Methyl conjugation in uraemia: catechol-O-methyltransferase.

1 Erythrocyte (RBC) catechol-9-methyltransferase (COMT) activity is significantly higher in erythrocytes from uraemic patients on maintenance haemodialysis, 18.7 +/- 1.4 units/ml RBC (mean +/- s.e. mean, n = 22) than in the blood of randomly selected subjects, 12.0 +/- 0.2 units/ml (mean +/- s.e. mean, n = 557, P < 0.001). 2 Uraemic plasma contains larger quantities of endogenous methyl acceptors than does normal plasma, and it reversibly inhibits RBC lysate COMT activity to a greater degree than does normal plasma. 3 There are large individual variations in the degree of inhibition of RBC COMT activity plasma from patients with renal failure. Inhibition varied from 10-43% when 40 microliters plasma from each of 19 randomly selected uraemic patients was tested, and there as a direct correlation between the inhibition of COMT by plasma from an individual uraemic patient and its content of endogenous methyl acceptors (r = 0.64, n = 19, P < 0.01). 4 Kinetic studies with pooled uraemic plasma demonstrate that inhibition of COMT by uraemic plasma is uncompetitive with respect to both the catechol substrate and the methyl donor for the reaction, S-adenosyl-L-methionine. 5 Plasma from uraemic patients does not inhibit partially purified rat liver COMT, an observation which suggests that the inhibition is not due to a direct effect on COMT but requires the presence of other constituents of the RBC lysate, perhaps other methyltransferase enzymes.     

Pharmacokinetics of unlabelled and14C-labelled pindolol in uraemia

Summary The elimination of pindolol in 25 patients with various degrees of renal failure has been studied after an intravenous dose of 3 mg. A linear correlation was not found between the elimination rate of pindolol and the endogenous creatinine clearance, and the half-life of the unchanged drug was independent of the severity of the renal failure. This implies greater metabolism of pindolol in anuric patients and the extrarenal elimination rate constantk _mwas increased. Three patients with severe renal failure were given 3 mg¹⁴C-pindolol. They showed almost constant plasma levels of radio-activity for 6 h and then slow excretion with a half-life of 48 h, because of accumulation of metabolites in the blood. Up to 90% of the metabolites are glucuronides and sulphates which have no beta-blocking or other clinical activity. Thus, to produce beta-adrenergic blockade the same dose of indolol is required in healthy patients as in those with uraemia.     

Inhibitory effect of uraemia on the hepatic clearance and metabolism of nicardipine.

1. The principal aim of this study was to investigate the effect of renal impairment on the pharmacokinetics of nicardipine following intravenous and oral dosing. 2. The plasma clearance of nicardipine was significantly lower at 6.5 ml min-1 kg-1 in patients with impaired renal function, compared with a mean value of 10.4 in patients with normal renal function and with 12.5 ml min-1 kg-1 in patients on regular haemodialysis treatment. 3. In comparison to the patients with normal renal function, there were significant increases in AUC and Cmax in the patients with renal impairment. These increases were particularly marked during chronic dosing - AUC was increased by 163%, Cmax by 127% and apparent oral bioavailability by 90%. There were no such increases in the dialysis group whose values were similar to those for normal renal function. 4. There were no significant differences in volume of distribution or protein binding, nor in the measured indices of hepatic function to account for the reduction in drug clearance in the patients with renal impairment. 5. The results of this study indicate that renal impairment may have a significant and potentially important impact on the disposition of a drug which, under normal circumstances, is highly extracted by the liver. Accumulation of a metabolic 'inhibitor' substance is a possible explanation.     

The short term effects of bezafibrate on the hypertriglyceridaemia of moderate to severe uraemia

Hypertriglyceridaemia, an atherogenic risk factor, is a well recognised complication of uraemia, and is present in the earliest stages of the disease. Bezafibrate is an effective hypolipidaemic agent, and its effect in moderate to severe uraemia is documented in this study. Significant reductions in serum triglyceride and cholesterol have been achieved after 1 month's therapy with a reduced dosage of bezafibrate. A reduction in the hyperinsulinaemia was also seen, but no change in the fractional removal rate of injected lipid emulsion (K2) was observed. An accelerated decline in some patients' renal function was observed, which was partially reversed on cessation of treatment. Reversible elevations in the serum creatinine phosphokinase were also seen, but no patient exhibited the myositis-like syndrome associated with clofibrate.     

Lithium-induced uraemia in rats: survival and renal function and morphology after one year

Chronic renal failure was induced in Wistar rats by administration of a LiCl-containing (40 mmol/kg) diet from birth until an age of 55-65 weeks. The 55 weeks mortality was 51% in Li-uraemic rats versus 6% in control rats. In surviving rats the mean plasma Li levels were 0.6-0.7 mmol/l after 16 weeks and 1.0-1.1 mmol/l after 48 weeks. The mean plasma urea level was 14 mmol/l after 16 weeks and 22 mmol/l after 48 weeks of treatment compared with 8 mmol/l in the controls rats. In 55 weeks old Li-uraemic rats inulin clearance was reduced by 62% and Li clearance by 39%. Thus, fractional Li excretion was increased (from 20 to 34%) in rats with chronic Li-uraemia. Li-uraemic rats also had polyuria and failed to concentrate their urine in response to exogenous vasopressin. Systolic and mean arterial blood pressures were not significantly changed in rats with Li-uraemia. Morphological examinations of the kidneys showed large cortical cysts formed by dilated distal tubules and collecting ducts and widespread interstitial fibrosis. Proximal tubular mass was reduced by 50% and glomerular volume was also significantly reduced. The results indicate that in rats with Li-induced uraemia renal function and morphology deteriorate during Li-exposure up to an age of one year, associated with increased mortality.     

Effect of uraemia and anephric state on the pharmacokinetics of tenoxicam in the rat.

Renal alterations, uraemia and nephrotic syndrome induced in experimental animals caused a reduction in the plasma albumin concentration of 25 and 30%, respectively. As a result of this decrease, the unbound fraction of tenoxicam in uraemic rats (0.06 +/- 0.02) and in anephric rats (0.11 +/- 0.08) increased with respect to the control group (0.03 +/- 0.004). The induced hypoalbuminaemia did not modify the blood to plasma concentration ratio. Both plasma clearance (CL) and apparent volume of distribution at steady-state (Vdss) rose significantly with the increase in the unbound fraction: (Vdss 55 +/- 6 mL (control rats); 69 +/- 12 mL (uraemic rats); 96 +/- 30 mL (anephric rats); CL = 7 +/- 1 mL h-1 (control rats); 12 +/- 4 mL h-1 (uraemic rats); 15 +/- 7 mL h-1 (anephric rats)). Tenoxicam elimination was found to be restrictive, with an extraction ratio less than 0.1 in the three groups. The induction of nephrotic syndrome was observed to have a significant effect on intrinsic metabolic activity, intrinsic clearance of tenoxicam being reduced by 30% in the anephric rats (161 +/- 38 mL h-1) with respect to the values obtained in the control group (228 +/- 22 mL h-1).     

血液透析治疗12例尿毒症合并脑出血的疗效分析

目的：分析短时、高频血液透析在无抗凝或小剂量低分子肝素抗凝时治疗尿毒症合并脑出血的疗效。方法：回顾性分析本院2007年8月～2011年3月收治的尿毒症合并脑出血患者12例,在入院后常规内科治疗的基础上加无肝素或小剂量低分子肝素抗凝,短时、高频血液透析治疗,即住院第1周每日透析1次,每次2～2.5h。结果：所有患者均顺利渡过脑出血急性期,挽救了患者的生命,为患者后期康复、功能锻炼创造时机。结论：短时、高频血液透析在无抗凝或小剂量低分子肝素抗凝时治疗尿毒症合并脑出血是安全、有效的,值得临床推广应用。     

Usefulness of the bleeding time to predict the risk of clinical bleeding in patients with uraemia

In a prospective study of haemostatic status of 15 uraemic Nigerians a highly significant prolongation of bleeding time (p less than 0.001) and significantly lower haematocrit levels (p less than 0.001) were detected in comparison to healthy controls. A highly significant positive correlation (r = +0.778) between prolongation of bleeding time and blood urea was present. Six patients had overt clinical bleeding with significantly prolonged bleeding time (p less than 0.01) compared to uraemics without overt bleeding. Blood urea was significantly different in both groups (p greater than 0.1). Platelet count, prothrombin time, partial thromboplastin time and Hess tourniquet test did not differ between the uraemic patients and controls. Haemostatic dysfunction has been noted in Nigerian uraemics we studied. Bleeding time is a useful but simple means of assessing such dysfunction.