Pharmacokinetics of amoxycillin and clavulanic acid in haemodialysis patients following intravenous administration of Augmentin.

1. Serum concentrations of amoxycillin and clavulanic acid were measured in patients with end-stage renal disease (ESRD) following intravenous administration of 1.2 g Augmentin. Augmentin was administered on a non-dialysis day and 2 h prior to a 4 h dialysis session. 2. The mean values of total serum clearance, mean residence time, volume of distribution at steady state, and terminal half-life for amoxycillin on the non-dialysis day were 14.4 ml min-1, 19.2 h, 14.9 l and 13.6 h, respectively. 3. The mean values of dialysis clearance, total serum clearance during dialysis, fractional drug removal during haemodialysis and half-life during dialysis for amoxycillin were 77.1 ml min-1, 91.5 ml min-1, 0.64 and 2.30 h, respectively. 4. The mean values of total serum clearance, mean residence time, volume of distribution at steady state, and terminal half-life for clavulanic acid on the non-dialysis day were 43.6 ml min-1, 4.4 h, 11.0 l and 3.05 h, respectively. 5. The mean values of dialysis clearance, total serum clearance during dialysis, fractional drug removal during haemodialysis and half-life during dialysis for clavulanic acid were 92.8 ml min-1, 136 ml min-1, 0.65 and 1.19 h, respectively. 6. The total serum clearance on the non-dialysis day, which represents non-renal clearance, was lower than that in normal subjects for both amoxycillin and clavulanic acid. These data would suggest some degree of hepatic impairment in patients with ESRD.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular, endocrine and renal effects of atrial natriuretic peptide in essential hypertension.

Plasma concentrations of human atrial natriuretic peptide (hANP) and effects of synthetic alpha-hANP on blood pressure (BP), on endocrine and metabolic variables, and on renal function were investigated in 10 patients with essential hypertension. Alpha-human atrial natriuretic peptide was given intravenously as a 50-micrograms bolus followed by a 45-min infusion at 0.1 microgram/kg per min. The following effects were observed: (1) a marked rise in plasma alpha-hANP, (2) a progressive fall in BP (from 181/127 to 165/109 mmHg) and plasma volume, (3) a probably baroreflex-mediated sympathetic activation, evidenced by raised heart rate and plasma norepinephrine levels, (4) an increase in serum free fatty acids and circulating insulin (+45%), (5) an enhanced diuresis (+770%) and excretion of sodium (+665%), chloride (+524%), phosphate (+518%), other electrolytes, amino acids and free water clearance, (6) biphasic responses in the glomerular filtration rate (GFR) and p-aminohippurate (PAH) clearance, with initial increases (+40 and 30%, respectively) followed by a rapid return to (GFR), or even a fall below (PAH clearance) control values, and (7) a marked rise in the filtration fraction. Plasma antidiuretic hormone and urinary prostaglandin E2, F2 alpha and dopamine levels were not modified during alpha-hANP infusion, while plasma renin increased. Discontinuation of alpha-hANP was followed by rises in plasma aldosterone, the aldosterone:renin ratio and cortisol. Compared with previously studied normal subjects, in the hypertensive patients alpha-hANP caused a distinctly greater diuresis and electrolyte excretion but lowered BP only slightly more. In essential hypertension, as in normal man, alpha-hANP circulates in the blood and may exert a wide spectrum of cardiovascular, metabolic, endocrine and renal actions.

Chemotherapy-induced complete remission of a malignant fibrous histiocytoma of bone. An 11-year follow-up.

In a young woman with multiple malignant fibrous histiocytoma of bone and soft tissue with a rapidly progressive course, long-term chemotherapy with prednisone and cyclophosphamide resulted in a complete remission still lasting after an 11-year follow-up.

Differential effect of impaired renal function on the kinetics of clavulanic acid and amoxicillin.

Amoxicillin and clavulanic acid are prescribed as a fixed drug combination. The purpose of the present study was to assess the influence of various degrees of renal insufficiency (glomerular filtration rate [GFR], less than 5 to greater than 75 ml/min per 1.73 m2) on the pharmacokinetics of amoxicillin and clavulanic acid following oral (500 and 125 mg of amoxicillin and clavulanic acid, respectively) and intravenous (1,000 and 200 mg, respectively) dosing. The volume of distribution and the systemic availability were independent of the renal function, while the total body clearance and the renal and the nonrenal clearance of amoxicillin and clavulanic acid decreased with decreasing renal function. The decrease in the total body clearance was more pronounced for amoxicillin than for clavulanic acid. This explains the increase in the ratio of the area under the plasma concentration versus time curve of amoxicillin to that of clavulanic acid with decreasing glomerular filtration rate after oral dosing; for example for a GFR of 75 ml/min, the ratio of amoxicillin to clavulanic acid was 4.9 +/- 1.2; for a GFR of 35 to 75 ml/min, 5.3 +/- 2.4; for a GFR of 10 to 35 ml/min, 11.9 +/- 5.8; for a GFR of 5 to 10 ml/min, 13.4 +/- 9.1; and for patients on hemodialysis, 14.7 +/- 5.3. Dosage recommendations are suggested which prevent undue accumulations of amoxicillin while maintaining adequate concentrations of clavulanic acid.

Blood levels and renal effects of atrial natriuretic peptide in normal man.

Since mammalian atria were recently found to contain vasoactive and natriuretic peptides, we investigated the following in normal humans: plasma human atrial natriuretic peptide concentrations, effective renal plasma flow (ERPF), glomerular filtration rate (GFR), urinary water and electrolyte excretion, blood pressure (BP), and catecholamine, antidiuretic hormone (ADH), angiotensin II, and aldosterone levels before, during, and after intravenous administration of the newly synthetized alpha-human atrial natriuretic peptide (alpha hANP). In 10 subjects alpha hANP given as an initial bolus of 50 micrograms followed by a 45-min maintenance infusion at 6.25 micrograms/min increased plasma alpha hANP from 58 +/- 12 to 625 +/- 87 (mean +/- SEM) pg/ml; caused an acute fall in diastolic BP (-12%, P less than 0.001) and a hemoconcentration (hematocrit +7%, P less than 0.01) not fully explained by a negative body fluid balance; increased GFR (+15%, P less than 0.05) despite unchanged or decreased ERPF (filtration fraction +37%, P less than 0.001); augmented (P less than 0.05- less than 0.001) urinary chloride (+317%), sodium (+224%), calcium (+158%), magnesium (+110%), phosphate excretion (+88%), and free water clearance (from -0.76 to +2.23 ml/min, P less than 0.001) with only little change in potassium excretion; and increased plasma norepinephrine (P less than 0.001) while plasma and urinary epinephrine and dopamine, and plasma ADH, angiotensin II, and aldosterone levels were unchanged. The magnitude and pattern of electrolyte and water excretion during alpha hANP infusion could not be accounted for by increased GFR alone. Therefore, in normal man, endogenous alpha hANP seems to circulate in blood. alpha hANP can cause a BP reduction and hemoconcentration which occur, at least in part, independently of diuresis and are accompanied by sympathetic activation. An increase in GFR that occurs in the presence of unchanged or even decreased total renal blood flow is an important but not sole mechanism of natriuresis and diuresis induced by alpha hANP in man.

[Armand Trousseau (1801-1867) and the placebo effect]. / Armand Trousseau (1801-1867) et l'effet placebo.

In 1834 Armand Trousseau (1801-1867) used a placebo, consisting of pills containing only starch, to show that these pills were as effective as homeopathic dilutions. On another occasion he claimed to have produced marked diuresis in patients with edema by cutaneous application of digitalis and scilla solutions; in fact the diuresis resulted from prior high-dose oral digitalis therapy. Complete ignorance of pharmacokinetics at that time was largely responsible for his error.

Acute changes in renal function induced by bisoprolol, a new cardioselective beta-blocking agent.

The acute effects of bisoprolol 10 mg i.v., a new beta1-selective adrenoceptor antagonist, on heart rate, mean blood pressure (mBP), glomerular filtration rate (GFR), para-aminohippuric acid clearance (CPAH), sodium clearance, urine volume and plasma renin activity (PRA), were studied in 6 patients with essential hypertension. Heart rate decreased by 23%, mBP remained unchanged, and GFR decreased by 14% and CPAH by 23%. PRA was depressed on average by 25%. Urine volume and sodium clearance also declined by 9 and 13%, respectively, but the changes were not statistically significant. The fall in heart rate was significantly correlated with that in GFR and CPAH. Changes in GFR were correlated significantly with those in CPAH. The acute changes in renal function induced by bisoprolol are considered to be due to a reduction in cardiac output and increased systemic vascular resistance.

Hypertension as related to renal function in diabetes mellitus.

The relationships between blood pressure and renal function were investigated in 78 hypertensive patients with diabetes mellitus type I or II. Renal function was assessed by determining the glomerular filtration rate and the para-aminohippurate clearance in 32 and serum creatinine in 46 subjects. In the latter, the reciprocal serum creatinine, corrected for age and changing creatinine/insulin clearance ratio, was used as an estimate of glomerular filtration rate. In the 54 patients with serial determinations, the duration of follow-up averaged 10.5 years. In older patients with type II diabetes without clinical proteinuria, hypertension developed either before or after the onset of diabetes. When it appeared, renal function was only slightly reduced. During follow-up, the decline in reciprocal serum creatinine averaged 2.7% per year, a figure very similar to that found in nondiabetic patients with benign essential hypertension. It did not correlate with the blood pressure. In patients with a proteinuria greater than 2.5 g per day and histologic and/or clinical evidence of diabetic glomerulosclerosis, the severity of hypertension correlated inversely with the level of renal function. The rate of decline in function averaged 11% per year but varied widely. It was not significantly related to the blood pressure. These data suggest that different types of hypertension (essential, diabetic, and nephrogenic) may be associated with diabetes mellitus. The rate of decline in renal function is closely related to the presence or absence of clinical proteinuria but not to the level of blood pressure.

Rapidly progressive glomerulonephritis accompanying Legionnaires' disease.

A rapidly progressive, crescentic glomerulonephritis with acute oliguric renal failure occurred simultaneously with legionnaires' disease (LD) in a 52-year-old man. The diagnosis of LD was based on a sixfold rise in indirect fluorescent antibody titer against Legionella pneumophila serogroup 4. Treatment with erythromycin lactobionate resulted in a clinical resolution of pulmonary manifestations. The impairment of kidney function, however, was progressive and within two weeks led to end-stage renal failure requiring regular hemodialysis. This observation suggests that LD may trigger severe acute glomerulonephritis.

Renal glycosuria in renal homograft recipients.

Transient renal glycosuria was observed in eight renal transplant patients during the recovery phase from initial tubular necrosis or acute rejection. In these subjects and three homograft recipients without glycosuria we performed glucose titration experiments. Three patients were found to have type A glycosuria, two had type B and three type C. The titration curve was normal in the three patients without glycosuria. In addition, most subjects presented with hypophosphataemia and hyperphosphaturia. Apart from a direct correlation between the point of splay of the glucose titration curves and the fractional clearance of phosphate, there was no clear-cut relationship between the handling of glucose and phosphorus. Mild hyperchloraemic acidosis was observed in six subjects, but this was unrelated to the type and grade of glycosuria. It is concluded that in homograft recipients the tubular alterations have a patchy and unpredictable distribution and may cause a variety of symptoms which do not necessarily occur in close association.

Renal glycosuria in patients with the nephrotic syndrome.

Transient or persistent renal glycosuria may occur in patients with the nephrotic syndrome. In an attempt to elucidate its mechanism, glucose titration experiments were performed in 20 nephrotic patients. The type A titration curve was found in one and type B in four patients with severe organic changes and low glomerular filtration rate. The remaining subjects displayed a particular type of curve (type C) characterized by a low point of splay but an otherwise almost physiological tracing. In type B and C patients the maximal rate of reabsorption per ml glomerular filtrate (TmG/GFR) was significantly increased and correlated inversely with the filtration fraction. In these patients the point of splay correlated with the glomerular filtration rate and the sodium clearance, but not with the plasma albumin concentration or the rate of proteinuria. These observations suggest that type A was due to diffuse tubular atrophy, and type B to increased nephron heterogeneity resulting from chronic organic changes. Type C was presumably caused by a potentially reversible alteration of the late proximal or distal glucose transport related to the nephrotic syndrome itself.

Long-term effects of captopril on renal function in hypertensive patients.

The effect of captopril up to 450 mg/day on blood pressure and renal function were investigated during sustained treatment of 10 patients whose severe hypertension had not responded to previous therapy. All the patients were kept on diuretics and most of them on beta-blockers, too. A control determination of glomerular filtration rate (GFR) and para-aminohippuric acid clearance (CPAH) was performed during the prior treatment. The effect of the addition (or substitution) of captopril were assessed after an average of 25 days (short-term) and 26 weeks (long-term). Short-term treatment produced a 15.5% decrease in mean blood pressure and interindividually variable effects on renal function. On average GFR was somewhat lower and CPAH slightly higher than the control values (not significant). This pattern is quite similar to the effects of most other antihypertensive drugs. On long-term therapy GFR rose by a mean of 9% (NS) and CPAH by 17% (p less than 0.02). However, in a patient who developed a captopril-induced nephrotic syndrome, GFR dropped to 56% and CPAH to 50% of the control values. In another patient a transient rise in serum creatinine accompanied a severe drug reaction.

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.

Rate of functional deterioration in polycystic kidney disease.

Renal function was evaluated in 44 patients with adult polycystic renal disease at different stages of the affection. In 38 patients single or serial determinations of the glomerular filtration rate and the effective renal plasma flow were performed. In 21 of these patients and in an additional group of six subjects, serial determinations of serum creatinine were obtained. The data show that renal function does not decrease at a constant rate between birth and endstage renal failure. It remains well preserved for many years but decreases rapidly at a later stage. The relationship between indices of renal function (glomerular filtration rate, PAH-clearance and/or reciprocal serum creatinine) and the age of the patients might be described adequately by assuming that the impairment in renal function is proportional to the growth of the cysts and that the radius of the cysts increase at a slow but constant rate. Possible contributory factors are secondary infection and hypertension.

Acute effects of combined vasodilation and beta-adrenoceptor blockade with prizidilol on renal function.

1 The effects of a single oral dose of 600 mg of prizidilol on renal function were studied 5 to 6 h after dosing in six normal subjects and eight patients with essential hypertension. 2 Mean arterial blood pressure was reduced to 92% of the control value in normal subjects and to 75% in hypertensive patients. Heart rate increased slightly. 3 In normal subjects, effective renal plasma flow was increased to 107% of control values while glomerular filtration rate (83%), filtration fraction (79%), sodium (84%) and potassium (50%) clearances were significantly decreased. 4 In hypertensive subjects, effective renal plasma flow was increased to 120% of control values, while glomerular filtration rate (67%), filtration fraction (57%), sodium (27%) and potassium (72%) clearances were significantly decreased. 5 Plasma noradrenaline increased significantly in normal subjects (150%) and in patients (173%). Plasma renin activity, aldosterone and epinephrine levels did not change consistently. 6 The results indicate that the acute effects of prizidilol on blood pressure and renal function are more marked in hypertensive than in normotensive subjects. Prizidilol increases renal plasma flow like hydralazine and depresses glomerular filtration rate and fractional sodium excretion like endralazine. In addition to the fall in arterial pressure, efferent vasodilation and/or a specific effect on the glomerular ultrafiltration coefficient Kf may account for the striking decrease in filtration fraction.

Enhanced cardiovascular pressor reactivity to norepinephrine in mild renal parenchymal disease.

The cardiovascular pressor responsiveness to infused norepinephrine (NE) or angiotensin II (AII) as related to endogenous plasma NE or renin levels was assessed in 20 patients with mild parenchymal kidney disease (plasma creatinine 2.20 +/- 0.58 mg/dl, +/- SEM) and in 20 normal subjects approximately matched for sex and age. The two groups did not differ significantly in mean body weight, heart rate, blood volume, plasma electrolytes, exchangeable or urinary sodium, plasma aldosterone, epinephrine and renin levels, or AII threshold or pressor doses. Basal (including pre-infusion) plasma NE levels, the relationship between plasma NE measured during NE infusion and the corresponding NE infusion rate, as well as the total plasma clearance of NE (5.0 +/- 0.8 vs. 5.5 +/- 0.5 liter/min) also did not differ significantly between the two groups. In contrast, the threshold or pressor doses of infused NE decreased significantly in the patients with kidney disease (94 +/- 11 vs. 134 +/- 14 ng/kg/min and 21 +/- 3 vs. 40 +/- 7 ng/kg/min; P less than 0.05). Moreover, based on analysis of covariance, the individual pressor doses as related to basal plasma NE levels were distributed differently (P less than 0.01) between the patients and normal subjects. These findings suggest that the kinetics of plasma NE are unaltered largely in early stage kidney disease. However, such patients tend to develop an exaggerated pressor responsiveness to NE in the presence of normal plasma NE levels. This disturbance may favor the development of hypertension.