthoracic Doppler echocardiography. Coronary flow velocity reserve measurement and venous blood sampling were performed before and after 4 weeks of treatment. We also obtained CFVR and venous blood data in the 8 healthy controls.. Coronary flow velocity reserve was significantly lower in patients than controls (temocapril group 2.74 +/- 0.28, candesartan group 2.65 +/- 0.30, controls 3.53 +/- 0.23, P < .0001 for both, respectively). Blood pressure was reduced in both diabetic groups (n = 12 each) similarly 4 weeks after treatment. There were no significant differences between the 2 groups in venous blood data before or after treatment. However, CFVR increased significantly in the temocapril group (2.74 +/- 0.28 to 3.31 +/- 0.36, P < .0001), but not in the candesartan group (2.65 +/- 0.30 to 2.71 +/- 0.43, P = ns).. Coronary flow velocity reserve in patients with type 2 diabetes improved after treatment with temocapril but not with candesartan, suggesting that angiotensin-converting enzyme inhibitor, but not angiotensin II type 1 receptor antagonist, might have beneficial effects on coronary microangiopathy associated with type 2 diabetes.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biphenyl Compounds; Blood Flow Velocity; Coronary Circulation; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Exercise Test; Female; Hemodynamics; Humans; Male; Middle Aged; Single-Blind Method; 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

The effect of angiotensin converting enzyme inhibitor, temocapril hydrochloride on the serum lipoproteins, and especially on the size of low density lipoproteins (LDL) of hypertensive diabetic patients, were studied. Temocapril hydrochloride (5 mg/day) was administered to 32 hypertensive type 2 diabetes patients for 16 weeks. During treatment, systolic and diastolic blood pressures decreased significantly from 162/95 mmHg to 138/76 mmHg at 16 weeks (p<0.001), and serum levels of total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) showed significant reduction, but those of HbA1c, triglycerides (TG) and high density lipoprotein cholesterol (HDL-C) showed no significant changes. LDL particle size evaluated by polyacrylamide gel disc electrophoresis was normalized from small size. It is concluded that temocapril hydrochloride favorably affects the serum lipoprotein metabolism of hypertensive type 2 dependent diabetes mellitus patients.

Topics: Antihypertensive Agents; Blood Pressure; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypertension; Lipids; Lipoproteins, LDL; Male; Particle Size; Thiazepines; Triglycerides

Compared with other angiotensin-converting enzyme (ACE) inhibitors, the elimination of temocapril is less dependent on renal function. To investigate the metabolic and antihypertensive effects of temocapril in diabetic hypertensives, 30 patients with diabetes mellitus type 2 and mild to moderate hypertension [diastolic blood pressure (BP) 90-115 mm Hg] and without azotemia (plasma creatinine < 180 microM) were evaluated in a prospective randomized double-blind placebo-controlled study. After a 4-week placebo run-in, they received temocapril, 20 mg daily (n = 19), or placebo (n = 11) for 6 weeks. Insulin sensitivity index (SI), determined by the Minimal Model method of Bergman, serum lipoproteins, plasma renin activity, fibrinogen, and microalbuminuria were assessed at the end of the placebo run-in phase and the double-blind treatment phases. Temocapril but not placebo administration produced a significant decrease in supine BP (152/92+/-5/3 vs. 162/98+/-5/2 mm Hg; p < 0.01) and increase in plasma renin (p < 0.05). Variation of SI during temocapril treatment did not reach statistical significance (0.95+/-0.2 before vs. 1.44+/-0.4 x 10(-4)/min/mU/L after treatment). During administration of temocapril or placebo, no significant changes in fasting plasma glucose, insulin, and serum levels of total triglycerides, cholesterol, lipoprotein cholesterol fractions, or fibrinogen were observed. Microalbuminuria decreased significantly on temocapril treatment (49+/-10 vs. 79+/-17 mg/24 h; p < 0.01) but not on placebo. These findings demonstrate that in hypertensive patients with diabetes mellitus type 2, short-term treatment with temocapril is neutral to insulin sensitivity, lipoprotein metabolism, and fibrinogen, and significantly reduces microalbuminuria.

Topics: Adult; Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Carbohydrate Metabolism; Diabetes Mellitus, Type 2; Double-Blind Method; Enalapril; Female; Fibrinogen; Humans; Hypertension; Kidney Function Tests; Lipoproteins; Male; Middle Aged; Patient Compliance; Prospective Studies; Thiazepines

Measurements of serum asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, and coronary flow velocity reserve (CFVR) using transthoracic Doppler echocardiography were performed at baseline and after 4 weeks of temocapril therapy (2 mg/day) in 18 patients with type 2 diabetes. Although blood pressure, fasting blood sugar and lipid profiles remained unchanged, serum ADMA concentrations decreased significantly (0.51+/-0.08 to 0.46+/-0.07 micromol/l, p<0.01) and CFVR increased significantly (2.78+/-0.36 to 3.35+/-0.46, p<0.001) after the treatment. Moreover, a strong correlation was observed between the difference of ADMA and that of CFVR (r=-0.80, p<0.001). Temocapril reduced serum ADMA concentrations, improved CFVR beyond its blood pressure lowering effect. Our results suggest that decrease in ADMA by temocapril treatment is related to improvement of coronary circulation as determined by CFVR in patients with type 2 diabetes.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Arginine; Coronary Circulation; Diabetes Mellitus, Type 2; Female; Humans; Male; Thiazepines

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

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs) have potent antioxidant effects in addition to antihypertensive effects.. We investigated the ability of ACEIs and ARBs to enhance the superoxide scavenging ability of polymorphonuclear leukocytes (PMNLs) from type 2 diabetic patients (n = 32) and healthy subjects (n = 32). The scavenging ability (U/10(3) cells) of superoxide was measured by electron spin resonance. We used ascorbic acid as a positive control antioxidant and tested captopril, temocapril (an inactive form of ACEI), and temocaprilate (an active form of ACEI) as ACEIs, as well as RNH-6270 as an ARB.. Captopril, temocaprilate, and RNH-6270 showed dose-dependent enhancement in scavenging ability. The scavenging ability with captopril and temocaprilate was greater than with RNH-6270. The changes in scavenging ability induced by all of the drugs in diabetic patients were similar to the changes in healthy subjects. A high-glucose medium (400-800 mg/dL) greatly attenuated the drug-induced enhancement of scavenging ability.. We demonstrated that both ACEIs and ARBs enhance superoxide scavenging by PMNLs from type 2 diabetic patients and that a high-glucose environment markedly attenuates the ability of these drugs to augment superoxide scavenging.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antioxidants; Ascorbic Acid; Blood Glucose; Captopril; Diabetes Mellitus, Type 2; Female; Free Radical Scavengers; Humans; Imidazoles; In Vitro Techniques; Male; Middle Aged; Neutrophils; Superoxide Dismutase; Superoxides; Tetrazoles; Thiazepines

Improvement of insulin resistance by ACE inhibitors has been suggested; however, this mechanism has not been proved. We postulated that activation of the bradykinin-nitric oxide (NO) system by an ACE inhibitor enhances glucose uptake in peripheral tissues by means of an increase in translocation of glucose transporter 4 (GLUT4), resulting in improvement of insulin resistance. Administration of an ACE inhibitor, temocapril, significantly decreased plasma glucose and insulin concentrations in type 2 diabetic mouse KK-Ay. Mice treated with temocapril showed a smaller plasma glucose increase after glucose load. We demonstrated that temocapril treatment significantly enhanced 2-[3H]-deoxy-D-glucose (2-DG) uptake in skeletal muscle but not in white adipose tissue. Administration of a bradykinin B2 receptor antagonist, Hoe140, or an NO synthase inhibitor, L-NAME, attenuated the enhanced glucose uptake by temocapril. Moreover, we observed that translocation of GLUT4 to the plasma membrane was significantly enhanced by temocapril treatment without influencing insulin receptor substrate-1 phosphorylation. In L6 skeletal muscle cells, 2-DG uptake was increased by temocaprilat, and Hoe140 inhibited this effect of temocaprilat but not that of insulin. These results suggest that temocapril would improve insulin resistance and glucose intolerance through increasing glucose uptake, especially in skeletal muscle at least in part through enhancement of the bradykinin-NO system and consequently GLUT4 translocation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Biological Transport; Blood Glucose; Bradykinin; Cell Line; Deoxyglucose; Diabetes Mellitus, Type 2; Glucose Transporter Type 4; Insulin Receptor Substrate Proteins; Insulin Resistance; Kinetics; Male; Mice; Mice, Inbred C57BL; Monosaccharide Transport Proteins; Muscle Proteins; Muscle, Skeletal; Nitric Oxide; Phosphoproteins; Phosphorylation; Protein Transport; Thiazepines

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

The aim of this study was to investigate whether a combined treatment of ACE inhibitor and exercise training is more effective than either treatment alone in alleviating the insulin resistant states in the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a model of type 2 diabetes. OLETF rats (25 weeks old) were randomly divided into 5 groups; sedentary control, exercise-trained, temocapril (ACE inhibitor; 2 mg/kg/day)-treated, with and without exercise, and losartan (AT1 receptor antagonist; 1 mg/kg/day)-treated. Long-Evans Tokushima Otsuka rats were used as a non-diabetic control. Body weight, the amount of abdominal fat and blood pressure were higher for OLETF rats than for control rats. However, glucose infusion rate (GIR), an index of insulin resistance, was decreased greatly in OLETF rats. The fasting levels of blood glucose, insulin and lipids were also increased in the diabetic strain. In OLETF rats, both temocapril and losartan reversed hypertensive states significantly, whereas GIR and hyperlipidemia were improved when rats were treated with ACE inhibitors, but not with the AT1 receptor antagonist. Exercise training decreased body weight and the amount of abdominal fat, and also increased GIR in parallel with improved dislipidemia. The combination of the ACE inhibitor with exercise training also improved obesity, hyperinsulinemia, dislipidemia and fasting level of blood glucose, and this combination resulted in the greatest improvement of insulin resistance. These results suggest that the combination of ACE inhibitor and exercise training may be a beneficial treatment for mixed diabetic and hypertensive conditions.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Blood Pressure; Body Weight; Combined Modality Therapy; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Exercise Therapy; Glucose Clamp Technique; Glucose Tolerance Test; Insulin; Insulin Resistance; Male; Obesity; Physical Conditioning, Animal; Rats; Rats, Inbred OLETF; Rats, Long-Evans; Thiazepines; Treatment Outcome