Effect of furosemide on the renal excretion of digoxin

Digoxin serum and urine levels were determined by radioimmunoassay in 6 subjects (4 patients with heart disease and 2 volunteers without heart disease) who had been maintained on oral digoxin (0.25 or 0.5 mg daily). Observations were made during a 3-day control period and then during 8 days of concomitant digoxin and oral furosemide (40 mg daily) therapy. Serum digoxin levels determined 10 and 24 hr after each dose of digoxin averaged 1.2+/-0.1 ng/ml (M+/-SE) during control and 1.3+/-0.1 during the last 3 days on digoxin and furosemide. The daily urinary excretion of digoxine averaged 51+/-6% of the oral dose during control and 52+/-6 during the entire period of furosemide administration. The renal clearance of digoxin and creatinine averaged 94+/-7 and 87+/-11 ml/min, respectively, during control; corresponding values were 88+/-8 and 85+/-9 for urine collections demonstrating a distinct diuretic effect of furosemide and 87+/-8 and 75+/-10 for urine collections not demonstrating such an effect during diuretic therapy. The results suggest that the diuretic effect of furosemide does not significantly affect the excretion of digoxin     

Effect of intravenous furosemide on the renal excretion of digoxin

The effect of an 80-mg intravenous dose of furosemide on the urinary excretion of digoxin was determined in three adult men with normal renal function, each of whom was taking 0.25 mg digoxin daily on a chronic basis. On two separate days, serum samples were taken and urine was collected every 2 hours over an 8-hour period for determination of digoxin, creatinine, calcium, and sodium concentrations. On the first day of study, a saline bolus was given intravenously, and on the second day, furosemide was given. In all subjects, urinary digoxin excretion increased after furosemide in direct proportion to the increase in urine volume. No consistent correlation was seen between digoxin excretion and creatinine, calcium, or sodium output. No significant changes in serum digoxin were found in this active study. These results are consistent with the hypothesis that increasing glomerular filtration rate or total urine volume increases the renal excretion of digoxin and may result in increased total urinary output of this glycoside.     

Experience with once daily dosing of gentamicin: considerations regarding dosing and monitoring

Plasma concentrations of gentamicin following a fixed dose of 240 mg once daily to patients with normal renal function were measured. The purpose was to establish guidelines to achieve a sufficiently high peak concentration with an appropriately low risk of accumulation. In 40 patients, 1-hour concentrations of plasma gentamicin had a median of 9.3 mg/l (range: 4.5-19.0 mg/l) and 9.7 mg/l (range: 3.6-14.6 mg/l) on days 1 and 3 of gentamicin treatment, respectively. Thirty-nine patients had 1-hour concentrations > 5 mg/l. The 1-hour concentrations varied considerably intra- and interindividually but showed a significant inverse correlation with body weight, surface area and the estimated endogenous creatinine clearance. The plasma gentamicin elimination half-life correlated significantly with age and inversely with body weight and creatinine clearance. There was no increase in the mean plasma creatinine from day 0 to day 4. No patients showed signs of nephrotoxicity, although 2 patients, both elderly and with low body weight, showed signs of beginning gentamicin accumulation. In conclusion, gentamicin treatment with the dose of 240 mg once daily in 3 days to adults with normal kidney function generally does not require adjustment or monitoring. However, the dose should be increased in young patients with an excessive body weight, and decreased doses are needed for old and underweight patients. Monitoring of trough plasma gentamicin concentration is not necessary with treatment duration of 3 days or less.     

Adjustment of magnesium sulfate infusion rate in patients with preterm labor

OBJECTIVE: Our purpose was to investigate factors that might influence serum magnesium levels during intravenous magnesium sulfate tocolytic therapy. STUDY DESIGN: Thirty-three women receiving magnesium sulfate for preterm labor participated in this prospective, observational study. Gestational ages were 24 to 34 weeks. Four groups of women were identified according to the maintenance magnesium infusion rate required for arresting preterm labor after 5 g of therapy induction: 1.5, 2, 2.5, and 3 g/h. Serum magnesium samples were drawn after a predefined period of at least 18 hours of arrested preterm labor, at a minimum of every 6 hours. Variables examined included serum albumin; serum protein; serum ionized calcium; serum creatinine; creatinine clearance; 24-hour urine output; maternal height, weight, body surface area; and body mass index. RESULTS: By use of a multivariate stepwise regression model we identified four variables that independently and significantly contributed to the model: magnesium infusion rate (P < .001); total serum protein level (P < .001); serum creatinine level (P = .009); and maternal weight squared (P = .026). Seventy-two percent of the variance was accounted for by use of these parameters. A predictive linear model, developed to relate these factors, produced the following formula: Suggested magnesium infusion rate = 0.89 x Serum magnesium concentration (mg/dL) - 3.16 x Serum creatinine (mg/dL) - 0.66 x Serum total proteins (g/dL) + 0.0001 x (maternal weight)2 (kg) + 2.30. CONCLUSIONS: Serum creatinine, serum protein, and maternal weight can be used to adjust the dose of magnesium sulfate in patients with premature labor to achieve therapeutic serum levels of magnesium more rapidly and safely.     

Urinary creatinine excretion in the ICU: low excretion does not mean inadequate collection

BACKGROUND: It has been assumed that a urinary creatinine excretion rate of less than 10 mg/kg per day means an inadequately collected urine sample. OBJECTIVE: To determine the frequency of a urinary creatinine excretion rate of less than 10 mg/kg per day in intensive care unit patients with an adequately collected urine sample. METHOD: In a prospective study of creatinine excretion rates, 24-hour urine samples were evaluated for urinary creatinine in 209 critically ill patients with indwelling Foley catheters. Patients from three adult intensive care units in New York City were divided into two groups. Group 1 patients excreted less than 10 mg/kg per day of urinary creatinine, and group 2 patients excreted at least 10 mg/kg per day. Groups 1 and 2 were first evaluated by dividing the creatinine excretion data by actual body weight. Since actual body weight may overestimate body weight in the critically ill patient, data from groups 1 and 2 were also evaluated using lean body weight. RESULTS: Urinary creatinine excretion was less than 10 mg/kg per day in 36.8% of patients using actual body weight and 29.7% of patients adjusted for lean body weight. The average age of patients in group 1 was 74 +/- 17 years for both actual body weight and lean body weight. The average age of group 2 patients was 60 +/- 19 years for actual body weight and 62 +/- 19 years for lean body weight. There was a significant difference in age between group 1 and group 2 patients for both actual body weight and lean body weight. The proportion of female vs male patients with reduced creatinine excretion was significantly greater, whether the actual body weight or lean body weight adjustment was used. CONCLUSIONS: A urinary creatinine excretion rate of less than 10 mg/kg per day occurs in about one third of critically ill patients, who are more likely to be elderly and female.     

Vancomycin pharmacokinetics in neonates and infants: a retrospective evaluation

OBJECTIVE: To evaluate the frequency with which current loading and maintenance vancomycin dosages achieve target serum concentrations based on pharmacokinetic parameters obtained after the initial dose. Also, to identify the daily vancomycin dosage necessary to achieve target serum concentrations at steady-state and to determine if any relationships exist between vancomycin pharmacokinetic parameters and various patient characteristics. SETTING: Neonatal intensive care unit (NICU) at Georgia Baptist Medical Center. PATIENTS/METHODS: Twenty-three infants with suspected or documented gram-positive infection who received intravenous vancomycin between July 1990 and November 1991 were included in this retrospective analysis. Gestational age range from 23 to 41 weeks and postconceptional age (PCA) at the time of the study ranged from 26 to 46 weeks. Vancomycin therapy was initiated with a loading dose of 15 mg/kg, followed by a maintenance dosage of 20-30 mg/kg/d, which was usually given as 10 mg/kg q8-12h. All vancomycin doses were administered using a syringe pump. Peak and trough serum concentrations were obtained following the first dose. Vancomycin pharmacokinetic parameters were determined using a one-compartment model. Infants receiving indomethacin within two weeks prior to study were analyzed separately (group 2, n = 4). All other infants were included in group 1 (n = 19). RESULTS: For group 1, vancomycin clearance (Cl), volume of distribution (Vd), and half-life were (mean +/- 1 SD) 0.072 +/- 0.032 L/kg/h, 0.52 +/- 0.08 L/kg, and 5.6 +/- 1.6 hours, respectively. For both groups, loading doses provided 1-hour postinfusion peak concentrations of 25-35 mg/L in one of every two infants studied, whereas only three percent of initial maintenance doses were projected to provide desired peak and trough concentrations at steady-state. For group 1, the mean daily dosage necessary to provide target peak (25-35 mg/L) and trough (5-10 mg/L) concentrations at steady-state was larger than that initially prescribed (29.6 +/- 13.1 vs. 22.2 +/- 4.7 mg/kg/d). For group 2, the mean daily dosage required to achieve target peak and trough concentrations at steady-state was smaller than that initially prescribed (14.8 +/- 4.3 vs. 20.0 +/- 0.1 mg/kg/d) and was exactly half of that required for group 1. Excellent correlations were observed between PCA and vancomycin Cl (L/h) (r = 0.92; p < 0.0001), body weight and Vd(L) (r = 0.94; p < 0.0001), body weight and vancomycin Cl (L/h) (r = 0.85; p < 0.0001), PCA and Vd (L) (r = 0.89; p < 0.0001), and body surface area and Vd (L) (r = 0.93; p < 0.0001) for group 1. Moderate correlations were also noted between PCA and Cl relative to body weight (L/kg/h), postnatal age and Cl (L/kg/h), and PCA and vancomycin dosage requirements (mg/kg/d). No linear correlation was observed between any patient characteristic and Vd standardized for body weight. CONCLUSIONS: Our data demonstrate the need for a more accurate method of estimating initial vancomycin dosage requirements in this NICU population. Although some of the relationships revealed in this study could be used to determine vancomycin dosage for infants in the range of approximately 30-36 weeks PCA, we hesitate to suggest this approach presently because of the potential limitations of our study design. Further prospective study is needed to confirm these observations. In addition, further study is necessary to describe the time course of the interaction between vancomycin and indomethacin in infants with successful and unsuccessful closure of their patent ductus arteriosus.     

Renal clearance of digoxin in premature neonates

The renal clearances of digoxin and creatinine were determined in seven premature neonates (mean gestational age = 29.9 wk, range = 26 to 36 wk) at a postnatal age of 1 to 9 days (mean = 4.1 days). The corrected renal digoxin clearance (mean, 10.4 ml/min/1.73 m2; range, 2.5 to 36.7) was highly dependent on gestational age and body weight, r being 0.95 and 0.96, respectively (exponential curve). The linear slope of corrected renal digoxin clearance vs. creatinine clearance plot approached unity (r = 0.99), indicating that digoxin and creatinine were handled similarly by the kidney in these premature neonates (i.e. glomerular filtration with some degree of tubular secretion). Our finding of slower renal digoxin clearance helps to explain the higher serum levels and longer half-life of this drug in premature neonates.     

Predictability of creatinine clearance estimates in critically ill patients

OBJECTIVES: a) To evaluate the predictive ability of different creatinine clearance methods as compared with the criterion standard, inulin clearance; and b) to determine which of the predictive methods yields the most accurate estimation of creatinine clearance. DESIGN: Prospective study. SETTING: Medical intensive care unit (ICU) of a university-affiliated tertiary care hospital. INTERVENTIONS: Glomerular filtration rate was measured by the criterion standard, inulin clearance. PATIENTS: Twenty mechanically ventilated adults. MEASUREMENTS: Renal function was assessed by the following procedures: inulin clearance using a standard protocol, 30-min creatinine clearance, 24-hr creatinine clearance, and creatinine clearance estimates by the Cockcroft-Gault equation. Ideal body weight, total body weight or lean body mass with actual serum creatinine or serum creatinine concentration corrected to 1 mg/dL (85 mumol/L) in cachectic patients were sequentially incorporated into the Cockcroft-Gault equation. RESULTS: The Cockcroft-Gault equation, using ideal body weight and the corrected serum creatinine concentration, was the best predictor of inulin clearance with the smallest bias (9.7 +/- 8.6, 95% confidence interval 5.7 to 13.8). The bias encountered with the 30-min creatinine clearance was not different from that value with the 24-hr creatinine clearance (21.6 +/- 33.0, 95% confidence interval 6.2 to 37.1 vs. 25.4 +/- 28.3, 95% confidence interval 11.8 to 42.9). Good correlations existed between inulin clearance and the Cockcroft-Gault equation, using ideal body weight and the corrected serum creatinine concentration (r2 = .81; p = .0001), as well as between inulin clearance and the Cockcroft-Gault equation, using the lower of ideal or total body weight and the higher of the actual serum creatinine concentration or corrected serum creatinine (r2 = .75; p = .0001). The 30-min creatinine clearance and the 24-hr creatinine clearance had poorer agreement with inulin clearance. The incorporation of a corrected serum creatinine value into the Cockcroft-Gault equation consistently led to better predictions and higher correlation coefficients. CONCLUSIONS: The utilization of the Cockcroft-Gault equation as used clinically (the lower of ideal or total body weight and the higher of actual serum creatinine or corrected serum creatinine concentration to 1 mg/dL [85 mumol/L]) results in more accurate predictions of glomerular filtration rate in the medical, critically ill patient than urine creatinine clearance measures. If creatinine clearance measures are used, the 30-min collection provided results not different from those results obtained with 24-hr urinary collections.     

Determination of plasma digoxin in newborn infants. Practical applications

Measurement of plasma digoxin concentrations in infants after three increasing dosage levels shows that the optimal dose of this glycoside in 20 microgram/kg/day, i.e. a loading dose of 20 microgram/kg followed every 8 hours by a maintenance dose of 7 microgram/kg. The plateau concentration achieved is 3.0 +/- 0,5 ng/ml 8 hours after the last administration. When digoxin levels exceed 5 ng/ml (overdosage, renal failure or low body weight), toxic manifestations occur.     

Impairment of digoxin clearance by coadministration of quinidine

Seven healthy volunteers received a single 1.0-mg dose of intravenous digoxin in a drug-free control trial and again during concurrent therapy with therapeutic doses of quinidine. Digoxin kinetics were determined from multiple serum digoxin concentrations measured during 72 hours after dosage. Compared to the control state, quinidine coadministration reduced mean digoxin volume of distribution (15.1 vs. 12.4 l./kg), prolonged its elimination half-life (47.7 vs. 75.7 hours), and significantly reduced total clearance (6.06 vs. 2.18 ml/min.kg). Both renal and extrarenal digoxin clearances were impaired by quinidine. In nine cardiac patients receiving long-term digoxin therapy (0.25 mg twice daily), quinidine coadministration elevated mean morning digoxin levels from 1.37 to 2.0 ng/ml (P less than 0.001) and evening levels from 1.44 to 1.97 ng/ml (N.S.). If digoxin concentrations at the site of action are increased by quinidine, the interaction is likely to be of clinical importance in many patients.     

"Tandir": an old and well known cause of burn injury in the Middle East

This study was conducted to determine the effect of acarbose on serum concentrations of digoxin in healthy male volunteers. A randomized crossover design with three phases was used. In phase 1 participants received 0.5 mg of digoxin alone. In phase 2 they received 0.5 mg of digoxin 0.5 hours after a 200-mg dose of acarbose. In phase 3 they received 100 mg of acarbose 0.5 hours before each meal three times daily for 3 days. On the fourth day, they received 0.5 mg of digoxin 0.5 hours after a 100-mg dose of acarbose. Area under the concentration-time curve (AUC0-48) and mean maximum concentration (Cmax) were significantly lower and tmax significantly increased in phases 2 and 3 compared with phase 1. These results indicate that the absorption of digoxin is reduced by administration of acarbose, and that one of the major mechanisms of this interaction may be due to the pharmacodynamics of acarbose.     

Serum and cerebrospinal fluid pharmacokinetics of intravenous and oral lamivudine in human immunodeficiency virus-infected children

We studied the pharmacokinetics of intravenously and orally administered lamivudine at six dose levels ranging from 0.5 to 10 mg/kg of body weight in 52 children with human immunodeficiency virus infection. A two-compartment model with first-order elimination from the central compartment was simultaneously fitted to the serum drug concentration-time data obtained after intravenous and oral administration. The maximal concentration at the end of the 1-h intravenous infusion and the area under the concentration-time curve after oral and intravenous administration increased proportionally with the dose. The mean clearance of lamivudine (+/- standard deviation) in the children was 0.53 +/- 0.19 liter/kg/h (229 +/- 77 ml/min/m2 of body surface area), and the mean half-lives at the distribution and elimination phases were 0.23 +/- 0.18 and 2.2 +/- 2.1 h, respectively. Clearance was age dependent when normalized to body weight but age independent when normalized to body surface area. Lamivudine was rapidly absorbed after oral administration, and 66% +/- 25% of the oral dose was absorbed. Serum lamivudine concentrations were maintained above 1 microM for >/=8 h of 24 h on the twice daily oral dosing schedule with doses of >/=2 mg/kg. The cerebrospinal fluid drug concentration measured 2 to 4 h after the dose was 12% (range, 0 to 46%) of the simultaneously measured serum drug concentration. A limited-sampling strategy was developed to estimate the area under the concentration-time curve for concentrations in serum at 2 and 6 h.     

Digitalis intoxication: specifity and significance of cardiac and extracardiac symptoms. part II. Patients with extracardiac symptoms of digitalis intoxications (author's transl)

In 1148 cases the serum digoxin concentration (SDC) was correlated with the extracardiac signs of digitalis intoxication. There is a considerably overlap of SDC levels of patients with and without extracardiac signs of toxicity even though the mean SDC's of these two groups differ significantly. An increasing percentage of clinical intoxicated patients with increasing SDC levels was found at digoxin concentrations of 2.0 ng/ml and higher. At lower SDC levels patients with and without extracardiac signs of digitalis intoxication did not differ significantly in their mean SDC but in mean age and in mean creatinine concentration indicating that at least part of the symptoms in these patients might be due to a more severe illness. We could show that many of the extracardiac signs of digitalis intoxication are also seen in patients with impaired kidney function at low SDC levels and may lead to a wrong diagnosis. The most common complaint in patients with SDC's of 2.0 ng/ml and more is nausea (39.4%), followed by tiredness (30.4%), dizzyness (23.7%), vomiting (23.1%), headache (16.0%), visual disturbances (13,5%), colour (yellow) seeing (6;7%), diarrhea (4.2%) and severe neuro-psychiatric disturbances (3.8%). In patients with digitalis-induced arrhythmias the sequence of symptoms is the same only with a somewhat higher percentage rate. Only about one half of the patients with digitalis-induced arrhythmias and SDC values up to 2.5 ng/ml showed also extracardiac signs of intoxication. Therefore these signs are not to be taken as early symptoms of digitalis intoxication. Divided into subgroups (patients with/without digitalis-induced arrhythmias, patients with SDC values of more/less than 2.0 ng/ml) the patients with and without extracardiac signs of digitalis toxicity are compared with each other in regard to: mean body height and weight, concentration of digoxin, potassium and creatinine, digoxin dosage and mean age. The greatest differences were found between patients with combined cardiac and extracardiac signs of intoxication and patients with neither cardiac nor extracardiac signs of intoxication: These intoxicated patients are of significantly higher mean age and lower body weight, their mean concentration of digoxin and creatinine and the digoxin dosage administered are significantly greater, but there is no significant difference in potassium concentration. An important group of patients, namely the elderly with impaired kidney function, are especially prone to develop digitalis intoxication. In this group, however, the extracardial symptoms are of little benefit in the diagnosis of digitalis intoxication. In these patients rhythm disturbances and intoxication-like symptoms are frequently caused by other reasons. In most cases the SDC value can clarify the diagnosis without withdrawal of the drug.     

Procollagen propeptide and pyridinium cross-links as markers of type I collagen turnover: sex- and age-related changes in healthy children

The correlations among age, gender, body size parameters, and type I collagen metabolism were evaluated in 183 healthy infants, aged 8.5-27.5 months. Collagen formation was assessed by measuring serum type I collagen carboxy-terminal propeptide, and degradation was determined by urinary pyridinoline and deoxypyridinoline (measured by high performance liquid chromatography) and cross-linked N- and C-terminal telopeptides of type I collagen (measured by NTx and CrossLaps assays). A new RIA specific for deoxypyridinoline was also evaluated. The results provide reference values at 10 months and 2 yr of age, including cross-linked C-terminal telopeptides (1492 +/- 685 and 1510 +/- 446 in boys; 1705 +/- 612 and 1849 +/- 611 micrograms/mmol creatinine in girls; mean +/- 1 SD). There was a good correlation between the high performance liquid chromatography and RIA data for deoxypyridinoline, showing that the RIA method is suitable for use in healthy children. Some correlations were found among peptide-bound cross-links, serum type I collagen carboxy-terminal propeptide, and the anthropometric parameters, suggesting that these peptides reflect bone resorption and also overall body type I collagen. Finally, there were age- and sex-related differences in the urinary excretion of the collagen degradation markers, suggesting that, unlike boys, girls maintain a high degree of collagen degradation up to the age of 24 months despite a decrease in their rate of collagen formation.     

Plasma-digoxin concentration in patients at time of hospital admission (author's transl)

Plasma-digoxin and serum creatinine concentrations were determined on admission in 145 unselected patients previously digitalized as outpatients. Adequate digitalization was found in 62.7%, inadequate doses in 15.9% of patients. In the latter group the daily dosage reported by the patients failed to correlate with the plasma-digoxin concentration by radioimmunoassay. One-fifth of all patients had clinical evidence of digitalis intoxication. Of these, 69% had plasma-digoxin concentrations of more than 2.0 ng/ml and 31% less than 2.0 ng/ml. Mean digoxin concentration for all patients with signs of digitalis intoxication was 2.5+/-0.9 ng/ml. In patients simultaneously receiving spironolactone or canrenoate-K+ there was danger of falsely high values for digoxin because of interference of those drugs with the radioimmunoassay.     

A specific antidote for the treatment of digitalis poisoning in uremic patients

Two chronic haemodialyzed patients with digitalis intoxication are reported. One of them took digoxin 0.25 mg three times daily for an unknown period and the other took digitoxin 0.1 mg twice daily for two weeks. The symptoms of intoxication were mainly concealed by uremic syndrome. The diagnosis was established by noticed sinus bradycardia, first- and second-degree atrioventricular block in ECG and the determination of sera levels of glycosides (serum digoxin concentration was 7.36 ng/ml, serum digitoxin concentration was 46.5 ng/ml) in both cases. Considering the probable long elimination period of digitalis and the potentially life-threatening situation the patients were given digoxin-specific antibody (Fab) fragments with potassium replacement therapy. The symptoms disappeared within a few hours after therapy, side effects and rebound toxicity did not develop. In connection with these cases the aim of this report is to publish a method which can reverse the life-threatening digitalis intoxication in patients suffering from renal failure as well. As to the above method, the authors have not found any similar case reports in the Hungarian medical literature.     

Biochemical evaluation of digoxin dosage in patients with heart failure

The investigations were carried out in 56 patients aged 54 to 84 years, treated with a supporting dosage 0.25 mg of digoxin because of chronical insufficiency of the heart, according to the NYHA classification II and III degree, in whom the functions of liver and kidneys have not been ascertained. A fourfold determination of digoxin concentrations in the blood was established in the time of distribution balance. From among the examined patients three groups were separated: receiving the drug chronically at 8.00 a.m. (group A), receiving it at 8.00 p.m. (group B) and group C, for which the sacral method was used. Depending on medical indications the patients received during the examination other drugs. In group C the therapy was limited to diuretic drugs. In no clinical symptoms of digitalism could be observed. Subtherapeutic levels of digoxin (< 0.8 ng/ml) were found in the three groups on an average in 50% of the patients. The high percentage of patients with nontherapeutic concentration in blood serum confirms once more, that treatment with digoxin without checking their concentration in the serum does not give the certainty of suitable dosage. The results of the studies show that the optimalization of digoxin therapy from the point of pharmacological view should be based on a penetrating estimation of the whole of the clinical image, the checking of the image with the help of the concentration determinations of the drug.     

Factors affecting epirubicin pharmacokinetics and toxicity: evidence against using body-surface area for dose calculation

PURPOSE: An exploratory study to test whether body-surface area (BSA) should be used for the calculation of epirubicin dose. PATIENTS AND METHODS: The relationship between pretreatment characteristics and the effects of epirubicin were investigated in 20 chemotherapy-naive patients. Measurements of body size, renal and hepatic function, and other factors were correlated with epirubicin pharmacokinetics (PK) and epirubicin-induced neutropenia. All patients received 150 mg of epirubicin infused continuously over 120 hours, regardless of body size. Factors were analyzed by univariate and multivariate linear regression. RESULTS: There were no correlations between BSA or weight with any PK parameter or with the degree of neutropenia. In multivariate analysis, indicators of liver function were the only factors that correlated with neutropenia and epirubicin PK. Thus, correlations for neutropenia were seen with antipyrine clearance (P = .003), activated partial thromboplastin time (APTT) (P = .005) and serum transferrin (P = .01). Further, the area under the concentration-time curve (AUC) for epirubicin correlated with prothrombin index (P < .01), antipyrine clearance (P < .01), and serum bile salt concentration (P = .03), and there were similar correlations for epirubicin steady-state concentration (CpSS). Epirubicin clearance correlated with antipyrine clearance (P = .02). PK parameters for dihydroepirubicin correlated with prothombin index, serum transferrin, and bile salt concentrations (P < .001 for all correlations). Because of the number of statistical examinations performed, some of these correlations may be spurious. However, some are likely to be real, since the same variables repeatedly correlated with different epirubicin-associated outcomes. There were no correlations between epirubicin PK indices or neutropenia and serum aminotransferase levels or other biochemical liver function tests, creatinine, or any of the clinical factors examined. CONCLUSION: These results led us to question the use of BSA for epirubicin dose calculation. In contrast, quantitative liver function tests may give a better indication of drug handling and toxicity and may be useful to determine more accurate methods for dose calculation of epirubicin.     

Ototoxicity of amikacin

Amikacin was used in 77 treatment courses at a dosage of >/=7.5 mg/kg every 8 h, and patients were monitored for ototoxicity by following serial audiograms, serum creatinine, and amikacin blood levels. Patients were leukopenic (58), were infected by gentamicin-resistant organisms (11), or had cystic fibrosis (8). Three patients developed tinnitus, but none had vertigo or nystagmus. Of 55 courses with pre- and post-treatment audiogram, 13 (24%) were associated with development of high-frequency hearing loss, which was usually bilateral. No patient had conversational hearing loss, and audiograms reverted to normal in three patients. Onset of cochlear damage occurred in one patient after therapy was stopped. The group with high-tone hearing loss, in comparison to the group without audiographic changes, received a larger mean total dose (24 versus 9.6 g), were treated for a longer duration (19 versus 9 days), and more frequently had previous aminoglycosides. Fifty-seven percent of patients with a "peak" serum level exceeding 32 mug/ml and 55% of patients with "trough" levels exceeding 10 mug/ml developed cochlear damage. There was no difference between the groups in age, body weight, previous cochlear damage, renal disease before or during therapy, or average daily dose. Both monitoring of blood levels and limiting duration of therapy may prevent amikacin ototoxicity.