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.

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.

Epidemiological profile of hypertensive disease and renal risk factors in black Africa.

OBJECTIVE: To describe the characteristics and renal function of hypertensive patients at their first hospital admission in Sub-Saharan Africa. DESIGN: Retrospective study of all hypertensive patients. SETTING: Department of Cardiology and Internal Medicine of Yalgado Ouedraogo National Hospital in Burkina Faso, a country in Sub-Saharan Africa. PATIENTS: Three hundred and seventeen consecutive hypertensive patients (systolic blood pressure > or = 160 mmHg or diastolic blood pressure > or = 90 mmHg, or both, or patients receiving antihypertensive treatment) referred between 1 November 1988 and 31 October 1990. RESULTS: The hypertensive patients accounted for 36.5% of admissions and included 198 males and 119 females (mean +/- SD age 49 +/- 14 years). Two-thirds of the patients belonged to the poorer socio-economic groups. Hospital admission was necessary because of the symptoms and complications of hypertension: 43% had diastolic blood pressure > 130 mmHg, 73.5% had at least one target organ affected and 38.2% had renal involvement in the form of chronic renal failure or as proteinuria > 1.5 g/24 h. Patients with renal involvement were younger and had blood pressure that responded less well to acute treatment. One-fifth of the patients died during their hospital stay, and most of these had impaired renal function.

Pharmacokinetics of rilmenidine.

Rilmenidine, an alpha 2-adrenoceptor agonist, was studied (1 mg single dose) in order to determine the effects of pathology on its basic pharmacokinetic parameters. Because of the mainly renal elimination of rilmenidine, studies involved hypertensive, elderly hypertensive, renal insufficient and hepatic insufficient patients. Hypertension was found to influence neither the absorption, the distribution nor the elimination processes; the linearity in the range of 1 to 2 mg and the absence of accumulation in long-term treatment were confirmed. In contrast, in the elderly, the absorption phase was delayed. The slight decrease in the apparent volume of distribution (-12%), with a notable decrease in the apparent total clearance (-50%) led to a prolonged elimination half-life (+50%). In renal failure, linear relations between the degree of renal impairment and the elimination parameters were shown. These relations allow the evaluation of the predicted steady-state level of rilmenidine for a given degree of renal failure. In hepatic insufficiency, the modification of rilmenidine disposition concerned exclusively the elimination phase in which apparent clearance was decreased approximately 20%. In conclusion, these results lead to a decreased dosage regimen in patients with severe renal failure.

Stress-induced renal functional alterations in normotensives.

This study was performed to assess changes in renal function accompanying cardiovascular responses to mental stress. Glomerular filtration rate (GFR, inulin clearance), renal plasma flow (RPF, PAH clearance), filtration fraction (FF), sodium excretion, and segmental sodium tubular reabsorption (lithium clearance) were measured in 15 normal volunteers during rest and stress. The psychological stress test used is based on a computerized version of the Stroop word color conflict test. Stress induced a significant (P less than .05) and sustained increase in blood pressure and heart rate. During stress, GFR and RPF did not change whereas FF increased significantly (P less than .05) and sodium excretion tended to decrease. The decrease in sodium excretion was due to a significant (P less than .05) increase in proximal reabsorption, which may be mediated by renal hemodynamic changes. The observed significant increase in FF suggests an increase in postglomerular arteriolar resistances, which may account for the increase in proximal sodium reabsorption through an alteration in peritubular Starling forces. In the long run, the stress-associated increase in sodium reabsorption may contribute to the development of hypertension.

Basal prostaglandin synthesis by the isolated perfused rat kidney.

In order to assess the main characteristics of the prostaglandin (PG) biosynthesis by the isolated perfused rat kidney, the urinary and venous outputs of PGE2, PGF2alpha, 6-keto-PGF1alpha and of thromboxane (Tx)B2 were followed during 120 min after an equilibration period of 30 min. Single pass kidneys were perfused with a Krebs-Henseleit solution added with Polygeline at a constant flow rate providing a perfusion pressure about 90 mm Hg. From the beginning of the study, major differences could be observed in the renal biosynthetic rate of the 4 PG studied which were mainly excreted into the venous effluent. During the perfusion, urinary and venous outputs of PGE2, PGF2alpha and of TxB2 remained stable whereas those of 6-keto-PGF1alpha sharply increased and were found inversely related to the glomerular filtration rate (r = -0.95; p n 0.001). Finally, the urinary and venous outputs of each of the four PGs studied were found positively related. It is concluded that the isolated perfused rat kidney is a valuable preparation for studying the biosynthesis of PGs and that, at least in thi model, the urinary excretion of PGs is a good index of their renal synthesis.

Magnesuria induced by thiazides and the influence of triamterene.

The effects on magnesium excretion of 4 short-term diuretic treatments (methyclothiazide 2 mg either alone or associated with increasing doses of triamterene) were evaluated in 8 normal volunteers and compared to spontaneous variations during placebo administration. The thiazide exerted a small but significant magnesuric effect, which was prevented only by the lowest dose (25 mg) of triamterene. Larger doses had no protective effect on thiazide-induced magnesuria. Independently of their absolute effects on magnesium excretion, all diuretics impaired the normal ability of the kidneys to compensate fully for the expected changes in magnesium reabsorption induced by extracellular volume contraction.

Nephrotic syndrome in procainamide induced lupus nephritis.

We report a case of the nephrotic syndrome occurring in a patient with procainamide induced LE. It was associated with bilateral pleural effusions, pericarditis, fever, positive LE cell preparation and a high titer of antinuclear antibodies. No anti-DNA antibodies were found. Renal biopsy showed mesangial proliferation with few IgM and C3 deposits and interstitial infiltrates; electron microscopy revealed subendothelial deposits. Clinical improvement occured after steroid therapy and there was no recurrence 24 months after withdrawal of prednisone.

Is erythropoietin treatment safe and effective in myeloma patients receiving hemodialysis?

Still few data are available on efficacy and safety of recombinant erythropoietin (rEPO) in patients with myeloma and end-stage renal failure (ESRF); two such hemodialysed patients are reported in whom only partial response was observed, despite iron, folic acid supplementation and, in one case, high doses of rEPO (320 IU/kg/week). Despite improvement in well being and no need of further transfusion, hemoglobin did not reach 80 g/l. One patient developed recurrence 4 weeks after starting rEPO. Patients with ESRF and myeloma should benefit from rEPO but particular attention should be paid to marrow proliferation.

Cyclosporin A-sensitive nephrotic syndrome preceding Hodgkin's disease by 32 months.

A 20-year-old man developed a massive nephrotic syndrome, rapidly complicated by pulmonary embolism and septicemia. Two renal biopsies taken 3 months apart showed minimal change glomerulonephritis. Treatment with prednisolone 1.5 mg/kg/day failed to induce a sustained remission, then monotherapy with cyclosporin A (CsA, 5 mg/kg/day) was started. Complete remission was obtained after 15 weeks. CsA was gradually tapered to 3 mg/kg/day. Twenty-two months after starting CsA, a routine examination disclosed a right sub-clavicular lymph node, of which histological examination showed a class 4 large cell Hodgkin's lymphoma. CsA was abruptly withdrawn and a polychemotherapy resulted in lymphoma remission after four courses. Ten months later, Hodgkin's disease is currently in remission and there is no relapse of proteinuria.

The nephrotic syndrome in adults aged over 60: etiology, evolution and treatment of 76 cases.

A study of the clinical, etiological and histological features of the nephrotic syndrome occurring in 76 adults aged over 60 was performed. Membranous nephropathy was the most frequent type (40%). 32% of the cases of membranous nephropathy were associated with another disease which was a malignant one in 22% of the cases. In 2 cases a renal vein thrombosis was associated with the malignant disease. Amyloidosis appeared to be the most frequent cause of the secondary nephrotic syndrome (13%), and was often associated with plasma cell dyscrasia. The study also showed the importance of lipoid nephrosis among elderly patients with the nephrotic syndrome (20%). Amongst these cases it is necessary to consider the association of minimal changes with a systemic disease, and the histological diagnosis of focal hyalinosis. Indeed the presence in elderly patients of arteriolar, interstitial and glomerular lesions of hyalinosclerosis makes interpretation difficult. With corticosteroid therapy complete remission was frequent in patients with lipoid nephrosis.

Comparison of hemostasis with two high-flux hemocompatible dialysis membranes.

Eight adults with chronic renal failure were dialyzed using polyacrylonitrile (AN 69) or polysulfone (PS) membranes with a high (HHR) or low (LHR) continuous non-fractionated heparin regimen--a total of either 90 or 50 IU/kg body weight. With the HHR, for a mean anti-Xa (aXa) activity of around 0.40 IU/ml, no plasma activation of coagulation was observed; fibrinopeptide A (FPA) was in agreement with the residual blood volume (RBV) and the state of the bubble trap, especially with the PS membrane. With the LHR, for a mean aXa below 0.21 IU/ml, there was only moderate activation of coagulation. The PS membrane gave different results from the AN 69 membrane, RBV values on the HHR and aXa being lower on both the HHR and LHR, with FPA values being regularly lower on the LHR. The decrease in plasma beta-TG on the LHR was more marked with the PS than with the AN 69 membrane due to loss on dialysis or adsorption, as shown by the arterio-venous difference. The increase in plasma PF4 was related to the effect of heparin. However, there was no platelet activation. On the LHR, platelet count and intraplatelet beta-TG and PF4 levels remained very stable. The two high-flux membranes were very hemocompatible and require only low doses of heparin, but the dialyzer with AN 69 membrane need its geometry improving.

[Course of renal function in malignant hypertension. Effect of treatment. Study of 30 cases followed for 5 to 18 years]. / Evolution des fonctions rénales dans l'hypertension artérielle maligne. Influence du traitement. Etude sur 30 cas suivis de 5 à 18 ans.

Renal insufficiency is the most frequent complication of malignant hypertension (MHT). The initiation of effective hypotensive treatment is generally followed by a rapid improvement of renal functions, but the long-term evolution has been only rarely studied. A group of 30 patients was retrospectively selected on the following criteria: Malignant hypertension: mean DBP 138 +/- 20 mmHg, hypertensive retinopathy stage III-IV; Early renal insufficiency: mean Inulin clearance (CIN) 66 +/- 26 ml/min, mean PAH clearance (CPAH) 364 +/- 161 ml/min; Clinical and functional follow-up ranging from 5 to 18 years. Among these patients, two groups were defined according to the quality of BP control: good or fair responders (GR) with a DBP always less than 110 mmHg, poor responders (PR) with a DBP occasionally greater than or equal to 110 mmHg. The results show in the two groups an improvement of CIN at 3 years, followed by a stabilization then a decrease after the 6th year. However the early improvement is significantly lower in PR. Despite similar initial values (GR = 54.7 +/- 31.3; PR = 51.4 +/- 13.2), CIN remains always lower in PR (at 9 years = GR 72.4 +/- 30.6; PR 56.0 +/- 19.8). During the first 3 years, CPAH increases in GR, whereas it decreases in PR, resulting in significantly different values at 3 years. At 9 years, CPAH remains improved in GR (329.1 +/- 109.3 vs 281.7 +/- 173.8 initially) but decreased in PR (256.0 +/- 166.9 vs 307.3 +/- 119.5 initially). The parallel improvement of CIN and CPAH in GR confirms a favorable effect of BP control on early vascular lesions.(ABSTRACT TRUNCATED AT 250 WORDS)

[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.

[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)

[Renal function during stress in hypertensive patients]. / Fonction rénale au cours du stress chez l'hypertendu.

In this study, the measurement of blood pressure values, glomerular filtration rate (GFR, inulin clearance), renal plasma flow (RPF, PAH clearance), the filtration fraction (GFR/RPF), natiuresis and proximal sodium resorption (measured by lithium clearance), was performed at rest and during a computerised psychological stress test (Stroop word color conflict test) in 12 normotensive and 10 hypertensive subjects. The stress induced in the normotensives induced a significant increase of the filtration fraction and proximal tubule sodium resorption. The hypertensive kidney, submitted to a basal vasoconstriction greater than that of the normotensive kidney, does not react to stress. In the hypertensives, proximal sodium resorption occurs but is not significantly greater than at rest. In the long-term, the increased sodium resorption during stress could contribute to the development and the persistence of essential hypertension.

Pharmacokinetics of milnacipran in renal impairment.

The pharmacokinetics of a single 50 mg dose of milnacipran, a new non tricyclic antidepressant drug, were compared in 8 chronic renal failure subjects (Clc(reat) between 9 to 84.5 ml.min(-1)) and in 6 healthy volunteers. Concentrations of unchanged (F2207 racemate and F2695 and F2696, enantiomers) and glucuroconjugated drug (main metabolite) were measured using HPLC and GC-MS. As for drugs mainly eliminated via renal route, the pharmacokinetics of milnacipran were markedly affected by impaired renal function with the elimination half-life of severely impaired subject being approximately three times that of the control group. Milnacipran apparent total clearance and renal clearance were positively correlated with glomerular filtration rate, while non-renal clearance and apparent volume of distribution were unaffected by renal impairment. Plasma concentrations of the glucuroconjugate were gradually increased in plasma, while its total urine excretion remained unchanged. As for the racemate, pharmacokinetics of each enantiomer were modified by renal failure, although, as predictable from its higher renal clearance value, it was more marked for F2696 than for F2695. Considering that modifications were shown to be proportional to the degree of renal impairment and that milnacipran presents low variability, the necessary dose adjustment is therefore easy to predict.

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.

[Role of magnesium in the physiopathology and treatment of calcium renal lithiasis]. / Place du magnésium dans la physiopathologie et le traitement de la lithiase rénale calcique.

The inhibitory effect of magnesium on the first stages of renal calcium stone formation is modest in vitro and more pronounced in experimental in vivo studies. Magnesium deficiency has not yet been convincingly demonstrated in man. However, urinary magnesium concentrations are abnormally low in relation to urinary calcium concentrations in more than 25% of patients with kidney stones. A supplementary magnesium intake corrects this abnormality and prevents the recurrence of stones. Magnesium seems to be as effective against stone formation as diuretics. The modalities of magnesium therapy still have to be determined and its results to be confirmed. Magnesium, possibly added to drinking water, may well play a role in the primary prevention of renal calcium stones.