Rutger Larsson

Pharmacokinetics of [14C] omeprazole in patients with impaired renal function

Pharmacokinetics of [14C] omeprazole and its metabolites were studied after single intravenous and oral doses of 20 and 40 mg, respectively, to 12 patients with chronic renal insufficiency. Blood samples for determination of total radioactivity, omeprazole, OH‐omeprazole, sulfone, and sulfide were taken for 24 hours. Urine was collected over 96 hours for determination of total radioactivity and during the first 24 hours for additional assay of omeprazole and metabolites. The mean systemic availability was 70%. The mean plasma t1/2 of omeprazole was 0.6 hours. Unchanged omeprazole was not measurable in urine. Derived pharmacokinetic constants of intact omeprazole were within the range of those reported in healthy individuals. The accumulated 24‐hour excretion of radioactive metabolites was related significantly to creatinine clearance. The cumulative excretion of total radioactivity in urine over 96 hours in percent of given dose varied between 25% and 83%.

Effects of Ticlopidine in AV-fistula Surgery in Uremia

Two hundred and fifty-eight patients with uremia who were offered surgery for placement of an arteriovenous fistula for hemodialysis were recruited in nine regional dialysis centers. The patients were randomized to receive the platelet aggregation inhibitory compound ticlopidine, 250 mg b.d., or matching placebo. Study medication was targeted at 7, minimum 3, days before scheduled surgery and continued for 28 days after surgery. The overall rate of occlusion was 41/260 evaluable operations (16%), 25/131 (19%) in the placebo group and 16/129 (12%) in the ticlopidine group. The risk of early occlusion was a non-significant 35% lower in the ticlopidine group. Limited risk factor analysis did not clearly identify any subgroup other than females at greater risk of early thrombosis nor any subgroup deriving particular benefit from ticlopidine treatment.

Does Prophylactic Treatment with Felodipine, a Calcium Antagonist, Prevent Low-Osmolar Contrast-Induced Renal Dysfunction in Hydrated Diabetic and Nondiabetic Patients with Normal or Moderately Reduced Renal Function?

Twenty-seven patients (15 diabetics and 12 non-diabetics) with normal to moderately reduced renal function underwent femoral angiography with a low-osmolar contrast agent, iohexol (Omnipaque), under perexaminatory hydration. Fourteen patients were randomised to pretreatment with oral felodipine extended release (Plendil) 10 mg and 13 patients to placebo 3-4 h before angiography. GFR measured with [51Cr] EDTA-clearance decreased 24 hours after the angiography in the felodipine group from GFR 52.5 +/- 18.6 (mean +/- SD) to 46.2 +/- 16.5 ml/min (p < 0.01) and in the placebo group from 70.6 +/- 18.6 to 62.6 +/- 26.4 ml/min (p < 0.01). Serum creatinine increased significantly in the felodipine group from 128 +/- 61 to 139 +/- 67 mumol/l (p < 0.05) but not in the placebo group (122 +/- 54 to 125 +/- 51 mumol/l (ns)). The values of serum creatinine returned to baseline levels 7 days after angiography. During hydration there was only a slight reduction of GFR after angiography with iohexol. Thus, felodipine had no major effect on GFR after iohexol but, as baseline GFR tended to be lower in the felodipine pre-treated patients, it might have had some renoprotective effect in patients with more advanced renal failure.

The Plasma Levels of Homocysteine Are Elevated in Moderate Renal Insufficiency but Do Not Predict the Rate of Progression

Background: Chronic renal failure is characterized by specific alterations of the lipoprotein metabolism. It is also characterized by elevated plasma levels of total homocysteine (tHcy). Hyperhomocysteinemia has been shown to be a risk factor for atherosclerosis in both the general population and in patients with end-stage renal disease. Aim: To analyze whether elevated tHcy levels also may contribute to a higher rate of progression of renal insufficiency in patients with moderately advanced renal failure. Methods: To investigate whether tHcy concentrations are associated with an accelerated rate of progression of renal insufficiency, we have correlated baseline plasma concentrations of tHcy with the progressive decline of renal function in an observational study of human chronic renal disease. Results: Sixty-three nondiabetic patients (49 men, 14 women) were studied as part of an observational study of patients with moderately advanced renal insufficiency. The average follow-up time of the patient population was 3.0 years, and the mean rate of decline in glomerular filtration rate (51Cr- EDTA clearance) was –3.2 ± (SD) 3.9 ml/min × 1.73 m2 body surface area. The mean plasma concentration of tHcy at the beginning of the study was 28.3 ± 12.0 µmol/l. Plasma tHcy concentrations correlated significantly with the glomerular filtration rate (r = –0.32, p < 0.01). However, there was no association between the initial plasma level of tHcy and the rate of progression as assessed by linear regression analysis (r = 0.02; NS). In contrast, increased levels of apolipoprotein B, low-density lipoprotein cholesterol, and proteinuria were all significantly associated with a more rapid decline in renal function. Conclusions: Patients with moderately advanced chronic renal insufficiency have elevated plasma levels of homocysteine. The tHcy plasma levels increase in parallel with the degree of reduction in renal function. However, the hyperhomocysteinemia is not prospectively associated with a higher rate of progression of the renal functional impairment. Hence, there is no indication that elevated homocysteine levels play a contributing role for an accelerated glomerulosclerotic process.

Effect of Gemfibrozil on Lipoprotein Abnormalities in Chronic Renal Insufficiency: A Controlled Study in Human Chronic Renal Disease

BACKGROUND Renal dyslipoproteinemia is characterized by the accumulation of intact and partially metabolized triglyceride-rich lipoproteins. Reduced lipolytic enzyme activities may be one of the major pathophysiological mechanisms contributing to a retarded catabolism of these lipoproteins in patients with renal insufficiency. OBJECTIVE To evaluate the effect of gemfibrozil treatment on renal dyslipoproteinemia. STUDY DESIGN A randomized, controlled open study with 2 parallel groups. OUTCOME VARIABLES Plasma concentrations of lipids, apolipoproteins and lipoprotein particles. PATIENTS AND METHODS Fifty-seven non-nephrotic, non-diabetic patients with moderately advanced renal insufficiency were randomized to either treatment with gemfibrozil at dosages from 300 to 900 mg/day (n = 28) or dietary counseling (n = 29). The intervention period was 12 months. Plasma concentrations of lipids, apolipoproteins and apoA- and apoB-containing lipoprotein particles were determined at the entry and after 6 and 12 months of treatment. RESULTS No serious adverse effects occurred during the study. Six patients experienced mild gastrointestinal symptoms and prematurely withdrew from the drug treatment. In the group treated with gemfibrozil the plasma concentrations of triglycerides, total cholesterol, very low density lipoprotein (VLDL) and low density (LDL) cholesterol decreased significantly by 47, 13, 43 and 14%, respectively, in comparison to baseline. High density lipoprotein (HDL) cholesterol increased significantly by 18%. ApoB, apoC-III, apoC-III in heparin-manganese precipitate (reflecting apoC-III in VLDL and LDL) and apoE decreased significantly by 21, 18, 26 and 49%, respectively. Furthermore, gemfibrozil treatment resulted in the reduction of plasma concentrations of complex (LP-Bc) and simple (LP-B) apoB-containing lipoprotein particles by 22 and 7%, respectively. However, these changes were not statistically significant. There was a slight, insignificant increase in the levels of LP-A-I:A-II particles and no change in the levels of LP-A-I particles. In contrast to the effect of the pharmacological intervention, the dietary counseling only resulted in minor changes in the plasma lipid and apolipoprotein profiles. The only significant changes were a 10% increase in HDL cholesterol and a 35% decrease in apoE. CONCLUSIONS Gemfibrozil treatment significantly reduces both plasma lipids and apoB, apoC-III and apoE concentrations in patients with moderately advanced renal insufficiency. The results of this study indicate that gemfibrozil enhances the clearance of apoB-containing triglyceride-rich lipoproteins.

Pharmacokinetics and Effect of Ticlopidine on Platelet Aggregation in Subjects with Normal and Impaired Renal Function

The pharmacokinetics and the effect of ticlopidine on platelet aggregation were determined in patients with chronic renal failure (n = 6), who were not on dialysis and had glomerular filtration of 16.9 ± 4.4 mL/min, and were matched with the pharmacokinetics and effects in healthy volunteers (n = 7). Participants were studied after acute oral administration of ticlopidine at the beginning of the study and after 36 days of treatment with 250 mg twice daily. For unchanged ticlopidine there were no significant differences between the concentration profiles for the two study groups. By day 36 the minimum concentrations in plasma were identical (0.35 ± 0.22 mg/L and 0.36 ± 0.21 mg/L, respectively). Using 14C‐labeled ticlopidine, the concentration profiles of radioactivity on day 1 were similar to those on day 36 for both groups. However, maximum concentrations and area under the concentration—time curve at 72 hours were both higher in patients with renal failure than in healthy volunteers. Treatment with ticlopidine progressively decreased sensitivity to adenosine diphosphate—induced platelet aggregation. At day 36, the concentration of adenosine diphosphate required to achieve 50% platelet aggregation was approximately 2.5 times greater than before treatment. Both patients and healthy volunteers exhibited closely comparable changes. The response to collagen induced platelet aggregation was not changed in patients by treatment with ticlopidine. In contrast, volunteers required a three‐ to fourfold increase in collagen concentration to achieve 50% platelet aggregation after 36 days of therapy. Although some differences in both pharmacokinetics and pharmacodynamics of ticlopidine have been demonstrated between patients and and healthy volunteers, results in this study demonstrated that a change of dosage is not required in renal failure.

Prizidilol, an antihypertensive with precapillary vasodilator and β‐adrenoceptor blocking actions, in primary hypertension

Single oral doses of 1.5, 3.0, 4.5, and 6.0 mg/kg prizidilol HCl, an antihypertensive with vasodilator and β‐adrenoceptor blocking actions, were given to 12 patients with primary hypertension on separate days. Systolic and diastolic blood pressure (BP) decreased after 4.5 and 6.0 mg/kg and systolic BP also after 3.0 mg/kg. The antihypertensive effect was evident in 1 to 2 hr with maximum effect in 4 to 5 hr (supine systolic BP 20 and diastolic 13 mm H g after 6.0 mg/kg); the effect was sustained for more than 8 hr. An initial slight reduction in heart rate (HR) after 1 to 2 hr was followed by a slight rise after 6 to 8 hr. There were higher plasma drug levels and greater antihypertensive effects after the 6.0‐mg/kg dose in slow acetylators (n = 5) than in rapid acetylators (n = 7). Due to its hydrazine moiety, prizidilol, like hydralazine, seems to be a substrate for the polymorphic N‐acetyltransferase enzyme system.

Plasma levels of lipoprotein (a) do not predict progression of human chronic renal failure

Chronic renal failure is frequently accompanied by elevated plasma levels of lipoprotein (a) [Lp(a)]. Elevated Lp(a) levels have been proposed to contribute not only to increased risk of atherosclerotic and thrombotic complications but also to the progression of renal insufficiency. To investigate whether higher Lp(a) plasma concentrations are associated with an accelerated rate of progression of renal insufficiency, we have correlated baseline plasma concentrations of Lp(a) with the progressive decline of renal function in an observational study of human chronic renal disease. Forty-nine non-diabetic patients (40 men, nine women) were studied as part of an observational study of patients with moderately advanced renal insufficiency. The average follow-up time of the patient population was 3.1 years, and the mean rate of decline in glomerular filtration rate (51Cr-EDTA clearance) was -2.8 (SD 4.1) ml/min/1.73 m2. The mean plasma concentration of Lp(a) at the beginning of the study was 19.2 (SD 18.6) mg/100 ml with a median value of 12.2 mg/100 ml. There was no association between the initial plasma concentration of Lp(a) and the rate of progression as assessed by linear regression analysis. Furthermore, the progression rate in patients within the highest quartile of the Lp(a) distribution (> or = 30 mg/100 ml) did not differ from that in patients with lower levels of Lp(a). In contrast, increased levels of apolipoprotein (apo) B, low-density lipoprotein (LDL)-cholesterol, and proteinuria were all significantly associated with a more rapid decline in renal function. Based on these results, it was concluded that elevated plasma levels of Lp(a) are not associated with an increased rate of progression of renal insufficiency in human chronic renal disease. However, the results of this study suggest that other apoB-containing lipoproteins may play a significant role in this process.

Accuracy of Hemodialysis Urea Kinetic Modeling

To test the accuracy of urea kinetic modeling (UKM), the classic fixed-volume model UKMf, two variable-volume models (UKMvb and UKMvd), direct dialysis quantification

Acute and steady-state pharmacokinetics and antihypertensive effects of felodipine in patients with normal and impaired renal function.

Eighteen patients (14 men and 4 women, aged 36–74 years) treated with metoprolol for a month were included in the study. Twelve had impaired renal function (IRF) with a glomerular fitration rate (GFR) of 7.5–77.1 mL/min and six having normal renal function (NRF) with a GFR of 84.9–113.0 mL/min. Plasma and urine concentrations of felodipine and metabolites, heart rate, and blood pressure were recorded over 24 hours on day 1 after an oral dose of 10 mg felodipine and 0.04 mg 3H‐felodipine IV and repeated on day 29 during continuous treatment with felodipine, 10 mg bid.