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Ten healthy subjects received 10 mg oral enalapril (MK 421) daily for a period of 8 days. Renal clearances of electrolytes, urate and phosphate were monitored and factored for glomerular filtration rate, as measured by creatinine clearance, with particular emphasis on the first and eighth day of treatment. Apart from a fall of around 10% in creatinine clearance between 1-2 h on both days 1 and 8, GFR remained unchanged throughout the study. Fractional sodium excretion increased in a biphasic manner by approximately 50% over control between 1-2 h and 4-8 h on day 1. Significant chloruresis (+39.0 +/- 12.9%) and kaluresis (+26.5 +/- 10.3%) occurred between 4-8 h. Urinary pH increased between 0-1 h (+0.29 +/- 0.12; P less than 0.05), and between 4-8 h (+0.50 +/- 0.08; P less than 0.01). The biphasic saluretic effect was also seen between 1-2 h and 4-8 h on day 8. Enalapril caused significant increases in urate and phosphate excretion on day 8 of therapy. There was a biphasic increase in fractional urate excretion at 1-2 h (+28.1 +/- 6.9%; P less than 0.05) and at 4-8 h (+21.0 +/- 6.0% P less than 0.01). Significant phosphaturia (+36.8 +/- 5.2%; P less than 0.05) was also observed at 4-8 h on day 8. Urinary drug excretion was also biphasic; over the first 2 h the predominant drug form was unchanged enalapril, whilst the peak excretion of the diacid metabolite, enalaprilat, occurred at 4-8 h.(ABSTRACT TRUNCATED AT 250 WORDS) [ABSTRACT FROM AUTHOR]

The effects of indacrinone (IND) have been investigated in a two part study. First, a total of 36 clearance studies have been performed in 14 healthy volunteers, under conditions of either maximal hydration or hydropenia, to compare the renal sites of action of single oral doses of IND, 20 mg, ethacrynic acid (EA), 100 mg, and hydrochorothiazide (HCTZ), 100 mg. Under conditions of maximal water hydration, IND increased fractional Na+ excretion from a mean of 1.19 +/- 0.05 to 4.93 +/- 0.67% of GFR. This was similar to the response seen with HCTZ, which increased fractional Na+ clearance up to 3.16 +/- 0.17% of GFR; EA increased fractional Na+ excretion up to 14.5 +/- 2.5% of GFR. The mean reduction in fractional free-water clearance (CH2O/GFR X 100%) invoked by IND, (delta = −34.8% of control) was similar to that produced by EA, (delta = −27.2% of control), and by HCTZ, (delta = - 26.6% of control). During hydropenia with superimposed mannitol diuresis, both IND and EA caused a fall in fractional free-water reabsorption (TcH2O/GFR X 100%), delta IND = −20.3% of control, delta EA = −70.1% of control. HCTZ produced a significant increase in fractional free-water reabsorption, delta HCTZ = −20.7% of control. In all studies, single doses of IND were both uricosuric and hypouricaemic. Fractional urate excretion increased from a mean 6.7 +/- 0.1 to 15.2 +/- 2.1% of GFR whilst plasma urate concentration fell from a mean of 0.36 +/- 0.03 to 0.34 +/- 0.03 mM (P less than 0.05) within 2- 3 h post drug. HCTZ and EA, in single doses, had little effect on urate excretion. In the second part of the study, a total of 16 healthy volunteers received either IND, 10 mg, or HCTZ 50 mg, orally for 8 days, whilst on a diet of controlled electrolyte content. Both drugs were well tolerated by both sets of subjects with no adverse clinical or pathological findings. Both IND and HCTZ caused a significant reduction in weight and standing systolic blood-pressure during the first 48 h of therapy. At the doses administered, IND and HCTZ displayed similar diuretic responses with respect to water, Na+, Cl-, Ca2+ and PO4(3-) excretion. IND produced less kaliuresis than HCTZ during the first treatment day but cumulative K+ loss was similar for both drugs over the eight days of therapy. Fractional urate excretion after IND remained elevated throughout the 8 days of therapy and the subjects remained isouricaemic for 7 days.(ABSTRACT TRUNCATED AT 400 WORDS) [ABSTRACT FROM AUTHOR]

1 The renal action of indacrinone (MK-196), a phenoxyacetic acid derivative with diuretic and uricosuric properties, has been studied in fifteen male subjects. 2 Increasing single doses of up to 60 mg of oral indacrinone produced a linear increase in urinary volume and excretion of Na+ and Cl-, whilst the responses of urinary K+, Ca2+, Mg2+ and uric acid excretion, rose to a plateau at the 40 mg dose. 3 Indacrinone evoked a rapid diuretic response which reached a maximum of 2-4 h and was largely complete at 8-12 h after administration. 4 During maximal hydration, indacrinone produced a substantial fall in fractional free water clearance (CH2O), from 8.89% to 5.83% of the filtered load of water, associated with an increase in osmolal clearance, from 1.38% to 5.78% of the filtered load of solute. The reduction in CH2O was of the same order as that produced by a dose of ethacrynic acid with comparable saluretic activity and significantly greater than that produced by an equi-saluretic dose of hydrochlorothiazide. These findings imply an action of indacrinone upon solute transport in the diluting segments of the distal tubule. 5 At the time of maximal indacrinone-induced saluresis, which amounted to an increase from 0.48% to 4.61% of the filtered load of NaCl, fractional urate clearance increased from 5.16% to 12.24% of the filtered load of uric acid. 6 Indacrinone is a long acting diuretic, sharing some properties in common with both loop diuretics and benzothiadiazines. The results are discussed in relation to structure-activity amongst derivatives of phenoxyacetic acid. [ABSTRACT FROM AUTHOR]

Twelve healthy male volunteers received single daily oral doses of enalapril (EN) 10 mg for 8 consecutive days. Serum samples for prolactin (PRL) assay were taken on day 0 (baseline) at 12.00 h and 16.00 h, and on days 1 and 8 at 08.00 h (pre-drug), 12.00 h and 16.00 h. The 08.00 h values on day 1 served as the pre-drug baseline. There were no significant changes from baseline in serum PRL levels on days 1 and 8. All mean serum PRL levels on day 8 were significantly (P less than 0.01) lower than the upper limit of the normal range (2-15 ng/ml) found for healthy males in this laboratory. It is concluded that therapeutic doses of EN (10 mg/day, p.o.) for 8 consecutive days do not raise mean serum PRL levels above the normal range in healthy male volunteers. [ABSTRACT FROM AUTHOR]

Aim: Diabetic cardiomyopathy is an increasingly recognized entity. The pathogenic factors that may contribute to its development, especially the earliest changes of diastolic dysfunction (DD), have not been clearly defined. Microvessel dysfunction and upregulation of profibrotic growth factors have been described as possible causes. The aim of this study was therefore to determine whether microvascular dysfunction and/or upregulation of the profibrotic connective tissue growth factor (CTGF) are associated with subclinical DD in subjects with type 2 diabetes., Methods: Forty subjects with type 2 diabetes and 20 age-matched non-diabetic controls, all of whom had no clinical evidence of ischaemic heart disease, cardiac failure or echo evidence of systolic ventricular dysfunction, were recruited. Microvascular function was measured by laser Doppler velocimetry, with examination of endothelium-dependent increase in blood flow following iontophoresis of acetylcholine (ACh) and endothelium-independent increase in blood flow in response to the nitric oxide donor sodium nitroprusside (SNP). CTGF levels were determined by Western immunoblotting., Results: DD determined on the basis of traditional echocardiographic criteria was similar in diabetic subjects compared with controls (28 vs. 20%, p = 0.5). Using left ventricular myocardial tissue Doppler-based indices for DD, the E/E' and the E'/A' ratios (where E is the flow related to early ventricular filling and E' and A' are early and late diastolic velocities, respectively) in diabetic subjects revealed evidence of more DD than controls (p = 0.046 and p = 0.007 respectively) . Comparing controls with no DD by conventional echocardiographic criteria (Group I), diabetes and no DD (Group II) and diabetes with DD (Group III), there was a significant trend in reduction of both endothelium-dependent (ACh fold change; p = 0.04) and endothelium-independent (SNP fold change; p = 0.0004) blood flow across the groups. The ACh and SNP responses, however, were not correlated significantly with quartiles of the E/E' ratio or the E'/A' ratio. CTGF plasma levels did not differ across the groups and CTGF did not correlate with parameters of microvascular function., Conclusions: This study indicates that while there is a significant association between DD and measures of microvascular function, the relationship between endothelial dysfunction, CTGF and subtle measures of DD is not strong. Other factors are therefore likely to play an important role in the early pathogenesis of subclinical cardiac DD in type 2 diabetes.

Abnormalities of endothelial function have been demonstrated in diabetes and are thought to play a role in the pathogenesis of diabetic complications. The aims of this study were to determine whether aminoguanidine, an inhibitor of glycation, can prevent endothelial and microcirculation abnormalities in a primate model of type 1 diabetes. Male baboons (Papio hamadryas) were assigned to one of the four groups: control, diabetes, control treated with aminoguanidine or diabetes treated with aminoguanidine. Diabetes was induced by streptozocin (60 mg/kg) and treated with once daily injection of insulin. Aminoguanidine was given subcutaneously (10 mg/kg), once a day. Diabetic animals had a mean duration of diabetes of 8.9 +/- 3.4 years and HbA1c of 8.9 +/- 1.1%. Microvascular function was measured by laser Doppler velocimetry, with examination of endothelium-dependent increase in skin blood flow (SkBF) following iontophoresis of acetylcholine (ACh) and endothelium-independent increase in SkBF in response to the nitric oxide (NO) donor sodium nitroprusside (SNP). Multiple regression analysis identified diabetes (P = 0.049) and aminioguanidine treatment (P = 0.026) as significant determinants of ACh response. The diabetic baboons treated with aminoguanidine had less Ach-mediated SkBF response compared with controls (1.39 +/- 0.32 vs. 2.26 +/- 0.61, F = 3.3, P = 0.04), but there was no difference between groups in SkBF response to SNP. We conclude that endothelial dysfunction can be demonstrated in this primate model of type 1 diabetes at a stage when overt diabetic complications are not present. This occurred in the absence of insulin resistance or significant hypercholesterolemia. Administration of aminoguanidine from the onset of diabetes was not able to prevent this abnormality and in fact aggravated the endothelial response. Effects of aminoguanidine on NO synthase may contribute to this phenomenon.