Apolipoprotein(a) polymorphism predicts the increase of Lp(a) by pravastatin in patients with familial hypercholesterolaemia treated with bile acid sequestration.

HMG-CoA reductase inhibitors effectively reduce the concentration of low density lipoproteins (LDL) in plasma. Lipoprotein(a) [Lp(a)] may be as atherogenic as LDL. A few studies, only one of which was placebo controlled, suggest that the HMG CoA reductase inhibitors either do not affect Lp(a) or they increase Lp(a). The response of Lp(a) to HMG-CoA reductase inhibition has not been related to apolipoprotein(a) phenotypes in previous studies. We conducted a double-blind, placebo controlled study of pravastatin in 51 patients with familial hypercholesterolemia (FH) (n = 43) or probable FH (n = 8). All patients had LDL-cholesterol concentration above 4.1 mmol l-1 despite treatment with diet and bile acid sequestration. In patients assigned to pravastatin (n = 34), the mean concentrations of total cholesterol and LDL cholesterol fell significantly (P < 0.01) when compared to placebo. Lp(a) increased (P < 0.01) from a mean (+/- SD) of 33.6 +/- 40.8 mg dl-1 to 41.1 +/- 46.1 mg dl-1 on pravastatin but was unchanged during placebo treatment. The percentage increase in Lp(a) was the same in patients with different apo(a) phenotypes, and hence the absolute increase in Lp(a) was greatest in patients with the low molecular weight apo(a) phenotypes.

DNA deletions in the low density lipoprotein (LDL) receptor gene in Danish families with familial hypercholesterolemia.

DNA samples from 25 unrelated Danish patients with familial hypercholesterolemia (FH) were screened by Southern blot hybridization to detect gross alterations in the low density lipoprotein (LDL) receptor gene. Three FH-patients were found to have a deletion. Two of these delete part of the cysteine rich domain, which comprises the ligand binding region of the LDL-receptor. The third deletion encompasses coding regions for the cytoplasmic part of the receptor. As two of these deletions could be equivalent to previously described LDL-receptor gene alterations, these data seem to support a notion of recombination hot spots which involve Alu-sequences.

Furosemide kinetics and dynamics in rats and humans.

1. Increasing doses of furosemide (F) were given intravenously to rats and humans and initial pharmacokinetics and pharmacodynamics were compared. 2. Weight-related initial renal excretion rate of F was twice as high in rats and serum concentration at 30 min was twice as high in humans (P less than 0.01). 3. Volume of distribution for F was 44% larger in rats (P less than 0.01). 4. Maximal weight-related diuretic and natriuretic responses were, like the theoretical maximal efficiency, 5-6 times higher in the rat. The potency was 230 times lower in the rats. 5. On a molecular basis species differences in kinetics disappeared when standardization was based on ERPF and species differences in dynamics disappeared when standardization was based on GFR.

Flecainide acetate in atrial flutter and fibrillation. The arrhythmogenic effects.

The arrhythmogenic effects of flecainide in atrial fibrillation and flutter were assessed in a consecutive material of 100 patients without severe heart failure (NYHA class I or II). Severe arrhythmogenic events occurred in 9% (4-16%) of the patients: within the first 5 days of treatment in seven patients, and in two patients after 60 and 240 days of flecainide treatment. Patients with proarrhythmic events tended to be older and to have a longer QRS duration. Following flecainide therapy conversion to sinus rhythm was achieved in 21 of 43 patients (49%) with atrial fibrillation and in 10 of 29 (34%) with atrial flutter. It is concluded that flecainide, although an effective antiarrhythmic drug, has potential proarrhythmic effects and therefore cautious use of this drug is mandatory.

Dose dependency of furosemide-induced sodium excretion.

Intravenous furosemide doses ranging from 5 to 120 mg were given to healthy young volunteers with and without individualized active rehydration with a sodium chloride solution. Sodium excretion rates and fractional sodium excretions (FENa) percentages were correlated significantly with dose and with urinary excretion rates of furosemide. The ED50 was below 5 mg and no additional natriuretic effect was seen above 40 mg. The efficiency (FENa percentage per microgram of furosemide excreted per minute during a certain clearance period) was dependent on hydration and on time. For the period 15 to 30 min a significant linear relationship between furosemide dose and the reciprocal of the efficiency indicated a higher efficiency for lower doses and a theoretical maximal value of FENa of 0.4% per micrograms of furosemide excreted per minute. A relative value for a dose-dependent efficiency reduction was calculated for each dose. The ED50 for dose-dependent efficiency reduction was about 12 mg i.v. Simultaneous measurements of lithium clearance indicated a proximal site of action for furosemide which was saturated at furosemide excretion rates above 50 micrograms/minute. For the major, distal, site of action no maximal value was demonstrated. It is concluded that a wanted balance between a strong natriuretic effect and weak sodium retaining mechanism not necessarily is achieved by a high dose and that information concerning that problem must be obtained from studies in relevant patient groups.