Efficacy and pharmacokinetics of piretanide in patients with congestive heart failure.

The efficacy and pharmacokinetics of the diuretic piretanide were studied in two groups of six patients hospitalized for congestive heart failure. A dosage of 2 x 6 mg day-1 to 2 x 12 mg day-1 of intravenous piretanide for 7 days was sufficient to abrogate most symptoms of cardiac insufficiency. When compared with another group of healthy volunteers, patients with congestive heart failure had reduced total body clearance of piretanide of about 50% which was attributable to a diminished renal but not non-renal clearance. The analysis of the interrelationship between urinary piretanide excretion and diuresis by means of a linearized Emax-model revealed a maximal diuresis of 231 ml h-1 and a urinary piretanide excretion to induce half-maximal diuresis of 245 micrograms h-1. Thus patients with congestive heart failure exhibit a decreased renal clearance of piretanide and a good response to this high ceiling diuretic after intravenous dosing.

Pharmacokinetics of ramipril in hypertensive patients with renal insufficiency.

In an open trial, the pharmacokinetics of ramipril and its active metabolite ramiprilat were studied in 25 hypertensive patients with various degrees of renal insufficiency given 5 mg ramipril p.o. for 14 days. Ramipril was rapidly absorbed and reached a peak concentration after 1-2 h. Cmax was greater in patients with severe renal insufficiency, which might indicate a reduced renal elimination rate, although, the rapid decline of the concentration-time curve for ramipril was almost independent of renal function. The mean initial apparent half-lives on Days 1 and 12, respectively, were 2.8 and 3.4 h (Group I: creatinine clearance 5-15 ml/min), 1.8 and 2.3 h (Group II: creatinine clearance 15-40 ml/min), and 1.9 and 1.9 h (Group III: creatinine clearance 40-80 ml/min). No accumulation was observed after multiple dosing. In contrast, the kinetics of its active acid metabolite ramiprilat was significantly influenced by renal function. The mean times to the peak plasma concentration were 5.7 h in Group I, 4.4 h in Group II and 3.8 h in Group III. The initial decline in plasma ramiprilat was dependent upon renal function; the mean initial apparent half-lives (Days 1 and 12, respectively) were 16.0 and 14.8 h (Group I), 10.1 and 9.5 h (Group II) and 10.6 and 8.0 h (Group III). Mean trough concentrations and absolute accumulation also increased with worsening renal function, and the renal clearance of ramiprilat was significantly correlated with the creatinine clearance. The subsequent long terminal phase at low plasma ramiprilat concentrations represented slow dissociation of the ACE-inhibitor complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacodynamic effects of a single 10-mg dose of the angiotensin converting enzyme inhibitor ramipril in patients with impaired renal function.

A single oral 10-mg dose of ramipril, a long-acting angiotensin converting enzyme (ACE) inhibitor, was given to 24 hypertensive patients with different degrees of renal function. Creatinine clearance ranged from below 15 ml/min (n = 9) to above 80 ml/min (n = 3). Serial blood samples were taken for the determination of ACE activity, plasma renin activity (PRA), aldosterone (ALDO), angiotensin II (AT II), and serum creatinine (CR). Blood pressure was also monitored before and after medication. After administration of ramipril systolic and diastolic blood pressure (BP) fell; the decreases were unrelated to renal function. Peak BP-lowering effect was seen at 6 h basal, 174 +/- 19.5/102.6 +/- 8.9 to 149.8 +/- 19.7/87.6 +/- 13.3 mm Hg (mean +/- SD; p less than 0.001). ACE inhibition occurred within 2 h, being maximal at 4 h: basal, 82.6 +/- 17.9 to 0.2 +/- 0.6 nmol/ml/min (p less than 0.001). The greater the renal impairment, the longer the ACE inhibition. Angiotensin II was reduced maximally at 10 h after dosing, from 10.4 +/- 5.4 to 6.2 +/- 3.6 pg/ml (p less than 0.01). Aldosterone also fell from 212 +/- 188.4 to 134 +/- 73.3 pg/ml at 6 h (p less than 0.01). Plasma creatinine was unchanged: 401.3 +/- 315.7 to 394.9 +/- 306.1 nmol/L (NS). Ramipril, given as a single oral dose, lowers BP in hypertensives with both normal and impaired renal function, inhibits ACE activity, and causes no change in serum creatinine.

Steady-state kinetics of ramipril in renal failure.

In an open trial, the pharmacokinetics of ramipril and its active metabolite ramiprilat were studied in 23 hypertensive patients with various degrees of renal insufficiency. During a 2-week treatment period, each subject took daily a 5-mg tablet of ramipril. Serum profiles and urinary excretion of the parent compound and ramiprilat, the active metabolite, were then evaluated. Peak concentrations of ramipril were slightly greater in patients with severe renal insufficiency; however, most of the ramipril was metabolized in the liver. The drug concentration-time curve was almost independent of renal function and no accumulation was observed after multiple dosing. In contrast, ramiprilat kinetics were significantly influenced by renal function. Initial apparent half-lives (8-16 h), mean trough concentrations (5-19 ng/ml), and absolute accumulation all increased with worsening renal function, and renal clearance of ramiprilat was significantly correlated with creatinine clearance. The subsequent long terminal phase at low ramiprilat serum concentration represents the slow dissociation of the angiotensin converting enzyme (ACE)-bound drug. This study indicates that in patients with severe renal insufficiency (creatinine clearance below 30 ml/min), smaller doses of ramipril will be required than in patients with normal or borderline normal renal function.

Therapeutic efficacy and tolerance of ramipril in hypertensive patients with renal failure.

In an open trial, the antihypertensive and hormonal effects of ramipril, a new nonsulfhydryl angiotensin converting enzyme (ACE) inhibitor, were studied in 23 hypertensive patients with various degrees of renal failure: group I, creatinine clearance 5-15 ml/min, n = 10; group II, creatinine clearance 15-40 ml/min, n = 7; group III, creatinine clearance 40-80 ml/min, n = 6. In a 2-week placebo run-in period, antihypertensive agents were reduced or discontinued. During the treatment phase, patients received a 5-mg tablet of ramipril once daily for a period of 2 weeks. Concomitant medication remained unchanged. In all groups, ramipril significantly decreased mean arterial blood pressure. Blood pressure response was not different in the three groups, although plasma ramipril levels were higher in patients with severe renal failure. In patients with high plasma renin activity (PRA), reduction of blood pressure was greater than in subjects with low PRA. Plasma ACE activity was suppressed to less than 20% of its initial value in all groups during the whole treatment period, and the suppression was more marked and lasted longer in patients with severe renal failure. A strong correlation between the plasma ramiprilat levels and the inhibition of plasma ACE activity was noted for all groups. Mean serum creatinine did not increase significantly; serum potassium levels rose from 4.5 to 4.9 mmol/L on day 14 (p less than 0.01). In conclusion, in patients with various degrees of renal failure, ramipril represents an effective and well-tolerated antihypertensive agent.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of renal function on the pharmacokinetics of ramipril (HOE 498).

The pharmacokinetics of ramipril (HOE 498) were studied after oral administration of a single 10 mg dose to 24 hypertensive patients with different degrees of renal function. The creatinine clearance ranged between 4.1 and 126 ml/min/1.73 m2 and was below 35 ml/min/1.73 m2 in 16 patients. Angiotensin converting enzyme activity and the concentrations of ramipril and its active diacid metabolite ramiprilat were measured in plasma up to 10 days after drug intake. Urine levels of ramipril, ramiprilat, their glucuronides and 2 major metabolites (a diketopiperazine and a diketopiperazine acid) were measured up to 4 days after medication. The plasma concentration-time curve of ramiprilat was polyphasic with an initial steep decline after the peak level and a subsequent very long terminal phase at low concentrations. Impaired renal function resulted in higher peak levels of ramiprilat, longer times to peak and a markedly slower decline of plasma ramiprilat levels. Hence, the duration of angiotensin converting enzyme inhibition was considerably prolonged in renal failure and depended on the severity of renal impairment. The urinary excretion of ramipril and its metabolites decreased with decreasing renal function and was linearly related to the creatinine clearance, suggesting an alternative pathway of elimination. The pattern of excretion rates of ramipril and its various metabolites was not affected by renal failure. In contrast to the marked changes in the renal elimination, no relevant differences were observed in the absorption of ramipril from the gastrointestinal tract. Systolic and diastolic blood pressure decreased in all groups. The single 10 mg dose of ramipril was well tolerated.

Pharmacokinetic and pharmacodynamic interaction between furosemide and metolazone in man.

In various clinical situations a poor diuretic response to furosemide may be improved by the addition of metolazone. The mechanism of this additive effect is unclear. The purpose of the present investigation was to establish whether metolazone changes the pharmacokinetics of furosemide and by this mechanism enhances the diuretic effect. Eight volunteers were given an intravenous infusion of 4 mg h-1 of furosemide for 12 h. After 6 h 2.5 mg metolazone were administered orally. The addition of metolazone increased diuresis, urinary excretion of sodium and chloride (P less than 0.01), but decreased urinary excretion of calcium (P less than 0.01), while furosemide excretion remained unchanged. Total body clearance and renal clearance values of furosemide were similar before and after administration of metolazone. Our data confirm the additive diuretic effect of the combination treatment metolazone-furosemide and show for the first time a distinct hypocalciuric action of metolazone, similar to thiazides. Moreover metolazone does not affect the pharmacokinetics of furosemide.

Pharmacokinetics of the loop diuretic piretanide in renal failure.

Piretanide 60 mg was administered intravenously over 30 min to 15 men with different degrees of renal failure. The mean piretanide serum concentration at the end of the infusion period was 5.72 +/- 1.51 micrograms/ml. Serum piretanide concentration-time curves declined biexponentially and 24 hours after medication the serum level had fallen to less than twice the detection limit. The terminal half-life ranged from 1.63 to 3.44 h. A relationship to creatinine clearance was not demonstrable. The mean metabolic clearance of piretanide was 107.7 +/- 47.6 ml/min/1.73 m2 body surface area and was the same as that reported for healthy subjects. The renal clearance of piretanide ranged from 3.33 to 43.9 ml/min/1.73 m2 body surface area and very closely correlated with the creatinine clearance (p less than 0.01). Its renal clearance depended principally on active secretion of the drug into the tubule, and glomerular filtration appeared unimportant. There was a close relationship between the amount of piretanide excreted in the urine and the creatinine clearance. Because the diuretic effect of piretanide depends on the concentration of the drug in the tubule, the observed correlation might be of use in evaluating the appropriate dosage of piretanide in patients with renal failure. The present data suggest that single daily doses of piretanide will not result in accumulation, even when high doses are administered to patients with advanced renal failure.

Comparison of the short-term effects of the loop diuretic piretanide and furosemide in patients with renal insufficiency.

The natriuretic effect of the new loop diuretic piretanide was investigated in patients with severe renal insufficiency and was compared with that of furosemide. In the first study 4 hospitalized patients (serum creatinine 407 to 1220 mumol/l) were examined after administration of piretanide (12, 24, 48 and 96 mg to two patients, and 24, 48, 96 and 192 mg to 2 other subjects, given every third day). In the second study 6 hospitalized patients (serum creatinine 194 to 698 mumol/l) were studied after receiving orally 2 different doses of piretanide and 2 different doses of furosemide orally, given every fourth day. The mean natriuretic effect of 48 mg and 96 mg piretanide was 250 and 340% of the control value for the entire group, and 311 to 480% in the subgroup of patients with serum creatinine below 530 mumol/l. For a given dose the natriuresis was inversely correlated with renal function, and at a given serum creatinine level the natriuretic response was dose-dependent. The drug had less effect on water and potassium diuresis than on natriuresis. No significant difference in natriuretic effect was found on comparison with furosemide given in the ratio furosemide:piretanide 3.33:1. The pharmacokinetic data showed a direct correlation between the dose and the mean plasma concentration and also between urinary recovery of the drug and the measured natriuretic response.

Pharmacokinetics of high doses of piretanide in moderate to severe renal failure.

The pharmacokinetics of piretanide was studied in 10 patients with chronic renal failure. After administration of a high oral dose (12 to 192 mg) of piretanide the kinetics behaved according to an open 2-compartment model. The elimination constant in the first phase (alpha) ranged from 0.385 to 0.756 h-1 and in the second phase (beta) from 0.079 to 0.274 h-1. The corresponding elimination half-lives ranged from 55 to 108 min (t 1/2 alpha) and from 152 to 524 min (t 1/2 beta). Only an average of 2.8% of the orally administered drug was recovered in 24 h urines. Nevertheless, a good correlation was found between urinary recovery or renal clearance of the drug and residual renal function. The elimination of piretanide by non-renal mechanisms appeared to be increased when renal function was greatly diminished.

Determination of the position of electroimmune precipitates of antigen--antibody systems on their respective quantitative precipitation curves.

Using corresponding monospecific antisera from the rabbit, the precipitation curves for albumin, alpha-1-antitrypsin, haptoglobin 1-1 and fibrinogen were produced. In parallel, four different dilutions of these antigens were examined by line immmunoelectrophoresis, employing the same antisera. The distance of the resulting line immune precipitates from the start served to calculate the amount of antigen-antiserum reacting with each other. After converting these values to the amount of antiserum used for producing the precipitation curves, the 'line antigen/antibody ratios' were drawn into the appropriate precipitation curves. All electroimmune precipitates (in this case, the 'line immune precipitates') were found to be located on the side of antigen excess of their corresponding precipitation curve.

Histamine release in human subjects by modified gelatin (Haemaccel) and dextran: an explanation for anaphylactoid reactions observed under clinical conditions?

Histamine release by modified gelatin (Haemaccel) and dextran (Macrodex) has been demonstrated in volunteers by direct and indirect methods. In a pilot study of Haemaccel, histamine release was observed in six of seven volunteers. The highest plasma histamine concentration was 4.8 ng/ml, the lowest 1.7 ng/ml: two of the subjects showed slight allergic reactions. Using Haemaccel batch 2551, 10 out of 12 subjects reacted to the rapid infusion of Haemaccel with increased plasma histamine concentrations, whereas none reacted to Ringer's solution. None of the 10 subjects had an allergic reaction, but an increase in gastric secretion was observed in eight. Changes in the venous basophil granulocyte count were found in both those who reacted and those who did not react to Haemaccel. After the rapid infusion of dextran the highest plasma histamine concentration was 5.0 ng/ml, the lowest 1.3 ng/ml. The withdrawal of blood had no influence on plasma histamine concentration. The incidences of histamine release produced by Haemaccel varied with different batches. Thus, it seems unlikely that immunological mechanisms are principally responsible. Nine instances of allergic and anaphylactoid reactions to plasma substitutes have been reported, seven after Haemaccel infusion, and two after dextran administration. One of the patients who received dextran died. Histamine release was always associated with Haemaccel infusion and corresponded in extent to the clinical symptoms observed, but there was no significant histamine release associated with the reactions to dextran.

Investigation of the apparent delay in mobility of albumin, alpha-1-antitrypsin, haptoglobin 1-1 and fibrinogen in electroimmunodiffusion.

Differences in mobility of free and complex-bound antigen molecules during electrophoresis in antibody-free and antibody-containing agarose gel were investigated with albumin, alpha-1-antitrypsin, haptoglobin and fibrinogen. The combination of line electrophoresis and one-dimensional single electroimmunodiffusion as designed for this purpose is described. Differences in time between the start of line electrophoresis and that of rockets, in view of their influence on the formation of the line precipitate, served as reference values. Three basic types of morphology of the line precipitate in the area of possible interaction between line and rocket precipitation were distinguished: total interruption, partial interruption and no interruption. By means of the time differences indicator system it was found that this apparent reduction in mobility during electroimmunodiffusion of the antigens tested was reversely proportional to the electrophoretic mobility of free antigens.

Electrophoretic separation of serum proteins on cellulose acetate followed by electrophoresis in antibody - containing agarose gel.

A modification of the crossed immunoelectrophoresis of serum proteins is described in which the first step is carried out on cellulose acetate membranes and the second in antibody-containing agarose gel. The use of a special chamber allows reproducible conditions. The cellulose acetate membranes with the protein fractions separated in the first step can, if desired, be stored at minus 20 degrees C until further use. The technique of reversed intermediate gel has been worked out and employed for the identification of the Laurell peaks and their localization in the pherogram. Crossed immunoelectrophoresis with cellulose acetate and agarose is simple, provides reproducible results and requires no apparatus other than a special gel chamber.