Arie Erman

Coenzyme Q10 in patients with end‐stage heart failure awaiting cardiac transplantation: A randomized, placebo‐controlled study

BACKGROUNDnThe number of patients awaiting heart transplantation is increasing in proportion to the waiting period for a donor. Studies have shown that coenzyme Q10 (CoQ10) has a beneficial effect on patients with heart failure.nnnHYPOTHESISnThe purpose of the present double-blind, placebo-controlled, randomized study was to assess the effect of CoQ10 on patients with end-stage heart failure and to determine if CoQ10 can improve the pharmacological bridge to heart transplantation.nnnMETHODSnA prospective double-blind design was used. Thirty-two patients with end-stage heart failure awaiting heart transplantation were randomly allocated to receive either 60 mg U/day of Ultrasome--CoQ10 (special preparation to increase intestinal absorption) or placebo for 3 months. All patients continued their regular medication regimen. Assessments included anamnesis with an extended questionnaire based partially on the Minnesota Living with Heart Failure Questionnaire, 6-min walk test, blood tests for atrial natriuretic factor (ANF) and tumor necrosis factor (TNF), and echocardiography.nnnRESULTSnTwenty-seven patients completed the study. The study group showed significant improvement in the 6-min walk test and a decrease in dyspnea, New York Heart Association (NYHA) classification, nocturia, and fatigue. No significant changes were noted after 3 months of treatment in echocardiography parameters (dimensions and contractility of cardiac chambers) or ANF and TNF blood levels.nnnCONCLUSIONSnThe administration of CoQ10 to heart transplant candidates led to a significant improvement in functional status, clinical symptoms, and quality of life. However, there were no objective changes in echo measurements or ANF and TNF blood levels. Coenzyme Q10 may serve as an optional addition to the pharmacologic armamentarium of patients with end-stage heart failure. The apparent discrepancy between significant clinical improvement and unchanged cardiac status requires further investigation.

Microalbuminuria as an early predictor of hypertensive complications in pregnant women at high risk

The value of microalbuminuria in predicting hypertensive complications in pregnant patients at high risk was tested in a prospective trial. A secondary aim was to compare the urinary albumin excretion rate between high risk hypertensive pregnant patients (study group) and pregnant patients at high risk of other complications, normal pregnant subjects, and nonpregnant subjects. Over the last 5 years, 276 patients were studied (142 in the study group v 134 controls). Albumin was measured in an 8-hour overnight urine collection throughout pregnancy using a radioimmunoassay technique. The pregnant women in both the study and control groups demonstrated a statistically significant increase in albumin excretion rate in the second and third trimesters compared with the first. Mean albumin excretion rate values were significantly higher in the study group (P = 0.0001). Using logistic and linear regression models, the presence of microalbuminuria in the early third trimester was proven to be predictive of hypertensive complications (odds ratio, 2.1; confidence intervals, 1.26 to 3.53) and birth weight (R2 = 0.7, P < 0.05) in the study group. Intrauterine growth retardation and neonatal outcome were less predictable. With the introduction of radioimmunoassays and in light of these significant clinical results, we believe that high-risk patients in whom abnormal proteinuria develops usually have a microalbuminuric phase weeks earlier, and this test has some predictive value for severe disease. In addition, the accepted definition of gestational proteinuria should be reconsidered.

Albumin determination in frozen urines--underestimated results.

Albumin determination by radioimmunoassay in fresh and frozen urine collections from 73 patients were performed. The values for albumin in fresh urines were 1-200 mg/24 h and were significantly higher (p less than 0.001) than the corresponding values in urines frozen for seven days (40.7 mg/24 h +/- 5.0 vs. 32.0 mg/24 h +/- 4.3). Similar results were obtained for protein determination, using turbidimetry, in urine collections from 45 proteinuric patients. Iodinated human albumin added to urine specimens was higher (p less than 0.001) in the pellets from frozen urines compared to urines kept at 4 degrees C for 1 and/or 7 days. By contrast, the radioactivity in the pellet of fresh urines kept at 4 degrees C for 1 or 7 days did not show any significant change. We suggest that freezing results in a partial albumin and protein sedimentation. Thus, determination of albumin in frozen urine specimens underestimates the real value by about 20%. This underestimation will limit our ability to diagnose borderline cases of microalbuminuria.

Microalbuminuria following gestational diabetes

Background. Microalbuminuria (MA) precedes clinical nephropathy in patients with insulin‐dependent diabetes mellitus, and is associated with an increased mortality, mostly due to cardiovascular disease in patients with non‐insulin‐dependent diabetes mellitus. Microalbuminuria is rarely detected in patients with diabetes of less than five years duration. Our study was designed to determine whether MA and its sequelae also appear 5‐8 years after pregnancy complicated by gestational diabetes mellitus (GDM).

Enhanced urinary albumin excretion after 35 weeks of gestation and during labour in normal pregnancy

This study reports on the urinary albumin to creatinine ratio during normal pregnancy, with special emphasis on the pre-delivery and labour periods. Albumin was determined in single voided urine specimens obtained from healthy non-pregnant women (n = 16) and healthy pregnant women (n = 203; Groups A and B, 133 females examined during clinic visits and presentation at obstetric department; Group C, 70 females examined during labour) by radioimmunoassay (RIA). The mean ratio (+/- SD) for albumin/creatinine (A/Cr) in non-pregnant women was 1.46 +/- 0.32 mg mmol-1 Cr. Thus, 2.10 mg mmol-1 Cr (mean+2 SD) was considered to be the upper limit of normo-albuminuria. During pregnancy, 73% of the women (97 out of 133, Groups A and B) excreted less than or equal to 2.10 mg mmol-1 Cr. During the first 35 weeks of gestation, 30 of 34 pregnant women (88%) excreted less than or equal to 2.10 mg mmol-1 Cr, the mean being 0.93 +/- 0.64 mg mmol-1 Cr (median 1.0 mg mmol-1). During 36-42 weeks of gestation, the median A/Cr was 1.93 mg mmol-1 Cr (range 0.43-12.16) and 32 of 99 (32%) had values greater than 2.10 mg mmol-1 Cr, an increase of more than two-fold (p less than 0.031) compared with the first 35 weeks. During labour, 61% of non-haematuric urines (33 of 54, Group C) were greater than 2.10 mg mmol-1 Cr, being 125% greater (p less than 0.006) than that observed during pregnancy. Thus in normal pregnancy, A/Cr is increased during the late period of pregnancy and during labour.

Cyclosporin A treatment enhances angiotensin converting enzyme activity in lung and serum of rats

Abstract— Nephrotoxicity and arterial hypertension are the most common side effects of treatment with cyclosporin A (CSA). Its effects on angiotensin converting enzyme (ACE) activity in the renal cortex, lung and serum of nephrotoxic rats have been investigated. Wistar rats were treated with CSA (20 mg kg−1 day−1 i.p.) or vehicle (olive oil containing 10% ethanol) for 14 days. On day 15, the rats were killed and ACE activity determined by radiometric assay using [3H]hippuryl‐glycyl‐glycine as substrate. CSA treatment resulted in a decrease in creatinine clearance, urine flow and body weight and a significant increase in serum and lung ACE activities (436 ± 9 vs 391 ± 7 nmol mL−1 min−1, P < 0.001; 184 ± 8 vs 142 ± 10 nmol mg−1 min−1 P < 0.01, respectively). In contrast, renal cortex ACE activity was reduced in the CSA‐treated rats (0.35 ± 0.02 vs 0.51 ± 0.02 nmol mg−1 min−1, P < 0.01). ACE activities in the renal cortex and serum were not affected by treatment with gentamicin (80 mg kg−1 day−1) for 11 days. In rats treated simultaneously with CSA and captopril (50 mg kg−1 day−1) ACE activity in the serum, lung and renal cortex was inhibited by 95, 93 and 92%, respectively. These changes in ACE activity were associated with a decreased systolic blood pressure in the rats receiving CSA and captopril. Therefore, ACE activity in the serum and lung of CSA‐treated rats was increased, while its activity in the renal cortex was reduced. This increased activity may support the suggestion that CSA induces hypertension through an angiotensin II‐dependent mechanism and/or an increased degradation of vasodilatory kinins.

The role of eicosanoids in cyclosporine nephrotoxicity in the rat

Nephrotoxicity is the most troublesome complication of cyclosporine (CSA) therapy. The present study was designed to investigate the effects of chronic treatment with CSA on the 24-hr urinary excretion of prostanoids (PGs) and thromboxane (Tx) and on the renal function in the absence or presence of indomethacin. CSA administration to Wistar rats (20 mg/kg/day, i.p.) for 14 days caused a significant increase in plasma creatinine, blood urea nitrogen (BUN), urine osmolality, fractional excretion of sodium and potassium and a reduction in creatinine clearance (CCr) and urine volume. These changes were associated with a significant reduction in urinary excretion of PGE2 (21.1 +/- 3.3 vs 33.0 +/- 2.5 ng/24 hr) and PGF2 alpha (13.4 +/- 1.4 vs 27.9 +/- 3.8 ng/24 hr) and an increase in TxB2 (12.1 +/- 3.0 vs 4.6 +/- 0.5 ng/24 hr), and 6-keto PGF1 alpha (56.2 +/- 7.7 vs 27.7 +/- 1.9 ng/24 hr). However, the synthesis of TxB2 and 6-keto PGF1 alpha by renal medullary and cortical slices prepared from CSA treated rats was not different from values obtained for vehicle treatment. In contrast, PGE2 synthesis by cortical slices prepared from the CSA group was increased. A single injection of indomethacin (10 mg/kg) to vehicle and CSA treated rats resulted in a significant reduction in PGs and TxB2 excretion. This, was associated with a further reduction in CCr (0.81 +/- 0.06 vs 1.03 +/- 0.04 ml/min) and an increase in BUN (38.5 +/- 5.2 vs 28.2 +/- 1.4 mg%) only in the CSA group. We suggest that the vasodilating PGs attenuate the renal toxic effects induced by CSA.

Inhibition of phosphofructokinase by the toxic cembranolide sarcophine isolated from the soft-bodied coral Sarcophyton glaucum

Sarcophine, a toxic cembranolide extracted from Sarcophyton glaucum, is known to have toxic effects on fishes, mice and rats, and also reacts with cysteine. Evidence is herewith presented to show that sarcophine inhibits the enzyme phosphofructokinase (ATP: d fructose 6-phosphate 1-phosphotransferase, EC 2.7.1.11) purified from rabbit skeletal muscle. Linear uncompetitive inhibition of the enzyme is indicated due to the reaction of the sarcophine with thiol groups of the enzyme. Sarcophine is shown to be a reversible inhibitor, and a model of the reaction course is offered.

Microalbuminuria : prognostic and therapeutic implications in diabetic and hypertensive pregnancy

Microalbuminuria is defined as urinary excretion of albumin that is persistently above normal, although below the sensitivity of conventional semiquantative test strips. Several studies have reported that Type 1 diabetic patients with microalbuminuria are apparently more likely to develop diabetic nephropathy eventually progressing to renal failure. Microalbuminuria is also a strong predictor of mortality in Type 2 diabetes, and is correlated with increased blood pressure in patients with benign essential hypertension. Radioimmunoassay revealed a significantly higher urinary albumin excretion rate in normal pregnant women in the third trimester of pregnancy, compared to the second and first, and compared to non‐pregnant women. Microalbuminuria was found in 30% of women who had a record of gestational diabetes mellitus. Published results are controversial regarding the assumption that microalbuminuria is an early predictor of pregnancy‐induced hypertensive complications.

Prostaglandin biosynthesis in rabbit kidney: mepacrine inhibits renomedullary cyclooxygenase.

Mepacrine was found to exert a dose-dependent inhibition of prostaglandin E2 synthesis in rabbit kidney medulla slices and in medullary microsomes. Mepacrine at 0.5 mM produced 90% inhibition of microsomal prostaglandin E2 biosynthesis from added arachidonic acid. This effect results from inhibition of medullary cyclooxygenase; the activities of the prostaglandin G2 hydroperoxidase and the prostaglandin H2 isomerases are unaffected. In experiments with medulla slices prelabelled with [14C]arachidonate, the effect of mepacrine on the inhibition of [14C]prostaglandin generation was significantly higher (2.5 to 3.5-fold) than its inhibition of [14C]arachidonate release. Hence, although mepacrine reduces prostaglandin production by decreasing the lipolytic release of arachidonate from medullary lipids, its inhibitory effect on prostaglandin cyclooxygenase activity is substantial and appears to contribute significantly to its overall inhibition of prostaglandin generation in kidney medulla. Mepacrine is thus not only a non-selective antilipolytic agent but also a potent cyclooxygenase inhibitor.