Pharmacokinetics of piroximone after oral and intravenous administration to patients with renal insufficiency.

The pharmacokinetics of piroximone (PI) were determined in patients with renal failure (inulin clearance less than 50 ml min-1 per 1.73 m2) using two protocols: (a) 10 patients received a single i.v. infusion of 0.5 mg kg-1 PI and the data were compared with those from seven healthy subjects receiving the same regimen; (b), a single oral dose of either 25 or 50 mg PI was given to 20 patients. PI concentrations were assayed by h.p.l.c. in plasma and urine over 48 h. After i.v. administration to healthy subjects PI was distributed rapidly and eliminated with a mean half-life of 1.3 +/- 0.2 h. The urinary recovery of unchanged PI was 64% of the dose. In the patients the extent of renal elimination of PI was decreased (-78%) in relation to the degree of renal insufficiency as assessed by inulin clearance (r = 0.97, P < 0.0001). Mean Cmax, AUC and t1/2,z values after i.v. infusion were increased by 47%, 127% and 77%, respectively, in comparison with healthy subjects. Similar results were obtained after oral administration. Until chronic dosing studies are undertaken, PI dosage should be adapted in relation to renal function.

Controlled low protein diets in chronic renal insufficiency: meta-analysis.

OBJECTIVE: To determine whether low protein diets retard the development of end stage renal disease. DESIGN: Meta-analysis of 46 trials since 1975, from which six randomised controlled trials were selected. SETTING: Five trials in Europe and one in Australia between 1982 and 1991. SUBJECTS: 890 patients with mild to severe chronic renal failure who were followed up for at least one year. 450 patients received a low protein diet and 440 a control diet. INTERVENTION: Difference in protein intake between control and treated groups of at least 0.2 g protein/kg/day. MAIN OUTCOME MEASURE: Number of renal deaths (the necessity to start dialysis or death of patient during study). RESULTS: 156 renal deaths were recorded, 61 in the low protein diet group and 95 in the control group, leading to an odds ratio of low protein to control of 0.54 with a 95% confidence interval of 0.37 to 0.79. CONCLUSIONS: This result, obtained on a large population of patients suffering from chronic renal insufficiency, strongly supports the effectiveness of low protein diets in delaying the onset of end stage renal disease.

[Adrenergic stimulation and renal synthesis of prostaglandins in genetically hypertensive rats of the Lyons strain]. / Stimulation adrénergique et synthèse rénale des prostaglandines chez le rat génétiquement hypertendu de souche lyonnaise.

An increased urinary excretion of thromboxane (Tx)B2 (Geoffroy & al., Hypertension 1986, 4 suppl 3: S37) and an elevated renal sympathetic activity (Sautel & al., Am J Physiol 1988, 255: H736) were simultaneously observed in the developing genetically hypertensive rat of the Lyon strain (LH). In the present work, the relationship between the adrenergic stimulation and prostaglandins (PGs) release was studied using isolated perfused kidney of 8 week-old LH rats and their normotensive controls (LN). Phenylephrine (PHE, 5 - 190 x 10(-8) M) and norepinephrine (NE, 1.2 - 96 x 10(-8) M) were administered in a single pass kidney perfused with a cell free solution and their effects were studied on the renal vascular resistances (RVR) and urinary excretion of TxB2 and 6-keto-PGF1 alpha (6KPGF) measured by specific radioimmunoassays after separation by HPLC. The results (mean +/- SE) obtained before (C) and after PHE and NE perfusions at concentrations: D1 = 31 and 10.5; D2 = 190 and 96 10(-8) M for PHE and NE respectively (* p less than 0.05 ** p less than 0.01 *** p less than 0.001 LH vs LN) were as follows: [table: see text] During the control period, kidneys of LH rats exhibited increased RVR when compared to LN controls but a similar PG excretion. The 2 concentrations of PHE and NE used which produced a similar increase in RVR strikingly stimulated the PG excretion. This effect which was more marked for NE than for PHE did not differ between the 2 strains for 6KPGF but was enhanced for TxB2 in kidney of LH rat.(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of renal insufficiency and haemodialysis on the kinetics of ciprofibrate.

1. The kinetics of the hypolipidaemic drug, ciprofibrate, were studied after a single oral dose (100 mg) in subjects with normal renal function (n = 6), patients with mild (n = 6) and severe (n = 6) renal insufficiency as well as in haemodialysed patients (n = 5). 2. Under fasting conditions, ciprofibrate, was absorbed rapidly in subjects with normal renal function, and its apparent elimination half-life was approximately 81 h. Both renal clearance (0.15 ml min-1) and cumulative renal excretion (less than 7% of the administered dose) were low. 3. Mild renal insufficiency did not alter the pharmacokinetics of ciprofibrate, but severe renal impairment significantly reduced both its renal clearance and cumulative urinary excretion and increased the apparent elimination half-life. 4. A 5 h haemodialysis session did not lower the plasma concentrations of ciprofibrate. 5. It is concluded that, from a pharmacokinetic point of view, a reduction in the dosage of ciprofibrate should be considered in patients with a glomerular filtration rate below 30 ml min-1/1.73 m2.

Effects of xamoterol on sodium excretion in volunteers.

Xamoterol has been shown to reduce the frequency of oedema and lung crepitations in heart failure. We examined its effects on blood pressure and renal function in healthy volunteers. Systolic blood pressure rose, sodium and chloride excretion increased and there was a strong correlation in individual subjects between rises in systolic blood pressure and in sodium excretion. Although no changes in glomerular filtration rates were seen, changes sufficient to explain the observed rise in sodium excretion are well within the experimental error of this study. Xamoterol may increase sodium excretion by an action on renal haemodynamics.

Influence of renal insufficiency on the pharmacokinetics of cicletanine and its effects on the urinary excretion of electrolytes and prostanoids.

1. The kinetics of a single oral dose (300 mg) of cicletanine a new antihypertensive drug with diuretic properties, and its effects on the urinary excretion of electrolytes and of the major stable metabolites of prostacyclin and thromboxane A2 were studied in patients with normal renal function (n = 6), mild (n = 9) and severe (n = 10) renal insufficiency. 2. In normotensive subjects with normal renal function, cicletanine was rapidly and regularly absorbed, its apparent elimination half-life established around 7 h, and both its renal clearance (0.4 ml min-1) and its cumulative renal excretion (0.85% of the administered dose), were low. Mild renal insufficiency did not significantly alter these parameters, while severe renal impairment reduced the renal clearance and the cumulative urinary excretion of cicletanine and increased its apparent elimination half-life (31 h). However the area under the plasma curve was not changed due to reduced plasma concentrations in these patients. 3. Cicletanine induced a rapid and marked (four fold as a mean) increase in the urinary excretion of water, sodium and potassium which lasted for 6 to 10 h, in subjects with normal renal function. Renal insufficiency did not alter the slope of the calculated plasma concentration-effects curves but reduced the maximum effect observed for water, sodium and potassium. 4. A single oral dose of cicletanine did not change the urinary excretion of 6-keto-prostaglandin F1 alpha and thromboxane B2 in the three groups of patients studied, the basal values of which being found to be closely related to the creatinine clearance.(ABSTRACT TRUNCATED AT 250 WORDS)

Uric acid renal handling: spontaneous changes and influence of a thiazide alone or associated with triamterene.

The spontaneous changes in renal handling of uric acid, the consequences of methyclothiazide (M) and of a combination of M with three doses of triamterene (25, 50, 75 mg) were assessed in eight normal men, in a ten-week placebo controlled, double-blind study. In untreated subjects, significant correlations were found between blood uric acid (bUA) and UAV, between bUA and FeUA, between FeUA and plasma renin activity (PRA) and between bUA and PRA. Spontaneous variations in bUA and UAV were shown to be predominantly dependent on changes in sodium status. All diuretics significantly increased bUA and decreased FeUA. Under diuretics, bUA kept correlations with FeUA and PRA similar to that observed in untreated subjects indicating that the changes were dependent only on variations in renal transport induced by changes in sodium status. Addition of triamterene to methyclothiazide significantly lessened the thiazide induced abnormalities in UA.

Pharmacokinetics of teicoplanin in renal failure.

By using a highly specific chromatographic technique, the effect of renal failure on the pharmacokinetics of the six main components of teicoplanin, taken individually or as a whole, was assessed for over 120 h after administration of a 3-mg/kg intravenous dose to healthy volunteers (group 1, n = 6) and to noninfected patients with moderate (group 2, n = 6) or severe (group 3, n = 7) renal failure. In subjects with normal renal function, total teicoplanin was mainly excreted in urine and its concentrations in plasma could be adequately fitted to a three-compartment model. Renal failure did not affect the model or the distribution of teicoplanin but strongly decreased its renal clearance (9.3, 3.2, and 0.6 ml/h per kg, respectively, for the three groups of subjects), in close relationship with the creatinine clearance (r = 0.973, n = 18, P less than 0.001). The cumulative urinary excretion of unchanged total teicoplanin was decreased (50, 21, and 5% of the given dose for groups 1 to 3) and the terminal half-life was enhanced (62, 96, and 111 h for groups 1 to 3) by renal impairment. The relative behavior of the six major components was only slightly affected by renal failure. Consequently, the dosage regimen adjustment could be based on the total teicoplanin concentration, and simulations with the mean estimated pharmacokinetic parameters suggest that the 6-mg/kg daily dose, known to be effective in patients with normal renal function, could be given every 2 and 3 days in patients with moderate and severe renal insufficiency, respectively.

[Influence of acute administration of ramipril on the excretion of uric acid]. / Influence de l'administration aiguë de ramipril sur l'excrétion d'acide urique.

The influence of a new ACEI, Ramipril (R) on renal handling of UA was investigated. 13 hypertensives with normal renal function received either R (10 mg p.o.) or placebo (P). Arterial pressure (AP), GFR (Inulin clearance), Renal Plasma Flow (RPF, PAH clearance), UA urinary excretion (UAV) and fractional clearance (FeAU: UA clearance/GFR) were studied for seven hours after drug administration. GFR remained stable in all cases. R had no effect on sodium excretion rate. Compared to P, R significantly increased UAV by 25 p. 100, FeAU by 32 p. 100, RPF by 26.5 p. 100 and decreased mean arterial pressure (MAP) by 10 p. 100. ACE activity was maximally suppressed at 2 hours. More than 80 p. 100 of the maximal changes in UAU and FeAU were observed within the first two hours, while a progressive increase in RPF up to the fifth hour, and a progressive fall in MAP up to the fourth hour was evident. Except for PAM, all these changes were still present at the end of the study (seventh hour). In conclusion, Ramipril increases the fractional excretion of uric acid. This effect is observed independently of any change in sodium balance and preceeds by two to three hours the changes in renal hemodynamics. The simultaneous changes in FeAU and in ACE activity indicate that the effect on uric acid excretion is presumably due to the fall in angiotensin concentration.

Influence of renal failure on the kinetics of zimeldine and norzimelidine.

The kinetics of zimeldine (Z) and its demethylated metabolite, norzimelidine (NZ), were determined after administration of a single 200 mg oral dose of Z to 6 healthy volunteers (Group I), and to patients with mild (Group II) and severe renal failure (Group III). Z and NZ concentrations were assayed by HPLC in serial plasma and urine samples over 6 days following the dose. In Group I Z was rapidly absorbed and metabolized into NZ, and then the plasma concentrations declined with apparent elimination half-lives of 8.4 h and 24.9 h for Z and NZ respectively, whilst the renal clearance of both compounds was low, Z 15.7 ml/min and NZ 33.0 ml/min. The plasma level of Z differed little between Groups I and III, but the area under the curve was significantly higher in Group III than in Group I subjects (AUC0-144 = 17.3 and 6.8 mumol X l-1 X h, respectively). Severe renal failure did not affect the peak plasma concentration of NZ but it did significantly increase peak time, apparent elimination half-life, and the area under the plasma concentration curve. A significant inverse relationship was found between renal clearance of NZ and plasma creatinine. Since NZ is as pharmacologically potent as Z, the results suggest that the dose of Z should be reduced in patients with severe renal insufficiency.

Pharmacokinetics of penbutolol and its metabolites in renal insufficiency.

The pharmacokinetics of penbutolol, its 4-hydroxylated metabolite and of their conjugates was studied in hypertensive patients with various degrees of renal impairment. A single oral dose of penbutolol 40 mg, was rapidly absorbed after a lag-time of 0.34 h. Its plasma concentration reached a maximum after 0.84 h and then declined bi-exponentially, with an apparent elimination half-life of 21.8 h. The hydroxylation of penbutolol was negligible and conjugation was of major importance for its elimination. Consequently, the kinetics of unchanged penbutolol were not altered by renal impairment. The 48 h-urinary excretion of penbutolol and its metabolites reached 13-14% of the administered dose, which is consistent with extensive metabolism of the drug. After treatment for 30 days with penbutolol 40 mg/d there was no accumulation of the parent drug but the concentration of its conjugates was increased. It is concluded that the dose of penbutolol need not be changed in patients with mild renal insufficiency, 4-hydroxypenbutolol is unlikely to participate in the anti-hypertensive effect of the drug, due to its low concentrations, and biotransformation of penbutolol may be enhanced during chronic treatment.

Pharmacokinetics of nalidixic acid associated with sodium citrate.

A pharmacokinetic study of sachets containing nalidixic acid (0.66 g) associated with sodium citrate (3.75 g)--NSC--was carried out in 10 healthy volunteers in order to determine the influence of the urine alcalinization due to sodium citrate on the elimination of nalidixic acid (NA) and its 7-hydroxy (HNA) and 7-carboxy (CNA) derivatives. Urine alcalinization enhanced markedly the urinary excretion of HNA, but not of NA and CNA. The urinary concentrations of bacteriologically active compounds--NA + HNA--remained above five times their minimum inhibitory concentration for 10 h following each dose. After a 3-day treatment using NSC three times daily there was no significant accumulation of NA and derivatives in the plasma and no significant change in their kinetics. Finally, from a pharmacokinetic viewpoint, the daily administration of 3 sachets of NSC each containing 0.66 g of NA seems valuable in the treatment of urinary tract infections.

Ranitidine kinetics in chronic renal impairment.

The effects of moderate to severe renal impairment on kinetics of the H2-blocker ranitidine were investigated in 16 patients divided into two groups. Mean inulin clearance (ClIn) was 35 +/- 18.3 ml/min/1.73 m2 in group I and 7.4 +/- 3.5 ml/min/1.73 m2 in group II. Each patient received a single 150-mg oral dose of ranitidine. Values determined were maximum plasma concentration (MC) and time of occurrence, AUC, elimination t 1/2 (t 1/2 beta), total amount of unchanged ranitidine recovered in urine, and ranitidine renal clearance (ClR). MC values were higher and longer delayed than values reported in subjects with normal renal function. The t 1/2 beta was longer in group I and group II and correlated with the degree of renal impairment. The amount of ranitidine excreted within the first 24 hr decreased (18% of the dose in group I and 6% of the dose in group II), and ClR correlated strongly with ClIn, indicating that the observed changes in ranitidine kinetics are mainly related to changes in its renal excretion.

[Comparative effects of an alpha 1 and beta 1-2 blocker (labetalol) and a beta-1 blocker (atenolol) in the hypertensive patient]. / Effets comparés d'un alpha 1- et beta 1-2-bloquant (labétalol) et d'un beta 1-bloquant (aténolol) chez l'hypertendu.

The effects of a single oral dose and of an 8 week treatment with labetalol--an alpha 1- and beta 1-2-adrenoceptor blocking agent--and with atenolol--a beta 1-adrenoceptor blocking agent--were compared in 52 hypertensives. A single oral dose of atenolol induced a marked bradycardia without decrease in blood pressure. On the contrary labetalol lowered blood pressure but not resting heart rate. After an 8 week treatment both drugs exhibited a similar antihypertensive effect. However labetalol did not decrease heart rate and plasma renin activity as markedly as atenolol did. It was concluded that the alpha 1 blocking properties of labetalol were of importance in the development of the antihypertensive properties that this drug exhibits after a single or multiple administrations.

Nalidixic acid kinetics in renal insufficiency.

1 A pharmacokinetic study of nalidixic acid (NA) and metabolites was carried out in 23 patients with differing renal function so as to determine the influence of renal insufficiency on the excretion and biotransformation rate of this antibacterial agent. Plasma and urine concentration of NA and of its 7-hydroxy (HNA) and 7-carboxy (CNA) derivatives were measured after a single oral administration. 2 Renal insufficiency did not markedly affect the renal clearance of NA while it significantly decreased the elimination rate of HNA, a compound which largely excreted into the urine. 3 Interestingly, CNA which could never be detected in the plasma of patients with normal renal function appeared in that of patients with renal insufficiency. Plasma concentrations of CNA and creatinine were positively related, and the amount of urinary CNA increased with the renal impairment. 4 These results suggest that HNA can still be biotransformed into CNA by the impaired kidney. Since CNA cannot be easily excreted in the urine of patients with renal insufficiency it is hypothesized that this compound back diffuses into the plasma. 5 Finally, the study of the urinary concentrations of NA and metabolites shows that a standard NA dosage can be used, at least in patients with mild renal insufficiency.

Ranitidine kinetics in normal subjects.

A 1-mg/kg IV bolus injection and a 150-mg (one tablet) oral dose of ranitidine were given to seven normal subjects. At least 1 wk separated the two doses. Ranitidine disappeared from plasma with a half-life of about 2.5 hr. Half of the oral dose was effectively absorbed and half of the absorbed amount was found unchanged in urine. Total body clearance was 10.1 ml/min/kg. Urinary clearance was the same after oral and intravenous doses (6.4 and 6.9 ml/min/kg, P greater than 0.10). Intravenous ranitidine kinetics included three phases, with a central distribution volume of 0.2 l/kg and a total distribution volume of 1.2 l/kg. Absorption kinetics were apparently order zero: of the 150-mg dose, 75 mg was absorbed during 5 hr at a constant rate of 15 mg/hr.

Nalidixic acid kinetics after single and repeated oral doses.

The kinetics of nalidixic acid (NA) and its two metabolites, 7-hydroxynalidixic acid (HNA) and 7-carboxynalidixic acid (CNA) were studied after a single oral dose and after two doses a day for 7 days. Total unconjugated NA, HNA, and CNA concentrations in plasma and urine samples were assayed by a new high-pressure liquid chromatographic (HPLC) technique. NA was rapidly absorbed and hydroxylated to HNA. Both were rapidly excreted in urine with an apparent elimination half-life (t1/2) of 6 to 7 hr. CNA was never detected in the plasma, although it accounted for about 25% of total urinary NA and metabolites. No major sex-related differences in the kinetics and the metabolic pattern were observed. During the 7-day treatment there was no significant cumulation of NA and HNA. The study demonstrated that the concentration of the active compounds, unconjugated NA and HNA, was more than five times the minimum bacteria inhibiting concentration for 8 hr after drug and slightly above this concentration during the next 4 hr.

[Treatment of severe resistant arterial hypertension with captopril. 58 patients, including 38 treated for more than 6 months (author's transl)]. / Traitement de l'hypertension artérielle sévère résistante par le captopril. A propos de 58 patients dont 38 traités depuis plus de six mois.

Of 58 patients treated with captopril, 3 have now received the drug for more than 2 years and 22 for more than one year. This study concerns 38 patients treated for 6 months, captopril having been given alone during the first 2 months. They all had severe hypertension (diastolic BP Greater Than 110 mmHg) which had resisted previous treatments in normally effective doses, including at least one beta-blocker, dihydralazine and a diuretic. After 6 months blood pressure levels were normal in 53% of the patients, reduced in 31% and unchanged in 16%. Clinical improvement was habitual with, in particular, disappearance or decrease of tiredness and dyspnoea. Since some side-effects of the drug, such as granulopenia, proteinuria and ageusia, are mainly observed with high dosage, captopril is usually administered in doses lower or equal to 400 mg/day. In resistant or malignant hypertension it must be used in combination with salt-free diet, a beta-blocker and/or prazosin. Clinical, haematological and renal surveillance is necessary during treatment. When these precautions are observed, captopril constitutes a very useful drug for the treatment of patients with severe resistant hypertension.