Accumulation of lovastatin, but not pravastatin, in the blood of cyclosporine-treated kidney graft patients after multiple doses.

OBJECTIVES: To study pravastatin and lovastatin pharmacokinetic and pharmacodynamic effects and their interactions with cydosporine (INN, ciclosporin) in kidney transplant patients after single and multiple doses. SUBJECTS AND METHODS: The pharmacokinetic and pharmacodynamic effects of administration of 20 mg/day oral pravastatin and lovastatin for 28 days and their interactions with cyclosporine (2 to 6 mg/kg/day) were studied in a double-blind, double-dummy, randomized, parallel-group multicenter trial in 44 stable kidney graft recipients. RESULTS: The median area under the curve [AUC(0-24)] of pravastatin was 249 microg x hr/L (range, 104 to 1026 microg x hr/L) after a single dose (day 1) and 241 microg x hr/L (114 to 969 microg x hr/L) after multiple doses (day 28) and was fivefold higher than values reported in the absence of cyclosporine. The median AUC(0-24) of lovastatin was 243 microg x hr/L (105 to 858 microg x hr/L) on day 1 and 459 microg x hr/L (140 to 1508 microg x hr/L) on day 28. Besides a significant accumulation during the study period (p < 0.001), the lovastatin AUC(0-24) values were twentyfold higher than values reported without cyclosporine. Coadministration of pravastatin or lovastatin did not alter cyclosporine pharmacokinetics. In this study, 20 mg/day doses of both drugs resulted in a significant improvement of the lipid profile and were well tolerated. CONCLUSIONS: In contrast to lovastatin, pravastatin did not accumulate over the study period, which is probably one of the reasons rhabdomyolysis has been reported in lovastatin-treated but not pravastatin-treated transplant patients receiving cyclosporine immunosuppression.

Cyclosporin A trough levels correlate with serum lipoproteins and apolipoproteins: implications for therapeutic drug monitoring of cyclosporin A.

In a prospective study over 6 months, the relationship between serum lipid parameters and CsA whole blood trough concentrations was investigated in 39 renal transplant recipients receiving a triple immunosuppressive therapy with cyclosporin (CsA), azathioprine and prednisone. CsA trough concentrations were measured with a selective monoclonal immunoassay (Abbott TDx). Six months after transplantation, significant positive correlations were observed between the CsA trough concentration and serum concentrations of triglycerides (r = 0.448, p < 0.01), total cholesterol (r = 0.360, p < 0.05), and apoB (r = 0.418, p < 0.01). After exclusion of patients with over hypertriglyceridemia (> 400 mg/dl), however, the associations were no longer significant. HDL-cholesterol (HDL-C) and apo AI concentrations showed significant inverse correlations with the CsA trough level (HDL-C: r = -0.427, p < 0.01; apoAI: r = -0.350, p < 0.05); the correlations with the CsA trough level were still significant (HDL-C: r = -0.379, p < 0.05; apoAI: r = -0.354, p < 0.05) after exclusion of patients with triglyceride levels of > 400 mg/dl. As a result of these divergent effects on the plasma lipids and lipoproteins, there was a strong positive association (r = 0.633, p < 0.001) between the CsA trough concentration and the total cholesterol/HDL-C ratio. Consequently, elevated total cholesterol/HDL-C ratios that represent an increased atherogenic risk tended to be associated with higher CsA trough levels. In monitoring CsA therapy of renal transplant recipients on maintenance immunosuppressive therapy, it may well be advisable to adjust CsA dosages to obtain CsA trough levels within the lower therapeutic range for patients with an unfavorably high TC/HDL-C ratio.

Beneficial impact of aorto-coronary graft markers on post-operative angiography.

OBJECTIVE: When coronary and graft angiography is required for patients with prior coronary artery bypass (CAB) graft surgery, it is often difficult to localize the proximal aorto-coronary graft anastamosis. Our goal was to quantify the potential benefit during subsequent angiography if the proximal anastamosis is marked by an aorto-coronary graft marker at the time of CAB. METHODS: Retrospective review of 414 angiograms that were performed for patients with prior CAB. Cohorts with an without graft markers were compared. RESULTS: In the group with aorto-coronary graft markers and > or = 2 aorto-coronary grafts, there were significant reductions in fluoroscopy time (30.5%, p < 0.0001), contrast volume (21.7%, p < 0.0001), and numbers of angiographic catheters used (17.0%, p = 0.0001). If only one aorto-coronary graft was placed and marked, a trend toward reduced fluoroscopy time was observed (23.8%, p = 0.07). CONCLUSIONS: This study demonstrates the objective benefit supporting routine placement of circumferential aorto-coronary graft markers during CAB, particularly if > 1 graft is required.

Decrease in lipoprotein(a) after renal transplantation is related to the glucocorticoid dose.

Serum lipoprotein(a) [Lp(a)] concentrations and apolipoprotein(a) phenotypes were determined in 46 patients with end-stage renal disease both before as well as 1 week and 1, 3 and 6 months after renal transplantation. Immunosuppressive therapy consisted of cyclosporin A, prednisone and azathioprine. Before transplantation median Lp(a) levels did not differ between the patients and a healthy control group. A highly significant decrease (P < 0.001) in Lp(a) levels was observed in both male and female patients 1 week after transplantation. This marked reduction in Lp(a) occurred at a time when patients were receiving the highest doses of corticosteroids. As steroid doses were gradually tapered, Lp(a) concentrations subsequently increased, although at 6 months levels were still significantly reduced (P < 0.01) in women. No significant correlation was observed between Lp(a) and whole-blood cyclosporin levels, nor was there any correlation with the azathioprine dose. The reduction in Lp(a) concentrations was seen for all apo(a) phenotypes observed in the study.

Anaphylactoid reactions during haemodialysis in sheep are associated with bradykinin release.

Anaphylactoid reactions have been observed in patients treated with AN69 dialysers and ACE inhibitors. Recently, it has been shown in vitro that AN69 membranes induce the release of high amounts of bradykinin in plasma. To verify the possible role of bradykinin in these shock-like reactions, six sheep were dialysed in a random fashion using AN69 or the new SPAN membrane with and without pretreatment with captopril. All animals were dialysed for 60 min via double-lumen Shaldon catheters. Blood samples were drawn at 0, 5, 10, 15, 30, and 60 min from the venous line. A total of 24 haemodialysis procedures was carried out: group A (n = 6), AN69 without captopril; group B (n = 6), SPAN without captopril; group C (n = 6), AN69 with captopril; group D (n = 6), SPAN with captopril. A significant bradykinin release was observed only in groups A and C, reaching peak values already after 5 min. Animals in group C showed the highest bradykinin values. In four of six animals in group C anaphylactoid reactions with severe hypotension were noted. From this animal model we conclude that dialysis with the AN69 membrane is associated with bradykinin release. Pretreatment with ACE inhibitors results in further increasing bradykinin levels, which lead to anaphylactoid reactions. In contrast, the new SPAN membrane was well tolerated without detectable changes in bradykinin concentrations.

The HELP-LDL-apheresis multicentre study, an angiographically assessed trial on the role of LDL-apheresis in the secondary prevention of coronary heart disease. II. Final evaluation of the effect of regular treatment on LDL-cholesterol plasma concentrations and the course of coronary heart disease. The HELP-Study Group. Heparin-induced extra-corporeal LDL-precipitation.

The efficacy of the heparin-induced extracorporeal LDL-precipitation (HELP)-apheresis procedure has been studied in an open prospective multicentre trial. After 2 years of regular weekly HELP-treatment the data from 39 of 51 patients could be evaluated according to the study criteria. Twelve of the initially recruited study patients were omitted from the evaluation either because of premature termination of the treatment or because they did not fulfil the exact guidelines of the study protocol. A mean of 2.831 plasma was regularly treated on average every 7.85 days. The mean pre-/post-apheresis LDL-cholesterol levels decreased from 286/121 mg dl-1 at the first HELP treatment to 203/77 mg dl-1 after 1 year and to 205/77 mg dl-1 after 2 years of regular apheresis; the corresponding values for fibrinogen were 314/144, 246/98 and 250/105 mg dl-1, respectively. In contrast, the mean pre-/post-apheresis HDL-cholesterol levels rose from 41/38 through 51/44 mg dl-1 after 1 year to 52/43 mg dl-1 after 2 years of treatment. The overall result was a normalization of the atherogenic index (LDL-/HDL-cholesterol ratio) from 6.9/3.2 to 4.0/1.9. The angiographies from 33 patients obtained before and after 2 years of regular treatment could be evaluated blindly using the cardiovascular angiography analysis system. The mean degree of stenosis of all segments decreased from 32.5% (SD = 16) to 30.6% (SD = 16.8) over the 2 years. A regression > 8% was observed in 50/187 (26.7%) segments, whereas 29/187 (15.5%) segments showed progression. In 108/187 (57.8%) segments the lesions were stable (< 8% deviation) over 2 years. We conclude that regular treatment with HELP-LDL-apheresis is able to stabilize progressive atherosclerotic disease and to induce almost twice as much regression as progression of atherosclerotic lesions.

Heparin extracorporeal LDL precipitation (HELP): an effective apheresis procedure for lowering Lp(a) levels.

Heparin-induced extracorporeal low-density lipoprotein precipitation (HELP) is based on the precipitation of apolipoprotein B (apo B) containing lipoproteins with heparin at low pH (4.85). In in vitro experiments we could show that Lp(a) is quantitatively (> 99%) precipitated from plasma by heparin in the pH range 4.6-5.2. The acute changes in Lp(a) after a single HELP-LDL apheresis were investigated in twelve patients with Lp(a) concentrations > 30 mg/dl. A single treatment caused a highly significant decrease (62%) in the concentration of Lp(a), similar to the decrease (60%) observed for LDL-cholesterol. Analysis of the data from ten patients with different apo(a) phenotypes indicated that Lp(a) is eliminated with almost 100% efficiency in the extracorporeal circulation, irrespective of apo(a) phenotype and plasma concentration. The mean rate of recovery of Lp(a) following HELP-LDL apheresis was slightly slower than that of LDL-cholesterol. Plasma Lp(a) concentrations were monitored in seven patients over 2 years. Mean Lp(a) concentrations after 2 years were lower than pre-treatment levels, indicating that repeated elimination of the lipoprotein does not lead to an induction in its synthesis. HELP-LDL apheresis should be particularly suitable for treatment of patients with elevated LDL-cholesterol levels who are also at increased coronary risk because of high Lp(a) concentrations.

Apolipoprotein A-I and apolipoprotein B containing lipoprotein particles in coronary patients treated with extracorporal low density lipoprotein precipitation (HELP).

Evidence for chemical and biological heterogeneity of human plasma lipoprotein density classes has been steadily accumulating over the last 15 years. Furthermore, several recent reports have indicated potential clinical significance of certain lipoprotein subspecies as either atherogenic or antiatherogenic. It is generally accepted that lipid lowering treatments can retard or even reverse development of atherosclerotic lesions. However, very little is known about effects of various lipid lowering treatments on specific lipoprotein particles. The purpose of this study was to explore the effects of heparin induced extracorporal low density lipoprotein precipitation (HELP) on various subspecies of plasma lipoprotein particles defined primarily by their apolipoprotein composition. Using particle specific enzyme immunoassays, the immediate changes in lipoprotein particle profiles were analyzed after a single HELP treatment in 12 patients with angiographically documented coronary artery disease. In a separate group of 6 patients, particles were repeatedly measured over a period of 96 h following a HELP treatment. Single HELP treatment caused an immediate and highly significant decrease (67%) in the concentration of simple lipoprotein particles containing apolipoprotein B (apo B) as a sole apolipoprotein (LP-B). Various subspecies of complex particles containing apo B and other apolipoproteins (Lp-B-complex) were also decreased although to a lesser degree (44-53%). HELP treatment caused an insignificant, 3% decrease of lipoprotein particles containing apo A-I but no apo A-II (Lp-A-I) and a 6% decrease in the concentration of particles containing both apo A-I and apo A-II (Lp-A-I:A-II). During the 96-h period following HELP treatment various apo B containing particles recovered at different rates in different patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Increase of glomerular filtration rate and renal plasma flow by insulin-like growth factor-I during euglycaemic clamping in anaesthetized rats.

Renal function was studied in anaesthetized rats receiving i.v. infusions of recombinant human insulin-like growth factor-I (IGF-I) under euglycaemic clamp conditions. IGF-I increased glomerular filtration rate up to 35% and renal plasma flow up to 100%, this increase being dose dependent with half-maximal stimulation at serum IGF-I concentrations of about 24 pmol ml-1. Renal vascular resistance was reduced up to 50%, filtration fraction decreased up to 30% and urine flow increased up to three fold while arterial blood pressure was unchanged. Renal haemodynamics were affected at serum IGF-I concentrations that did not stimulate total body glucose disposal during euglycaemic clamping. IGF-I seemed to regulate renal function through IGF-I receptors apparently independent of acute changes of glucose metabolism.

Simultaneous heparin extracorporeal LDL precipitation and hemodialysis. First clinical experience.

Simultaneous heparin extracorporeal LDL precipitation (HELP)-dialysis was carried out at weekly intervals in six patients with end-stage renal failure, associated hyperlipidemia, and a high risk of premature atherosclerosis. Evaluating 135 single treatments, a mean acute total cholesterol/LDL reduction of 31% and 39%, respectively, was found, while clearance of urinary substances was comparable to that in regular hemodialysis treatment. Treatment tolerance was excellent and no derangements in albumin, hemodialysis parameters, or blood coagulation were detected.

Complement activation and depletion during LDL-apheresis by heparin-induced extracorporeal LDL-precipitation (HELP).

The heparin-induced extracorporeal elimination of low density lipoproteins (LDL) is a well-established clinical procedure to markedly reduce cholesterol levels. The biocompatibility of this artificial filter system (HELP) was investigated by quantitation of representative complement proteins within the extracorporeal circuit using established ELISA procedures, based on monoclonal antibodies recognizing exclusively either native (C6, C7) or activated proteins (act.C3, C5a, TCC). HELP was found to be a self-limiting extracorporeal system with respect to complement activation, since act.C3 and TCC, generated mainly at the plasma filter, were partially adsorbed to the following HELP specific filters to concentrations which were lower than those obtained before the plasma filter. C5a, which increased 14.5-fold at the plasma filter was not eliminated by the following filters; however, elevated levels were not found in the patients at the end of apheresis and no leucocytopenia was observed.

[Behavior of the renal functional reserve in type I diabetic patients: effect of ACE-inhibition]. / Verhalten der renalen Funktionsreserve von Typ I Diabetikern: Einfluss der Konversionshemmung.

Renal functional reserve capacity was evaluated in 19 normotensive type I diabetics without microalbuminuria. All patients had normal basal renal function as assessed by 24-hour creatinine clearances higher than 120 ml/min. PAH, inulin, and creatinine clearances were carried out every hour before, during, and after infusion of an amino acid (AA) solution. The same experiment was repeated after ACE inhibition with captopril (25 mg). Two groups of patients were found: Group A (responders) showed a significant rise in GFR after AA infusion (inulin clearances from 117 +/- 8 to 138 +/- 10 ml/min) (p less than 0.05), whereas in Group B (non-responders) no significant change in GFR was observed. Groups were comparable in age, duration of diabetes, metabolic control, and mean arterial blood pressure. Group B, however, had a significantly higher basal inulin clearance (167 +/- 17 ml/min) than Group A (117 +/- 8 ml/min). In Group A ACE inhibition completely blocked the AA-induced rise in GFR, while basal GFR in Group B was significantly reduced (167 +/- 17 to 148 +/- 8 ml/min) after captopril administration. In both groups renal plasma flow was enhanced by ACE inhibition. A rise in glucagon was observed in all patients during AA infusion. It is concluded that type I diabetics with normal basal renal function already have reduced (Group A) renal functional reserve capacity, which is completely abolished (Group B) when concomitant hyperfiltration occurs. ACE inhibition reduces hyperfiltration and is capable of blocking the AA-induced rise in GFR in these patients.

[Maximal therapy of hypercholesterolemia in coronary heart disease]. / Maximaltherapie der Hypercholesterinämie bei koronarer Herzerkrankung.

Extracorporeal procedures to eliminate LDL from plasma now allow us to drastically lower the plasma LDL-concentrations to virtually every desired level. In a new therapeutic approach the combination of HMG-CoA reductase inhibitors with an LDL/fibrinogen apheresis procedure (the HELP-system) was evaluated in hypercholesterolemic CAD-patients. HELP treatment alone can lower the mean plasma LDL-cholesterol by about 50-60%, HMG-CoA reductase inhibitor therapy reduces the LDL-cholesterol by about 40%. The combination of both treatments resulted in a lowering of mean LDL-cholesterol to about 80% of baseline values. Improvement of blood rheology by lowering plasma viscosity and inhibiting erythrocyte aggregation became apparent. No relevant adverse effects were noted over a period of two years. This therapeutic strategy for maximal LDL-cholesterol lowering may be useful in secondary prevention of coronary heart disease in hypercholesterolemic patients if plasma LDL-C cannot be reduced by diet and drug treatment to desirable plasma levels (LDL-cholesterol less than 120 mg/dl). Preliminary data show an improvement in the symptoms of our CAD-patients treated with this combined therapy. Furthermore, within the near future a combined HELP and dialysis unit will be available for patients with terminal renal insufficiency and progressive atherosclerosis.

Low atrial natriuretic peptide plasma concentrations in 100 patients with essential hypertension.

Although atrial natriuretic peptide (ANP) plays a key role in electrolyte and volume regulation and causes direct vasorelaxation, controversial results have been reported in hypertensive patients. We studied 58 men and 42 women, aged 19 to 78 years, with essential hypertension (blood pressure: 150 to 210/95 to 110 mm Hg) using 24 h blood pressure recording, treadmill exercise and x-ray of the chest. In 70 patients ANP plasma concentrations were found to be completely within the normal range of healthy controls (17 to 38 fmol/mL; n = 50) and 52% were detected within the lower third or even below the normal range. In mild to moderate essential hypertension a diminished secretion of ANP may be responsible for an elevated blood pressure in these patients.

Long-term clinical experience with HELP-LDL-apheresis in combination with HMG-CoA-reductase inhibitors for maximum treatment of coronary heart disease associated with severe hypercholesterolemia.

Extracorporeal low density lipoprotein (LDL)-apheresis offers an adjunctive therapy to diet and drug treatment for reducing LDL concentrations in patients with excessively high cholesterol levels and those at high coronary risk. After nearly 4 years experience with the heparin-induced extracorporeal LDL/fibrinogen precipitation (HELP) system, based on heparin induced LDL precipitation at acidic pH, over 7,000 single aphereses have been performed on more than 100 patients in several clinics. Due to the simultaneous removal of LDL and fibrinogen, regular HELP-LDL-apheresis can normalize hemorrheologic parameters, thus explaining the observation of a rapid and lasting clinical improvement in signs and symptoms of coronary heart disease (CHD). The use of Simvastatin in combination with HELP significantly augments the reduction in LDL cholesterol to a level where regression of atherosclerotic lesions might be expected.