Long-term efficacy and tolerability of simvastatin in a large cohort of elderly hypercholesterolemic patients.

The long-term efficacy and tolerability of simvastatin, a 3-hydroxy-3-methylglutaryl-co-enzyme A (HMG-CoA) reductase inhibitor, was assessed during a 24-month follow-up period in 168 elderly hypercholesterolemic patients. After completing a 4 week double blind dose ranging study with simvastatin, 47 males and 122 females over 62 years of age with type II hyperlipidemia, a total cholesterol level above 6.5 mmol/l and clinically manifest cardiovascular disease were included in this extended study. A total of 159 patients completed the 12-month follow-up period and 141 patients were monitored over the full 24 months. All patients were started on 10 mg simvastatin once daily and the dosage was increased until the target levels of low density lipoprotein (LDL) cholesterol between 2.3 mmol/l (90 mg/dl) and 3.6 mmol/l (140 mg/dl) were reached. Fifty percent of patients reached the targeted LDL cholesterol goal of < 3.6 mmol/l (140 mg/dl) during the study. At study completion, 65 patients (39%) were taking 40 mg simvastatin per day, 56 patients (33%) 20 mg, 42 patients (25%) 10 mg and 5 patients (3%) only used 5 mg per day. Sixteen patients (9%) received concomitant lipid lowering therapy. Over 2 years, the mean decrease in LDL cholesterol ranged from 36% to 38%, the median decrease in triglycerides was 12% to 19% and the mean increase in high density lipoprotein (HDL) cholesterol ranged from 9% to 10%, respectively. Seven patients discontinued simvastatin because of adverse clinical or laboratory events, but only in two (1.1%) was this considered to be drug-related. Side-effects were mild and most frequently gastrointestinal in nature. Mean changes in asparate aminotransferase (AST) were not significantly different from zero and mean changes in alanine aminotransferase (ALT) and creatine phosphokinase (CPK) showed a small increase. We conclude that simvastatin is an efficacious and well-tolerated treatment for hypercholesterolemia in elderly individuals for extended periods.

HMG CoA reductase inhibitors lower LDL cholesterol without reducing Lp(a) levels.

Lp(a) is a plasma lipoprotein particle consisting of a plasminogenlike protein [apo(a)] disulfide bonded to the apo B moiety of low-density lipoprotein (LDL). Increased plasma levels of Lp(a), either independently or interactively with LDL levels, have been shown to be a risk factor for atherosclerosis. Recently, a new class of lipid-lowering drugs, HMG CoA reductase inhibitors, have been introduced. These drugs act by decreasing liver cholesterol synthesis resulting in up-regulation of LDL receptors, increased clearance of LDL from plasma, and diminution of plasma LDL levels. In this study, we examined the effect of HMG CoA reductase inhibitors on Lp(a) levels in three groups of subjects, five volunteers and two groups of five and 14 patients. In all 24 subjects, mean decreases were observed in total cholesterol (43 +/- 5%), total triglyceride (35 +/- 8%), very low-density lipoprotein (45 +/- 9%), and LDL cholesterol (43 +/- 5%). The mean change in high-density lipoprotein cholesterol was an increase of 7 +/- 8%. Despite the very significant decrease in LDL cholesterol levels (p less than 0.001), Lp(a) levels increased by 33 +/- 12% (p less than 0.005). This was not associated with a measurable change in the chemical composition or size of the Lp(a) particle. This emphatically suggests that Lp(a) particles, despite consisting principally of LDL, are cleared from plasma differently than LDL. The surprising finding of an increase in Lp(a) levels suggests this class of drugs may have a direct effect on Lp(a) synthesis or clearance independent of its effect on LDL receptors.

[Primary hyperaldosteronism (Conn syndrome) and pregnancy]. / Primärer Hyperaldosteronismus (Conn-Syndrom) und Schwangerschaft.

Because of the atypical symptomatology, which can mimic an EPH-gestosis, the physiological elevation of serum aldosterone in the third trimester and restricted diagnostic possibilities, the diagnosis of primary hyperaldosteronism during pregnancy is difficult. A case of an adrenal adenoma during pregnancy is reported.

Controlled trial of enalapril and hydrochlorothiazide in 200 hypertensive patients.

In a multicenter, multinational study, 200 patients with essential hypertension were treated with a fixed dose of Enalapril (E) 20 mg/day after a 2- to 4-week placebo period. All had diastolic blood pressure (DBP) 100 to 120 mm Hg at the end of the placebo period. They were then given E for 6 weeks. If DBP after this was greater than 90 mm Hg they were randomized double-blind to added therapy with hydrochlorothiazide (H) either 25 mg/day (E + H 25) or 12.5 mg/day (E + H 12.5) or placebo (E + P) for 4 weeks. Blood pressure was measured approximately 24 hours after taking the medication. In the whole group, BP fell from 171/107 to 156/97 mm Hg during monotherapy with E (P less than 0.001). Sixty-six patients reached DBP less than or equal to 90 mm Hg on E alone. Of the remainder, 42 were randomized to E + P. In these, BP fell by 5.9/3.4 mm Hg (P less than 0.05). Forty-two patients received E + H 12.5 and BP fell by 9.0/6.9 mm Hg (P less than 0.001). Forty-one patients received E + H 25 and BP fell by 5.6/6.3 mm Hg (P less than 0.05/0.01). The proportion of patients who reached DBP less than or equal to 90 mm Hg was 26% in the E + P group, 48% in the E + H 12.5 group (P less than 0.05 compared to E + P group), and 38% in the E + H 25 group. There were no other significant differences between the E + H 12.5 and E + H 25 groups except that S-potassium fell significantly (-0.2 mmol/L) in E + H 25. Both regimens were remarkably well tolerated. It can be concluded that H 12.5 mg/day potentiates the effect of Enalapril 25 mg/day at least as well as H 25 mg/day and better than placebo.

The antihypertensive effect of lisinopril compared to atenolol in patients with mild to moderate hypertension.

In a multicenter, parallel, double-blind study, lisinopril was compared with atenolol in the treatment of mild to moderate essential hypertension. Four hundred ninety patients were randomized to a once-a-day treatment with lisinopril 20 mg or atenolol 50 mg for 4 weeks, and the doses of lisinopril or atenolol were increased up to 80 mg or 200 mg, respectively, at 4-week intervals if sitting diastolic blood pressure (SDBP) was not well controlled. Hydrochlorothiazide (HCTZ) 12.5 or 25 mg was added after 12 weeks, if necessary, and titrated upward after 4 weeks to a maximum dose of 25 or 50 mg/day. Lisinopril and atenolol reduced SDBP to a similar extent. All reductions from baseline in sitting diastolic and systolic blood pressure were significant (less than 0.01). Lisinopril produced a significant (less than 0.01) greater reduction in sitting systolic blood pressure (SSBP) than atenolol. Addition of HCTZ caused further blood pressure reductions (p less than 0.01). Five patients (1.7%) on lisinopril and four (2.0%) on atenolol developed skin rashes during weeks 1-12. Two patients (0.7%) on lisinopril 80 mg developed proteinuria (greater than 1 g/day). Cough occurred more often with lisinopril (4.5%), and elevated triglycerides occurred more often with atenolol (2.0%).

The interaction of human apoB-containing lipoproteins with mouse peritoneal macrophages: a comparison of Lp(a) with LDL.

Cholesteryl ester accumulation in macrophages and foam cell formation is believed to play an important role in atherogenesis. The effect of Lp(a) on the incorporation of [14C]oleate into cholesteryl esters was studied in mouse peritoneal macrophages. In view of the physico-chemical similarities between Lp(a) and LDL, the results were compared with those obtained with LDL. Native Lp(a) and LDL did not stimulate cholesteryl ester formation. Incubation of macrophages with Lp(a)- or LDL-dextran sulfate complexes caused a significant increase in cholesteryl ester formation. A similar effect was observed when Lp(a) or LDL were incubated with macrophages in the presence of antibodies directed against the specific Lp(a) apoprotein or against LpB. Treatment of Lp(a) with acetic anhydride or malondialdehyde (MDA) was followed by precipitation of most of the lipoprotein. Therefore, these modifications were not suitable to study the uptake of modified Lp(a) by macrophages. Studies with acetyl-LDL or MDA-treated LDL caused the well-known stimulation of [14C]oleate incorporation into cholesteryl esters. Thus, the modification of Lp(a) by sulfated polysaccharides or by treatment with antibodies yields similar cholesteryl ester deposition in mouse peritoneal macrophages as observed with modified LDL. This might be one mechanism by which Lp(a) exerts its atherogenicity.

[A combination of methyldopa, hydrochlorothiazide and amiloride in the treatment of essential hypertension]. / Eine Kombination von Methyldopa, Hydrochlorothiazid und Amilorid bei der Behandlung der essentiellen Hypertonie.

41 patients (35 males and 6 females) with moderate hypertension were treated with a combination of methyldopa/hydrochlorothiazide/amiloride (M/HCT/A). In a double blind study the blood-pressure-lowering effect of this combination was compared with the effect of M or HCT/A alone. After 8 weeks of treatment, the combination of M/HCT/A lowered the elevated blood pressure more efficiently than the two monotherapies . M counteracted the potassium-loosing effect of HCT/A, but did not prevent the elevation of serum urea, creatinine and uric acid which is observed under treatment with HCT/A.

[The effect of an infusion of glucose-insulin-potassium and of heparin on the plasma free fatty acid levels and on blood glucose]. / Die Wirkung einer Infusion von Glukose-Insulin-Kalium und von Heparin auf die Konzentration der freien Fettsäuren des Plasma und der Blutglukose.

In the treatment of acute myocardial infarction infusion of glucose-insulin-potassium (GIP) and/or heparin are frequently administered. The effect of an infusion of GIP, heparin or GIP plus heparin on the concentration of plasma free fatty acids (FFA) and blood glucose was studied over a period of 90 min in 10 healthy volunteers. GIP caused a continuous decrease in the FFA level to 34% of the initial value. There was only a slight increase in blood glucose concentration. After the administration of heparin, a rapid increase was observed in the FFA level to nearly the double value of the initial concentration. Thereafter, the FFA level decreased in spite of continuous heparin infusion and after 90 min the FFA level was only 13% above the initial value. Heparin had no effect on the blood glucose concentration. The simultaneous administration of GIP plus heparin caused a rapid increase in FFA concentration, of the same magnitude as observed with heparin alone. Thereafter, the FFA level decreased slightly faster than with heparin alone. In some subjects, GIP plus heparin caused a substantially higher increase in blood glucose concentration than GIP alone. The possible implications of these metabolic effects on the course of acute myocardial infarction are discussed.

Studies on the role of specific cell surface receptors in the removal of lipoprotein (a) in man.

The binding of 125I-lipoprotein (a) [Lp(a)] to cell surface receptors was studied on cultured human fibroblasts. The results were compared with corresponding data obtained with 125I-low density lipoproteins (LDL). Equilibrium binding studies showed that Lp(a) is bound with high affinity by the cell surface receptors. The maximum binding capacity for Lp(a) was 37% lower than for LDL. For Lp(a) and LDL, the Scatchard plots displayed linearity, indicating a single category of binding sites. Half-maximal saturation occurred at a concentration of 9.52 +/- 1.04 nM for Lp(a) and 7.76 +/- 1.29 nM for LDL. Competition binding experiments revealed that Lp(a) and LDL are nearly equally potent in competing each other for the binding sites. Binding of Lp(a) and LDL were followed by suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Cyclohexanedione treatment of Lp(a) and LDL completely abolished receptor binding. Neither Lp(a) nor LDL were specifically bound by fibroblasts obtained from a patient with homozygous familial hypercholesterolemia (FH). The removal mechanisms for Lp(a) and LDL were further compared by in vivo studies. Radioiodinated Lp(a) and LDL were injected intravenously into 12 normolipemic individuals to measure kinetic parameters of these two lipoproteins simultaneously in each subject. Mean fractional catabolic rate (FCR) of Lp(a) was 0.260 +/- 0.060 and mean FCR of LDL was 0.377 +/- 0.077 (mean +/- SD). In each subject, FCR of Lp(a) was lower than the FCR of LDL; the mean difference was 31%. The absolute synthetic rate of Lp(a) was significantly lower than the corresponding value of LDL. In each individual, the percentage of total Lp(a) that was contained in the intravascular space was higher than the corresponding value of LDL; the mean difference was 19%. A highly significant positive correlation was found between FCR of LDL and FCR of Lp(a) (r = 0.853, P less than 0.01). No relationship was found between the serum concentration of LDL-apolipoprotein B and Lp(a). The serum level of Lp(a) was positively related to the absolute rate of Lp(a) synthesis (r = 0.979, P less than 0.01). The serum level of LDL-apolipoprotein B was inversely related to FCR of LDL (r = 0.613, P less than 0.05). In a patient with homozygous FH, FCR of LDL was 0.205 and FCR of Lp(a) was 0.210. The results of these studies show that Lp(a) is specifically bound with high affinity to the same receptors of human fibroblasts as LDL. The affinity and maximum binding capacity are slightly lower for Lp(a) than for LDL. The results of the turnover studies are consistent with the assumption that Lp(a) is removed from the plasma by similar mechanisms as LDL.

[Wegener's granulomatosis as a rare cause for kidney failure]. / Wegenersche Granulomatose als seltene Ursache einer Niereninsuffizienz.

Course and treatment of a case of Wegener's granulomatosis are reported. A 39-year-old man admitted to the hospital because of abnormal densities demonstrated by the X-ray examination of the chest. The patient developed a rapidly progressive renal failure with renal insufficiency. Diagnosis was obtained by biopsys from the upper respiratory tract and from the kidney. During hemodialysis and immunosuppressive therapy renal function improved and hemodialysis could be stopped. The patient was discharged from the hospital and kept on immunosuppressive therapy. The patient omitted the medication by himself and renal insufficiency reappeared. The disease was progressive and the patient died because of intestinal bleeding. Apart from the description of the symptoms of this rare disease, problems of diagnosis and treatment are discussed.

Turnover of lipoprotein (a) in man.

An elevated concentration of lipoprotein (a) [Lp(a)] in the serum has been considered a risk factor for coronary heart disease by various investigators. In the present study, the turnover of Lp(a) was investigated in nine individuals with serum Lp(a) levels ranging from 1 to 68 mg/100 ml. After intravenous injection of radioiodinated Lp(a), the radioactivity time-curve of the serum and the specific activitity time-curves of the isolated Lp(a) and Lp(a) apolipoproteins were measured for 14 d. More than 97% of the label was found in the protein moiety of Lp(a). During the entire study period, the serum radioactivity remained with Lp(a), only insignificant amounts of radioactivity were detectable in other lipoprotein fractions. The serum radioactivity time-curves and the specific activity time-curves of the isolated Lp(a) and Lp(a) apolipoproteins were identical. The kinetic parameters of Lp(a) turnover were calculated in terms of a two-compartment model. 76.5+/-5.1% (mean+/-1 SD) of total Lp(a) was contained in the intravascular space. The biological half-life of Lp(a) was 3.32+/-0.52 d, the fractional catabolic rate (FCR) was 0.306+/-0.054/d, and the rate of synthesis was 5.00+/-3.37 mg/kg/d. A positive correlation was found between serum concentration and synthetic rate of Lp(a) apoprotein. No relationship could be demonstrated between serum level and FCR of Lp(a). The results of this study indicate that Lp(a) is not converted to other serum lipoproteins. From the correlations between serum concentration and kinetic parameters of Lp(a) it is concluded that an elevated Lp(a) level is the consequence of an increased Lp(a) apoprotein synthesis.

Lipoprotein (a) is not a metabolic product of other lipoproteins containing apolipoprotein B.

125I-Labeled autologous very low density lipoprotein (VLDL) was injected intravenously into three lipoprotein (a) positive individuals. One other lipoprotein (a) positive subject received 125I-labeled VLDL from a a lipoprotein (a) negative donor. Specific activity of apolipoprotein B in VLDL, low density lipoprotein (LDL) and lipoprotein (a) was measured for 5 days. In the lipoprotein (a) fraction only traces of radioactivity could be detected, which were caused by contamination with labeled LDL. No precursor-product relationship existed between apolipoprotein B in VLDL or LDL and apolipoprotein B in lipoprotein (a). One lipoprotein (a)-positive individual was kept on a fat-free diet for 4 days to prevent chylomicron formation; no change in the serum level of lipoprotein (a) could be detected under these conditions. The data of this study indicate that lipoprotein (a) is not a metabolic product of VLDL or LDL. Also chylomicrons are not likely to play role as a precursor for lipoprotein (a). It is concluded that lipoprotein (a) is synthesized as a separate lipoprotein.

[Treatment of various types of hyperlipoproteinaemia with a combination of Mg-chlorophenoxy-isobutyrate and mesoinositol-hexanicotinate (author's transl)]. / Behandlung verschiedener Formen primärer Hyperlipoproteinämie mit einer Kombination aus Magnesium-chlorphenoxy-isobutyrat und Mesoinositol-hexanicotinat.

50 patients with different types of hyperlipoproteinaemia were treated with a combination of Mg-chlorophenoxyisobutyrate (700 mg) and mesoinositol-hexanicotinate (500 mg) (Atroplex) twice daily. 7 patients had type IIa, 39 patients type IIb or IV and 4 patients type V. After a period of one month without any treatment the patients were treated during two months. While the effects of this combination on cholesterol of type IIa patients was poor, the drug had an excellent lipid-lowering effect in the patients with type IIb, IV and V. After 14 days' treatment the plasma cholesterol and triglyceride levels in patients of type IIb or IV were significantly lowered. This effect became even more pronounced after one-month treatment. There was no significant difference between the effect of one-month treatment and that of two-month treatment. About two-thirds of the patients of type IIb or IV were responders. No serious side effects could be observed during our study.

[A comparison of bezafibrate and clofibrate in type II B and type IV hyperlipoproteinemia]. / Eine vergleichende Studie von Bezafibrat und Clofibrat bei Patienten mit Hyperlipoproteinämie vom Typ IIB und IV.

In 36 patients with primary hyperlipoproteinemia of type II B or IV the effect of bezafibrate, a new derivate of clofibrate, has been compared with the effect of clofibrate. In an open cross-over-study the effect of 1.5 g clofibrate p.d. has been compared with that of 450 mg bezafibrate p.d. for several months. The effect of bezafibrate on plasma triglyceride concentration and plasma cholesterol concentration was more pronounced than that of clofibrate. This difference was statistically significantly only in the concentration of plasma triglycerides of type IV patients. It is obvious that the difference between bezafibrate and clofibrate would have been more pronounced if the dose of bezafibrate had been in the optimal range. Serious side-effects caused by bezafibrate could not be observed.

[The role of lipoproteinlipase and hepatic triglyceride lipase in the metabolism of triglyceride-rich lipoproteins (author's transl)]. / Die Bedeutung der Lipoproteinlipase und der hepatischen Triglyzeridlipase beim Abbau Triglyzerid-reicher Lipoproteine.

After intravenous injection of heparin two triglyceride lipases are secreted into the plasma: Lipoproteinlipase and a "hepatic" triglyceride lipase. The properties of these two enzymes are extensively discussed in this review. The different methods of measurement of the two lipases are described in detail. The physiological role of lipoproteinlipase in the catabolism of triglyceride-rich lipoproteins is quite well understood. The function of the hepatic triglyceride lipase is not clear until now. The speculations about the possible role of the so-called "remnants" as a substrate of hepatic triglyceride lipase are discussed. The results of own investigations concerning the possible role of these two enzymes in the triglyceride metabolism under different pathophysiological conditions are presented.

Hepatic and extrahepatic triglyceride lipase activity in uraemic patients on chronic haemodialysis.

In eleven patients with chronic renal insufficiency treated by intermittent haemodialysis and in ten normal subjects, hepatic and extrahepatic triglyceride lipase activity of post heparin plasma was selectively measured, utilizing the different sensitivity of both enzymes to inhibition by protamine sulphate. In uraemic patients, hepatic triglyceride lipase activity was significantly decreased and extrahepatic triglyceride lipase activity was normal when compared with the control group. The uraemic subjects showed a moderate hypetriglyceridaemia; their serum cholesterol level, however, was normal. The high triglyceride concentration was due to an increase of very low density lipoproteins and low density lipoproteins of the density between 1.006 and 1.019 g/ml (LDL1). The concentration of low density lipoproteins of the density between 1.019 and 1.063 g/ml (LDL2) was decreased. LDL2 were relatively rich in triglycerides when compared with LDL2 from the control group.

Studies on the metabolism of the lipoprotein Lp (a) in man.

Lp(a) was isolated and labeled by reductive alkylation. Radioactivity only entered the protein moiety of the lipoprotein. No change in the immunological or physicochemical properties of Lp(a) was noted after the radiomethylation. After incubation of labeled Lp(a) with whole serum for 24 h in vitro, more than 99% of the radioactivity of the incubated sample was found in Lp(a). In 4 subjects Lp(a) was injected intravenously. A linear decline of the specific activity of Lp(a) in the serum was found when it was plotted semilogarithmically against time. Half-lives of Lp(a) in the serum were 35, 38, 53 and 58 h. In one subject, the "soluble" and the "insoluble" apoproteins of Lp(a) showed the same half-life as the whole Lp(a) molecule. This suggests that no exchange of Lp(a) apoproteins with lipoproteins of other density classes took place. At different times after the injection of Lp(a), 3--8% of the radioactivity of the serum was found in Lp B, and less than 2% of the radioactivity was detectable in VLDL and the fraction having a density of greater than 1.110 g/ml.

[Biguanides: reasons for withdrawal of drugs and remaining indications]. / Biguanide: Gründe für die Rücknahme von Präparaten und verbleibende Indikationen.

The pharmacological properties and the mode of action of biguanides is presented. In Austria, the association of lactic acidosis with biguanide therapy has led to a cancellation of the registration of buformin and phenformin. Only, if all contraindications for biguanide therapy are strictly observed, metformin can be prescribed for the treatment of obese patients with type II diabetes.