Combined liquid chromatography/radioimmunoassay with improved specificity for serum digoxin

This method for assaying digoxin in serum with improved specificity combines small-column extraction of serum, "high-performance" liquid chromatography, and RIA of the eluted fractions. Analytical recoveries of 1.0, 0.5, and 0.1 microgram/L standards were 95%, 93%, and 84%, respectively. The CVs for duplicates and replicates of sera with values of 0.5 to 1 microgram/L were 4 to 6%. Fifty-nine sera from 50 patients receiving digoxin were so studied. All digoxin metabolites appear to cross react with antibody to digoxin to various degrees. The most polar metabolites were quantitatively the most important, their average cross reactivity being 33%. For eight patients the value for digoxin by the present method was less than 60% of the RIA value. Sera from nine patients not taking digoxin but with falsely high digoxin values were also studied by the present method. The digoxin peak was well resolved from those for (a) digoxin metabolites (except dihydrodigoxin), (b) digitalis-like factors in neonates and in patients with renal failure or combined hepatic and renal failure, and (c) two cross reacting drugs and their metabolites.     

Extraction of digoxin and its metabolites from urine and their separation by Sephadex LH-20 column chromatography.

The efficiency with which serveral solvent systems extract digoxin and its metabolites from urine has been studied and column chromatography using Sephadex LH-20 has been used to separate digoxin and its metabolites. These procedures have been evaluated and used to study the excretion of 3H-digoxin-12alpha and its metabolites in urines collected serially in 7 patients and in bile in one. The percentage of the radioactivity excreted as metabolites in urine and bile was found to reach a peak within the first day and then to gradualy decline to minimal amounts in patients with advanced renal failure as well as those with good renal function. The maximum percentage measured as metabolites in 4 patients with the most advanced renal failure was 10%.     

Analytical performance of a monoclonal digoxin assay by dry chemistry on the Vitros 950

Digoxin assay in plasma/serum samples is used for therapeutic measurements as a guide to clinical management of cardiac patients. A thin dry film multilayer monoclonal immunoassay for digoxin, Vitros, was evaluated for analytical performance. The effect of digoxin-like immunoreactive substances (DLIS) was studied assaying plasma samples taken from 100 renal disease patients, 62 hepatic disease patients and 40 pregnant women not receiving digoxin. The Vitros digoxin assay was compared with the AxSym digoxin II assay using plasma samples from 180 patients treated with digoxin. The results revealed satisfactory precision and accuracy for therapeutic drug monitoring purposes: the coefficient of variation (CV%) was lower than 5%; results for dilutions were linear in the range 0.4-3.9 microlg/L and mean analytical recovery was 105%. Measurable DLIS concentrations were observed in 29% of hepatic disease patients and in 7% of renal disease patients with apparent digoxin concentration ranging from 0.4 to 0.75 microg/L. The incidence of DLIS was comparable to that observed with AxSym digoxin II. Comparative results from patient samples gave a regression line equation: Yvitros 950=0.96XAxym +0.14, r=0.89. The data revealed a mean difference of 0.09+/-0.26 microg/L significantly greater than zero (p=0.02). We concluded that Vitros digoxin assay for precision, accuracy and extent of DLIS interference may be a good method for therapeutic drug monitoring; care needs to be taken since assay results generated by Vitros and AxSym analysers are not necessarily interchangeable.     

The effect of parenteral feeding on the metabolism of arachidonic acid in patients with cancer of the esophagus and the stomach

Blood plasma and erythrocyte level of arachidonic acid (C20:4) and blood plasma level of its two metabolites (6-keto-PGF1 alpha and TXB2) have been investigated in 24 patients with esophageal and gastric cancer. In the preoperative period and during 8-10 days postoperatively 12 patients were on "glucose" energy supply (group I) and 12 patients were on "lipid" energy supply (group II). Daily calorie intake was 30-35 kcal/kg. In the preoperative period Lipofundin-S infusions produced a significant increase in C20:4 blood plasma and erythrocyte levels. An increase in TXB2 concentration was accompanied by a certain increase in 6-keto-PGF1 alpha content. At the same time in group I parenteral feeding caused no significant changes in the above parameters. Surgical trauma and anesthesia caused a considerable increase in 6-keto-PGF1 alpha blood plasma level in both groups (P less than 0.05), with a certain decrease in TXB2 level (P greater than 0.05). In the postoperative period, unlike "glucose", "lipid" energy supply stabilized C20:4 content in the erythrocyte membrane and favourably affected 6-keto-PGF1 alpha/TXB2 ratio. This is confirmed by a considerable increase in 6-keto-PGF1 alpha/TXB2 ratio, which in the course of the postoperative period was significantly higher in group II than in group I.     

Conservative management with percutaneous intervention of major blunt renal injuries

This retrospective study assessed the results of treatment of patients with renal trauma to determine the optimal management (conservative or surgical) for patients with grade III renal injuries. During the past 12 years 108 patients (including 43 children) with renal injuries were managed: 43 had grade I injuries (renal contusion), 33 had grade II (minor laceration), 31 had grade III (major laceration), and 1 had grade IV (pedicle injury). All patients with grades I and II injuries were successfully managed conservatively. The patient with renal pedicle injury underwent uneventful nephrectomy. Nineteen patients with grade III injuries (including 5 patients with shattered kidneys and 3 patients with polar avulsion) were managed conservatively, and 2 developed progressively enlarging urinomas that required percutaneous drainage with complete resolution. No patient in this group developed perinephric abscess or urinary fistulae, and no delayed nephrectomy was necessary. Long-term follow-up of 7 patients in this group, including 3 with shattered kidneys and 2 with polar avulsion, showed that none have developed hypertension. Twelve patients with grade III injuries were managed surgically. Six (50%) patients underwent total (4 patients) or partial (2 patients) nephrectomy. In 6 patients, the surgical intervention was only open drainage of the perinephric collection and/or parenchymal suturing. It was concluded that conservative management with timely percutaneous or endoscopic intervention in patients with major renal injuries results in minimal loss of renal tissue without significant late complications.     

Bile salts as endogenous digitalis like factors

Digitalis-like factors were assayed by radioimmunoassay of digoxin in 6 bile samples obtained from patients at autopsy and in plasma from three patients with combined hepatic and acute renal failure. None of the patients received digoxin. Digitalis like factor values in bile samples were 23 to 85 nmol digoxin equivalents/1. Bile salt concentrations ranged from 38-104 mmol/l in the bile and 28-184 mumol/l in the plasma of these subjects. Bile, plasma digitalis like factor extracts and bile salt standards (0.1-3 mM) showed concentration dependent displacement of [125I]-digoxin from digoxin antibody, inhibition of hog brain Na,K-ATPase and displacement of [3H]-ouabain from Na,K-ATPase. The concentration-displacement curves suggest that bile salts could account for 50-79% of the total digitalis like factors in the six bile samples and 2-7% in the plasma of the three patients. High performance liquid chromatographic fractionation of a bile sample showed digitalis like factor peaks co-eluating with standards of tauro- and glycocholate, tauro- and glycochenodeoxycholate and tauro- and glycodeoxycholate. These bile salt peaks accounted for 78% of the total digitalis like factors in all high performance liquid chromatographic peaks in bile, but only 7% of the total digitalis like factor activity in all high performance liquid chromatographic peaks in an extract of plasma from one of the patients with hepatic and renal failure. The bile salts appear to be examples of endogenous digitalis like compounds which do not act by simple competitive ligand binding to antidigoxin antibody and Na,K-ATPase. They make an important contribution to digitalis like factor activity in bile, but not in plasma.     

Relationship between urinary concentrating ability, arginine vasopressin in plasma and blood pressure after renal transplantation

Arginine vasopressin (AVP) and serum osmolality (Sosm) were determined in plasma before and after a 24-h period of water deprivation in 19 patients with post-renal-transplant hypertension (group I), 14 patients with normal blood pressure after renal transplantation (group II), and 16 healthy control subjects (group III). Urine was collected in four periods of 6 h each for measurement of urine volume (V), urine osmolality (Uosm) and tubular capacity for reabsorption of water (Tc water). AVP and Sosm increased significantly in all groups. The AVP levels were the same in groups I and II, but higher in group I than III both before and after water deprivation. In group II, AVP was higher than in group III only after water deprivation; V was significantly reduced in all groups. In groups I and II, V, Tc water and Uosm were the same. In group III, V was significantly lower than in groups I and II in the last three 6-h periods, and in group III, Tc water was higher in the first 6-h period than in groups I and II. There was a significant positive correlation between AVP and Sosm in all groups. In conclusion, renal water excretion cannot be reduced as rapidly and to the same degree in renal transplant recipients as in control subjects because of a decreased renal capacity for reabsorption of water. The higher AVP level in the transplant recipients may be a compensatory phenomenon for the decreased responsiveness of the renal collecting ducts in the transplanted kidneys. The sensitivity of the osmoreceptors to changes in osmotic stimuli was normal.     

Comparison of four digoxin immunoassays with respect to interference from digoxin-like immunoreactive factors

Objectives: Comparison of a new monoclonal digoxin assay with three polyclonal digoxin assays for their cross-reactivity to digoxinlike immunoreactive factors (DLIF) and digoxin metabolites.

Design and Methods: Sixty-:six nondigitalized patient samples from 5 different groups: neonates, women in 3rd trimester pregnancy, and patients with liver or renal diseases, or undergoing organ transplants, and 139 samples from digoxin-treated patients of 4 categories (hospital sick, liver, renal, and outpatients) were compared in 4 different digoxin assays: (a) ACS™ Digoxin (ACS) developed for the automated chemiluminescent Ciba Corning ACS 180^® system, (b) Baxter Stratus™ (Stratus, a fluoroimmunoassay), (c) Ciba-Corning Magic^TM (Magic, a radioimmunoassay), and (d) an in-house radioimmunoassay (RIA). The ACS^TM and RIA were also compared for their cross-reactivity to four principal digoxin metabolites.

Results and Conclusion: Among the nondigitalized specimens, no significant DLIF interference was found for all 4 assays among the pregnant women or liver and transplant patients. However, the neonates registered high DLIF interference with Magic™ and RIA, but none for ACS™ or Stratus™. DLIF interference in renal samples was highest in the Magic assay and lowest in RIA. Among the specimens with digoxin, a higher number of discrepant samples were found from the sick patients than from outpatients. In 75% of such discrepant samples, the ACS™ result was less than other assay results, suggesting DLIF as the probable cause. The two assays differed most in their cross-reactivity to the deglycated metabolites, digoxigenin and its mono-digitoxoside.     

Functional response of healthy and diseased glomeruli to a large, protein-rich meal.

Differential solute clearances and hormone assays were used to characterize the effect of a large, protein-rich meal (1.5 g/kg) on glomerular function in 12 healthy volunteers (group I) and 12 patients with chronic glomerular disease (group II). Changes from baseline during 3 h after the meal included an elevation of plasma osmolality, progressive urinary concentration, and increasingly positive fluid balance. Plasma renin activity and arginine vasopressin levels (measured in group II only) increased significantly. Nevertheless, the rate of peak postmeal renal plasma flow became elevated by 13 and 33% in groups I and II, respectively. Corresponding peak increases in postmeal glomerular filtration rate exceeded baseline by 10 and 16%. In the proteinuric subjects of group II the fractional clearances of albumin, IgG and uncharged dextrans in the radius interval 36-54 A, declined significantly after the meal. A similar depression of the fractional dextran-clearance profile was observed also in group I. Applying the fractional clearances of relatively permeant dextrans (radii less than or equal to 44 A) to a model of hindered solute transport through an isoporous membrane, we estimate that transmembrane hydraulic pressure difference increased by 12% in group I and by between 0 to 12% in group II after protein ingestion. We conclude (i) that oral protein ingestion increases glomerular ultrafiltration pressure and rate in both normal and diseased glomeruli, (ii) that this hemodynamic response may be mediated in part by the glomerulopressor hormones angiotensin II and arginine vasopressin, and (iii) that the foregoing hemodynamic changes exert no acute adverse effect on glomerular barrier size-selectivity.     

Pharmacokinetics of meropenem in patients with various degrees of renal function, including patients with end-stage renal disease.

The pharmacokinetics of meropenem were studied after intravenous infusion in 13 patients grouped according to the impairment of their renal function. Creatinine clearance (CLCR) was greater than 50, 50 to 30, and less than 30 ml/min in groups I, II, and III, respectively. Two other groups, groups IV and V, each comprising four patients with end-stage renal disease (CLCR, < 5 ml/min), were also studied, the former on days off of hemodialysis and the latter on days of hemodialysis. The elimination half-lives of meropenem were 1.54 +/- 0.70 h in group I patients, 3.36 +/- 1.02 h in group II patients, and 5.00 +/- 1.05 h in group III patients. Cumulative urinary excretion accounted for 48.5% of the dose in group I patients and decreased progressively with a decline in renal function. Hemodialysis shortened the elimination half-life of meropenem from 7.0 h to 2.9 h. H-4295, the main metabolite of meropenem, had a peak level in plasma of 0.5 to 1.0 h in patients with renal failure. The level of H-4295 decreased with hemodialysis. The dosing interval of meropenem should be prolonged in a regular proportion to the decline in CLCR (12 h in group II patients and 24 h in group III patients). In patients receiving hemodialysis, dosing after each hemodialysis session is recommended.     

Phenobarbital-Induced Alterations in Vitamin D Metabolism

The metabolic fate of intravenously injected vitamin D(3)-1,2-(3)H (D(3)-(3)H) was studied in two normal individuals on chronic phenobarbital therapy. Silicic acid column chromatography of lipid-soluble plasma extracts obtained serially for 96 hr after D(3)-(3)H injection demonstrated a decreased plasma D(3)-(3)H half-life and increased conversion to more polar metabolites. The polar metabolites formed included several with chromatographic mobility similar to known biologically inactive vitamin D metabolites and one with chromatographic mobility identical to 25-hydroxycholecalciferol. Disappearance of this latter material was also accelerated. A child with rickets and a normal volunteer studied before and after a 2 wk course of phenobarbital therapy demonstrated similar alterations in D(3)-(3)H metabolism. When liver microsomes from 3-wk-old Sprague-Dawley rats treated with phenobarbital were incubated with D(3)-(3)H, polar metabolites were produced with chromatographic mobility similar to the plasma D(3)-(3)H metabolites from phenobarbital-treated humans. Similar incubations employing 25-hydroxy-cholecalciferol-26-27-(3)H as the substrate also demonstrated an increased conversion to polar metabolites. The data suggest that the reported increased incidence of osteomalacia observed in patients on chronic anticonvulsant therapy may be the result of an accelerated conversion of vitamin D and its active metabolite, 25-hydroxycholecalciferol, to polar metabolites by druginduced liver microsomal enzymes.     

Substantial pharmacokinetic interaction between digoxin and ritonavir in healthy volunteers

BACKGROUND: Ritonavir is a potent in vitro inhibitor of several cytochrome P450 isozymes and ABC transporters including the efflux pump P-glycoprotein (P-gp). This study assessed the effect of repetitive ritonavir administration on digoxin distribution and total and renal digoxin clearance as a marker for P-gp activity in vivo. METHODS: In a randomized, placebo-controlled crossover study, 12 healthy male participants received oral ritonavir (300 mg twice daily) for 11 days. With the assumption that ritonavir steady state had been reached, 0.5 mg digoxin was given intravenously on day 3. Digoxin concentrations were determined in plasma and urine by radioimmunoassay, and plasma ritonavir concentrations were determined by liquid chromatography-tandem mass spectrometry. Digoxin kinetics was estimated by compartmental and noncompartmental analyses, by use of the area under the plasma concentration-time curve, and the corresponding digoxin amount excreted into urine was used for digoxin clearance calculations. RESULTS: Ritonavir significantly (P <.01) increased digoxin area under the plasma concentration-time curve from time 0 to infinity by 86% and its volume of distribution by 77% and decreased nonrenal and renal digoxin clearance by 48% and 35%, respectively. Digoxin terminal half-life in plasma increased by 156% (P <.01). CONCLUSION: This inhibition of renal digoxin clearance is likely caused by ritonavir inhibition of P-gp. Its extent is considerable and similar to the effect of other potent P-gp inhibitors on digoxin disposition such as quinidine. These findings may, therefore, indicate that the pharmacokinetics of P-gp substrates sharing the renal tubular elimination pathway will be affected when combined with therapeutic doses of ritonavir in antiretroviral treatment regimens. In addition and contrarily to quinidine, these data indicate that ritonavir promotes digoxin distribution in the body.     

Multifactorial evaluation of blood pressure fall upon hospitalization in essential hypertensive patients

1. Studies were prospectively performed on 72 hospitalized patients with essential hypertension. Blood pressure was normalized within 1 week of admission in 33 patients (group I), but did not decrease in 39 patients (group II). To determine the factors that differentiate group I from group II, cardio-renal haemodynamic and endocrinological indices were evaluated using multivariate analysis. 2. Systolic, diastolic and mean blood pressures on admission were higher in group II (P less than 0.001), whose optic fundi showed more severe changes (P less than 0.001). Although group II had greater left ventricular posterior wall thickness (P less than 0.02), left ventricular mass index (P less than 0.05) and systemic vascular resistance (P less than 0.01) on echocardiography, their cardiac index and ejection fraction were comparable with those of group I. 3. Renal blood flow (P less than 0.05) and glomerular filtration rate (P less than 0.01) were lower in group II than in group I. Renal vascular resistance was more elevated (P less than 0.01) in group II than in group I. 4. After severe sodium depletion and ambulation, group I showed a greater increase in plasma noradrenaline and adrenaline (P less than 0.05). On multivariate analysis, those with lower systolic blood pressure, better renal function and more reactive sympathetic nervous system were discriminated as group I. 5. These data suggest that group I patients have lower systolic blood pressure on admission, greater sympathetic reactivity and better renal function, all of which contribute to their spontaneous blood pressure fall after admission.     

Cefsulodin pharmacokinetics in patients with various degrees of renal function

The pharmacokinetics of cefsulodin were characterized in 19 patients with different degrees of renal function after a single 500-mg, 30-min intravenous infusion. Six subjects had a creatinine clearance (Clcr) of greater than 100 ml min-1 (group I), eight had a Clcr of between 12 and 42 ml min-1 (group II), and five had a Clcr of less than 10 ml min-1 (group III). Nine plasma and four urine samples were collected in the first 36 h. The plasma concentration-time data were fitted to a two-compartment open model. The mean beta-phase half-life was 1.77, 6.37, and 10.12 h in groups I, II, and III, respectively. A significant decline in plasma clearance (Clp) was also noted between the three groups: 136 to 49.6 to 27.2 ml min-1 in groups I, II, and III, respectively. Steady-state volume of distribution was 0.26 liter kg-1, regardless of renal function. The observed linear relationship between Clp and Clcr (Clp = 24.09 + 0.765 Clcr; r = 0.9566) can be utilized to revise dosage schedules for patients with any degree of renal impairment. The nonrenal clearance of cefsulodin was also noted to be significantly lower in groups II and III than in group I. Further investigations will be necessary to elucidate the mechanism(s) responsible for the decrease in the nonrenal clearance of cefsulodin.     

Influence of ACE Inhibition on Fluid Metabolism in Chronic Heart Failure and Its Pathophysiologic Relevance

BACKGROUND: In congestive heart failure with water retention, subtraction of body fluid by ultrafiltration causes greater diuresis and clinical improvement in patients who are angiotensin-converting enzyme (ACE)-inhibited, suggesting an influence of ACE inhibitors on fluid metabolism. METHODS AND RESULTS: Patients with moderate congestive heart failure were subjected to ultrafiltration (around 2000 mL) and followed up for 3 months. Usual outpatient therapy, consisting of digoxin, furosemide, and ACE inhibitors (18 patients, group A) and of digoxin and furosemide only (18 patients, group B), was continued throughout the trial. Hemodynamics, renal function, body fluid and electrolytes, plasma norepinephrine, renin activity, aldosterone, and plasma volume were monitored. At 30 and 90 days after ultrafiltration, hormones, renal function, functional capacity (based on cardiopulmonary tests), and extravascular lung water (chest radiograph score) were determined. Soon after ultrafiltration, body weight, plasma volume, and diuresis were reduced (hypovolemia) and hormones were raised (reaction to hypovolemia). In the next 4 days, all these variables reverted to the pre-ultrafiltration values in group B; in group A diuresis and plasma volume recovered, body weight was still reduced, and hormones became lower than baseline. These changes persisted in the next 3 months. An early reduction of extravascular lung water continued long term in group A only, associated with increase of exercise tolerance time and oxygen uptake and decrease of the dead space/tidal volume ratio. CONCLUSIONS: In congestive heart failure, ACE inhibition persistently prevented fluid accumulation once the excess of body fluid had been withdrawn with a nonpharmacologic method, resulting in sustained improvement in functional capacity. Reduction in circulating norepinephrine, aldosterone, and renin did not seem to be the cause but the consequence of this action, whose mechanisms remain undefined.     

Effects of amiloride on plasma and total body potassium, blood pressure, and the renin-angiotensin-aldosterone system in thiazide-treated hypertensive patients

Total body potassium content, plasma potassium concentration, blood pressure, and plasma concentrations of renin, angiotensin II, and aldosterone were measured in patients with essential hypertension after a run-in period of 8 wk on a regimen of hydrochlorothiazide (median dosage 75 mg/day). Patients were then randomly assigned to continued hydrochlorothiazide therapy (group I) or to receive adjunctive treatment with amiloride (group II, median dosage 15 mg/day or 5 mg per 25 mg hydrochlorothiazide) for the following 3 mo. There were no changes in group I patients during 3 mo on hydrochlorothiazide in plasma potassium, total body potassium content, or the renin-angiotensin-aldosterone system. Blood pressure was also unchanged. In group II patients addition of amiloride to hydrochlorothiazide induced a rise in plasma and total body potassium of approximately 15% and 4%. The potassium-retaining effect was maintained throughout the 12-wk period, although the maximal changes were observed after 8 wk of treatment. Supine blood pressure did not change, but there was a significant decrease in standing systolic blood pressure. There was a marked rise in plasma concentrations of renin, angiotensin II, and aldosterone.     

Pharmacokinetics of sparfloxacin in patients with renal impairment.

The pharmacokinetics of sparfloxacin were studied in 14 renal failure patients (group I, 7 with creatinine clearance of > 10 to 30 ml/min; and group II, 7 with creatinine clearance of < or = 10 ml/min) after a single oral dose of 400 mg. Plasma and urine samples were collected up to 144 h postdosing for determination of parent and total (parent-plus-glucuronide-conjugated) sparfloxacin levels, by high-pressure liquid chromatography assay and UV detection. The elimination of the drug in patients compared with that in healthy volunteers was markedly impaired. The mean elimination half-lives of sparfloxacin were 34.9 and 38.5 h in group I and group II, respectively, versus 19.1 h in healthy volunteers. Conjugated drug half-lives were 23.7, 35.0, and 15.3 h, respectively. The renal clearance of the drug was markedly reduced in the patients, with values of 6.8, 4.8, and 21.2 ml/min determined for group I, group II, and healthy subjects, respectively, for parent sparfloxacin and with values of 31.5, 14.0, and 327 ml/min for conjugated sparfloxacin. The nonrenal clearance of sparfloxacin was moderately, but not significantly, decreased in group II renal failure patients. No difference between the two groups of patients was detected in sparfloxacin levels in plasma. A significant relationship between pharmacokinetic parameters and creatinine clearance was observed only for renal clearance of parent or conjugated sparfloxacin.     

Pharmacokinetics of cefonicid in uraemic patients

Eight subjects with normal renal function and 20 uraemic patients with various degrees of renal insufficiency were given a single iv dose of 1.0 g cefonicid, as a bolus injection. Five groups of subjects were studied: group I, GFR greater than 80 ml/min, group II 30 less than GFR less than 80 ml/min, group III 10 less than GFR less than 30 ml/min, group IV GFR less than or equal to 10 ml/min and group V, haemodialysis patients. Cefonicid concentrations in plasma and urine were measured by microbiological assay (MA) and HPLC method. Results were similar with the two techniques. The mean peak plasma levels were 200-300 mg/l and the apparent volume of distribution was 0.18-0.20 1/kg for all patients. The elimination half-life (T 1(2) beta) increased as renal function decreased: 5.31 +/- 1.30 h in healthy subjects and 58.92 +/- 12.38 h in patients with end-stage renal disease. Urinary elimination of cefonicid was inversely related to the degree of renal impairment: 83% of the dose in 24 h in normal subjects and 13.6% of the dose in patients with severe renal failure. Total body clearance decreased from 23.9 +/- 3.4 ml/min/1.73 m2 (group I) to 1.9 +/- 0.2 ml/min/1.73 m2 (group V). Renal clearance fell from 19.0 +/- 4.9 ml/min/1.73 m2 (group I) to 1.0 +/- 0.4 ml/min/1.73 m2 (group IV). The fractional clearance and the non renal clearance were similar in normal subjects and in uraemic patients. Cefonicid is not haemodializable because of its high protein binding. Dosage of cefonicid should be adjusted according to the degree of renal impairment. Supplemental doses are not necessary after haemodialysis.     

Renal effects of cardiopulmonary bypass in the elderly

Cardiopulmonary bypass is widely believed to be injurious to renal function. The unknown consequences of renal dysfunction with modern techniques of bypass in the elderly caused us to examine creatinine clearance and the excretion of sensitive marker proteins in older adult patients undergoing CABG. Thirty male patients were divided into three groups: group I with an age up to 60 years, group II with an age between 61 and 70 years, inclusive and group III 71 years and over. Serum creatinine and urea, creatinine clearance, and alpha1-microglobulin (alpha1-MG), N-acetyl-beta-D-glucosaminidase (NAG), Tamm-Horsfall protein (TH) and immunoglobulin G (IgG) were all measured daily, pre- and postoperatively. Creatinine clearance remained lower in the older patients without significant differences. Raised excretion rates of alpha1-MG, and IgG were seen after CPB. The increase in alpha1-MG and NAG during the postoperative period revealed tubular damage in all elderly patients. Measurements of alpha1-MG, NAG and IgG represent useful supplements to standard clinical tests for recognizing early and differentiated changes in renal function.     

A method for the study of cation transport in vivo: effects of digoxin administration and of chronic renal failure on the disposition of an oral load of rubidium chloride

In order to study cation transport in vivo we have measured the changes in plasma and intra-erythrocytic rubidium concentrations following an oral load of rubidium chloride. The changes in plasma rubidium concentration are related to the distribution of rubidium to all the body tissues and the changes in intra-erythrocytic rubidium concentrations provide an example of rubidium uptake by one particular tissue. In eight healthy volunteers pretreatment with a loading dose of digoxin (20 micrograms/kg) enhanced the rise in plasma rubidium concentrations and attenuated the rise in intra-erythrocytic rubidium concentrations after the oral load of rubidium chloride. Ten patients with chronic renal failure, compared with a well-matched control group, were found to have changes similar to, but more marked than, those caused by digoxin, i.e. a much greater rise in plasma rubidium concentrations and a much smaller rise in intra-erythrocytic rubidium concentrations, after the oral load of rubidium chloride. These findings are consistent with wide-spread reduction in Na+, K+-ATPase activity in subjects who have taken a loading dose of digoxin and patients with chronic renal failure. They are, therefore, consistent with the findings of previous studies in vitro and show that it is possible to demonstrate changes in cation transport in vivo.