This novel study evaluated the effects of vardenafil and sildenafil on QT and corrected QT (QTc) duration using a model that minimizes experimental error to obtain the most accurate assessment of observed QTc effects. A placebo-controlled and positive-controlled, period-balanced, double-blinded, 6-way crossover study evaluated therapeutic and supratherapeutic oral doses of vardenafil (10 and 80 mg, respectively) and sildenafil (50 and 400 mg, respectively), therapeutic doses of moxifloxacin (400 mg), and a placebo in 58 healthy men (mean age 53 years), with dosing every 3 days. Six replicate, 12-lead, digital electrocardiograms (ECGs) were recorded at 3 time points before and 5 time points after dosing to cover the time course of maximum exposure to study drugs and their metabolites. An independent laboratory blindly analyzed approximately 17,000 ECGs. For the placebo, mean change in QTcF (Fridericia) duration 1 hour after dose (approximate Tmax of vardenafil and sildenafil) was 0 ms (±0.7 SD). QT/QTc variability was small across regimens, indicating statistically powerful results. Moxifloxacin demonstrated an expected 8-ms mean change and was the only drug to prolong absolute QT. Placebo-corrected mean changes in QTcF duration (90% confidence interval) at 1 hour after dose were 8 ms (range 6 to 9) for vardenafil 10 mg and 6 ms (range 5 to 8) for sildenafil 50 mg. QTci (linear and nonlinear per patient) yielded similar trends: 4 ms (range 3 to 6) for vardenafil 10 mg and 4 ms (range 2 to 5) for sildenafil 50 mg. Dose response demonstrated very shallow QTc relations for study drugs. Therapeutic and supratherapeutic doses produced only small increases in the QTcF interval, which were considered to be clinically irrelevant. This well-controlled, statistically powerful study in middle-aged men demonstrated that vardenafil and sildenafil produced no increase of absolute QT and only similar, small increases of the QTc interval, with a shallow dose-response curve. The study design and conduct may serve as a guide for future QT assessment of new drugs.

Purpose A placebo- and positive-controlled (Moxifloxacin, M 400 mg), double-blind, 6-way crossover study evaluated the effects of single oral therapeutic and supratherapeutic doses of vardenafil (V 10, 80 mg), and sildenafil (S 50, 400 mg) on QT/QTcF duration. Methods 59 healthy men (mean age 53) received at least one dose of study medication. Six replicate 12-lead digital ECGs were recorded at 3 time points pre-dose and at 5 time points post-dose (up to 4 hrs) to cover the time course of maximum exposure of S, V and metabolites. Plasma concentrations (Cp) of V, S and M were measured at the same time points. The QTcF-Cp data for V and S were analyzed using NONMEM. Interoccasion variability (IOV) in baseline QTc response across sessions was included in the model. Results: A direct effect Emax model best described the QTcF-Cp data for V and S. Emax and inter-individual variability (IIV) in EC50 were modelled to be the same for V and S. Evaluation of the PK/PD model using posterior predictive check showed good predictive performance. (See Table) Conclusion According to the PK/PD model, V and S showed similar maximal QTcF prolongation. Clinical Pharmacology & Therapeutics (2004) 75, P89–P89; doi: 10.1016/j.clpt.2003.11.339 Parameter Population Mean (%CV) IIV E0 (msec) 387 (0.4) 3.2 Emax (msec) 8.29 (6.1) 25.2 EC50V (ng/mL) 2.44 (34.4) 120.4 EC50s (ng/mL) 59.2 (33.6) 120.4 IOV on E0 (%CV) 1.80 (7.7) Residual Variability, (msec) 4.00 (7.0)

Patients with erectile dysfunction may use PDE5 inhibitors such as vardenafil (V) and sildenafil (S), which alter the hERG channel of transfected cells only at suprapharmacologic nonclinical concentrations. This study evaluated effects of therapeutic and supratherapeutic doses of V and S on QT/QTc duration. A placebo- and active-control (moxifloxacin, M, at therapeutic dose), period balanced, double blinded, 6 way crossover study evaluated single oral doses of V 10 mg, V 80 mg, S 50 mg, S 400 mg, M 400 mg and placebo in 58 healthy men (mean age 53) with doses separated by 3 days. Six replicate 12-lead digital ECGs were recorded at 3 time points prior to and 5 time points post dose to cover the full exposure of drugs and metabolites. An independent lab blindly analyzed the ECGs. PK blood samples were drawn at the same 5 time points post dose. For placebo, mean change in QTcF (Fridericia) duration from baseline at 1 hour post dose (approximate Tmax of V and S) was 0 msec (+/- 0.7 SD). QT and QTc variability was small across regimens, indicating statistically powerful results due to large sample size and number (17,000) of ECGs. M demonstrated an expected 8 msec mean change and was the only drug to prolong absolute QT. Placebo-corrected values of mean change from baseline at 1 hour post-dose for each regimen are shown below. QT corrected using linear and nonlinear methods and each individual's QT/HR data (QTci) yielded similar trends of drug effect on QTc. PK/PD modeling demonstrated a very shallow QTc-concentration relationship for V and S. Therapeutic and supratherapeutic doses of V and S produced no increase of absolute QT and similar small increases in QTc interval. We conclude that these findings, and the absence of postmarketing reports of torsades de pointes with S, indicate that small increases in QTc for V and S are clinically insignificant. This study design may serve as a guide for future definitive QT assessment. (See Table) Clinical Pharmacology & Therapeutics (2004) 75, P47–P47; doi: 10.1016/j.clpt.2003.11.178 Treatment Treatment effect (placebo-corrected, 90% CI) HR (bpm) Absolute QT (msec) QTcF (msec) QTci, linear correction (msec) V 10 mg 5 (4,6) -2 (-4,0) 8 (6,9) 4(3,6) V 80 mg 6 (5,7) -2 (-4,0) 10 (8,11) 6 (4,7) S 50 mg 4 (3,5) -2 (-4,0) 6 (5,8) 4 (2,5) S 400 mg 5 (4,6) -1 (-3,1) 9 (8,11) 5 (4,7) M 400 mg 2 (1,3) 3 (1,5) 8 (6,9) 7 (5,8)

Clinical Pharmacology & Therapeutics (2003) 73 , P86–P86; doi:

Objective: To evaluate the pharmacokinetics and pharmacodynamics of an infusion of SE 209670, a non peptide endothelin-A/endothelin-B receptor antagonist.Methods: The study was conducted in 2 parts. Part 1 was a placebo-controlled, single-blind, rising-dose crossover evaluation of the pharmacokinetics and safety of SE 209670 infused at doses that ranged from 0.2 to 1.5 mu g.kg(-1) for approximately 8 hours in 17 healthy male volunteers. In part 2, renal hemodynamic effects of a 4-hour infusion of SE 209670 were assessed in 10 healthy male volunteers in a 2-period, period-balanced, single-blind, randomized, placebo-controlled crossover study.Results: SE 209670 appeared to display Linear kinetics over the dose range from 0.2 to 1.5 mu g.kg(-1).min(-1). The half-life was approximately 4 to 5 hours. Plasma immunoreactive endothelin-l increased in an apparent dose-dependent manner, Mean renal hemodynamic responses (para-aminohippurate clearance) increased by approximately 15% relative to placebo (P = .007), Renal sodium excretion was similar during SE 209670 and placebo infusion.Conclusion: The pharmacokinetics of intravenous SE 209670 appeared to be linear, and infusion resulted in dose-related increases in immunoreactive endothelin-l, The lack of an ti-natriuretic effect and the renal vasodilator response observed in this study indicate that SE 209670 does not possess any partial agonist activity. Further, the renal hemodynamic response supported a potential physiologic role for endogenous endothelin in the maintenance of renal vascular tone in humans.

Study Objectives. To compare eprosartan pharmacokinetics in hemodialysis patients and in volunteers with normal renal function, and to determine the effect of hemodialysis on these values.Design. Open-label, parallel-group, single-dose study.Setting. Outpatient hemodialysis treatment center and an industry-affiliated clinical pharmacology unit. Patients. Ten healthy volunteers and nine hemodialysis patients.Intervention. A single oral dose of eprosartan 400 mg was administered to volunteers on 1 day and to patients on 2 days (a nondialysis and a dialysis day). Patients underwent high-flux hemodialysis.Measurements and Main Results. Concentrations of eprosartan in plasma and dialysate were assayed by high-performance liquid chromatography; plasma protein binding was determined by ultrafiltration. Eprosartan pharmacokinetics showed greater variability in patients than in volunteers. However, six of nine patients had exposures that were within the range observed for volunteers. Mean total AUC(0-t) was increased approximately 60% (95% CI -22, 225) in patients. Total C-max was similar between groups (PE = 1.01, 95% CI -40, 71). Mean percent fraction unbound (%f(u)) in patients (3.02%) was significantly greater than that in volunteers (1.74%). Unbound AUC(0-t) and unbound C-max were, on average, approximately 172% (95% CI 28, 479) and 73% (95% CI -1, 199) greater, respectively, in patients. After hemodialysis, the mean %f(u) decreased from 3.19-2.01%. Mean recovery of eprosartan in dialysate was 6.8 mg (range 0-23.1 mg) and hemodialytic clearance was approximately 11 ml/minute, which does not represent a significant portion of total clearance.Conclusions. Eprosartan was safe and well tolerated in both groups. Based on its known safety profile and because of its exaggerated pharmacokinetic variability in patients undergoing hemodialysis, treatment should be individualized based on tolerability and response. Supplemental doses of eprosartan after hemodialysis are unnecessary.

OBJECTIVE: To assess the effect of ranitidine on the pharmacokinetics of eprosartan in healthy male volunteers. DESIGN: Single-center, randomized, open-label, two-period, period-balanced, crossover study. PATIENTS: Seventeen healthy men aged 19 to 43 years. INTERVENTION: In each period (separated by a ≥7 d washout), subjects received a single 400-mg oral dose of eprosartan alone, or a single oral dose of eprosartan 400 mg and ranitidine 150 mg on day 4 after 3 days of ranitidine 150 mg twice daily. Serial pharmacokinetic samples were obtained for up to 24 hours following eprosartan dosing. MAIN OUTCOME MEASURES: Plasma and urine eprosartan concentrations during each treatment session. RESULTS: Eprosartan maximum concentration (Cmax), the AUC from time zero to the last quantifiable concentration (AUC0-t), and renal clearance (Clr) values were approximately 7%, 11%, and 4% lower, respectively, when administered with ranitidine compared with eprosartan alone. The 95% CIs for the ratio of eprosartan plus ranitidine compared with eprosartan alone were 0.81 to 1.07, 0.77 to 1.03, and 0.64 to 1.43, for Cmax, AUC0-t, and Clr, respectively, indicating no statistically significant difference between regimens. CONCLUSIONS: Repeated doses of ranitidine did not have a marked effect on the single-dose pharmacokinetics of eprosartan. OBJETIVO: Evaluar el efecto de ranitidina en la farmacocinética de eprosartan en pacientes voluntarios saludables. DISEÑO: Centro sencillo, estudio randomizado, rotulación abierta, dos períodos, período cruzado balanceado. PACIENTES: Díecisiete hombres saludables entre 19 a 43 años. INTERVENCIÓN: En cada período (separado por 7 d o más sín medicamento), los pacientes recibieron una dosis oral de eprosartan 400 mg solamente, o una dosis oral eprosartan 400 mg y ranitidina 150 mg 2 veces al día. Muestras en serie sobre la farmacocinética fueron obtenidas hasta 24 horas después de la dosis de eprosartan. MEDICIÓN DE RESULTADOS: Concentraciones en plasma y orina de eprosartan durante cada período de tratamiento. RESULTADOS: Los valores promedio de concentración máxima (Cmax), ABC0-t, y depuración renal (Clr) de eprosartan fueron aproximadamente 7%, 11%, y 4% más bajo, respectivamente, comparado con eprosartan sólo. En intervalos de un 95% de confianza, la razón de eprosartan y ranitidina comparado con eprosartan sólo fueron 0.81 a 1.07, 0.77 a 1.03, y 0.64 a 1.43 para Cmax, ABC0-t, y Clr, respectivamente, indicando que no hay diferencia estadística entre ambos régimenes. CONCLUSIONES: Dosis repetidas de ranitidina no producen un efecto marcado en la farmacocinética de eprosartan en dosis sencillas. OBJECTIF: Évaluer l'effet de la ranitidine sur la pharmacocinétique de l'éprosartan chez des volontaires sains. DEVIS EXPÉRIMENTAL: Étude à échantillonagealéatoire, ouverte, en chassécroisé comprenant deux périodes, et réalisée dans un seul établissement. PATIENTS: Dix-sept hommes sains, âgés entre 19 et 43 ans. INTERVENTION: Dans chaque période (séparée par 7 j de sevrage thérapeutique), les volontaires reçurent soit une dose unique de 400 mg d'éprosartan, ou une dose unique de 400 mg d'éprosartan et 150 mg de ranitidine au jour 4, suivant l'administration de 150 mg de ranitidine aux 12 heures les 3 premiers jours. Plusieurs échantillons pharmacocinétiques furent obtenus durant les 24 heures suivant l'administration d'éprosartan. MESURES DE L'ÉFFET: Concentrations urinaires et plasmatiques d'éprosartan durant chacune des deux périodes de traitement. RÉSULTATS: Quand l'éprosartan fut administré avec la ranitidine, la concentration maximale, la surface sous la courbe, et la clairance rénale d'éprosartan étaient en moyenne approximativement 7%, 11%, et 4% inférieures, respectivement, aux valeurs obtenues avec l'éprosartan administré seul. Aucune différence statistiquement significative n'a été observée entre l'éprosartan administré avec la ranitidine et l'éprosartan seul. Les intervalles de confiance à 95% pour les rapports des valeurs entre les deux groupes sont pour la concentration maximale 0.81 à 1.07, la surface sous la courbe 0.77 à 1.03, et la clairance rénale 0.64 à 1.43. CONCLUSIONS: L'administration de doses répétées de ranitidine n'a pas démontré d'effet marqué sur la pharmacocinétique d'une dose unique d'éprosartan.

The present study investigated the proportionality of exposure after single oral doses of 100, 200, 400, and 800 mg of eprosartan, a nonpeptide, nonbiphenyl angiotensin II receptor antagonist, in 23 healthy young men. Eprosartan was safe and well tolerated. Exposure to eprosartan increased with dose but in a less than proportional manner. For each two-fold dose increase, area under the concentration--time curve (AUC) increased an average of 1.6 to 1.8 times and maximum plasma drug concentration (Cmax) increased an average of 1.5 to 1.8 times. For both parameters, the greatest difference from the dose multiple was observed between the 400- and 800-mg doses. Dose proportionality of eprosartan, as assessed by an equivalence-type approach using the 100-mg dose as the reference and a 30% acceptance region (0.70, 1.43), was achieved for the 200- and 400-mg doses for AUC and the 200-mg dose for Cmax. The observed changes in the pharmacokinetics of eprosartan suggest slight saturation of absorption of eprosartan over the 100- to 800-mg dose range, most likely due to the physicochemical properties of the drug (pH-dependent aqueous solubility and lipophilicity).

The effects of antihypertensive agents, including angiotensin II receptor antagonists, on urine uric acid excretion may have important clinical consequences. Therefore, the effects of single and repeated doses of eprosartan on uric acid excretion were evaluated in 57 male patients with mild‐to‐moderate essential hypertension in a double‐blind, randomized, placebo‐controlled, repeated dose, dose‐rising, two‐period, period‐balanced, crossover study conducted in two parts. In part 1 (n = 33), the effects of eprosartan dose regimens of of 50 mg, 100 mg, and 350 mg once daily and 150 mg every 12 hours on uric acid excretion were assessed. In part 2 (n = 24), the effects of eprosartan dose regimens of 600 mg, 800 mg, and 1,200 mg once daily on uric acid excretion were assessed. Eprosartan was well tolerated. There were no appreciable changes from predose values in fractional excretion of uric acid (FEua), urine uric acid excretion, urine uric acid to creatinine (Uua/Ucr) ratios, or serum uric acid concentrations after single or repeated doses of eprosartan. Mean Uua/Ucr ratios for eprosartan doses of 50 mg, 100 mg, or 350 mg daily or 150 mg every 12 hours were comparable to those for placebo. Mean FEua values and Uua/Ucr ratios for eprosartan doses of 600 mg, 800 mg, or 1,200 mg daily also were comparable to those for placebo. Single and repeated oral doses of eprosartan ranging from 50 mg to 1,200 mg daily had no effect on serum uric acid concentrations or urine uric acid excretion in patients with mild‐to‐moderate essential hypertension.

Study design: The effects of orally administered eprosartan on changes induced by angiotensin II in blood pressure, renal hemodynamics, and aldosterone secretion were evaluated in healthy men in this double-blind, randomized, single-dose, placebo-controlled crossover study, which was conducted in three parts. Part 1 (n = 12) assessed the onset and duration of the effect of eprosartan 350 mg or placebo; part 2 (n = 14) assessed the dose-response profile of placebo or 10, 30, 50, 70, 100 or 201) mg eprosartan; and part 3 (n = 5) assessed the duration of the effect of 50, 100, or 350 mg eprosartan.Results: In part 1 of the study, 350 mg eprosartan caused complete inhibition of angiotensin II-induced presser and renal blood flow hemodynamic effects (effects on effective renal plasma flow [ERPF]) and inhibited angiotensin IT-induced stimulation of aldosterone secretion from 1 to 3 hours after administration. Eprosartan, 350 mg, inhibited the effects of exogenous angiotensin II by approximately 50% to 70% from 12 to 15 hours after dosing. Eprosartan had no angiotensin II agonistic activity and produced an increase in ERPF starting at 1 to 4 hours after dosing. In study part 2, at 3 hours after single doses of 10, 30, 50, 70, 100, and 200 mg, eprosartan inhibited angiotensin II-induced decreases in ERPF by 39.1%, 49.9%, 33.0%, 56.0%, 71.0%, and 85.7%, respectively, compared with placebo. In study part 3, 50, 100, and 350 mg eprosartan produced measurable inhibition of angiotensin II-induced decreases in ERPF from 12 to 15 hours after administration. In parts 2 and 3, the eprosartan angiotensin IT antagonism on blood pressure response and aldosterone secretion mirrored the angiotensin II antagonism on ERPF.

The potential for eprosartan, a nonbiphenyl tetrazole angiotensin II receptor antagonist, to affect the 24‐hour plasma glucose profiles in type II diabetic patients treated with glyburide was investigated in this randomized, placebo‐controlled, double‐blind (eprosartan—placebo phase only), two‐period, period‐balanced, crossover study. All patients received a stable oral dose (3.75–10 mg/day) of glyburide for at least 30 days before the first dose of double‐blind study medication was administered. Patients were randomized to receive either 200‐mg oral doses of eprosartan twice daily or matching oral placebo doses concomitantly with glyburide for 7 days during each treatment period. After a minimum washout period of 14 days, patients were crossed over to the alternate treatment. Serial samples to measure glucose concentrations in plasma were collected over a 24‐hour period on the day before administration of eprosartan or placebo and again on day 7. Mean glucose concentrations were comparable between treatment groups before administration of eprosartan or placebo. The point estimate (90% confidence interval) for the ratio of the average mean 24‐hour plasma glucose concentrations of eprosartan + glyburide to placebo + glyburide after 7 days of administration was 0.96 (0.90, 1.01). Eprosartan did not significantly alter the 24‐hour plasma glucose profile in patients with type II diabetes mellitus who were previously stabilized on glyburide.

The pharmacokinetic profile of penciclovir was determined after a single 500‐mg dose of its oral precursor, famciclovir, in 9 healthy volunteers and in 14 patients with chronic hepatic disease. Plasma and urine samples were analyzed for concentrations of penciclovir and 6‐deoxy‐penciclovir using a reverse‐phase high‐performance liquid chromatography (HPLC) method. Famciclovir was not quantifiable in patients with hepatic disease, and 6‐deoxy‐penciclovir was quantifiable in only a limited number of specimens. The extent of systemic availability of penciclovir, as measured by AUC0‐∞, was similar in patients with hepatic disease and in healthy subjects. In contrast, Cmax was significantly lower (average decrease of 43%) in subjects with hepatic disease relative to healthy normal subjects. Median Tmax for subjects with hepatic disease was significantly increased (by 0.75 hours) compared with subjects with normal liver function. These data suggest a decrease in the rate, but not the extent, of systemic availability of penciclovir in patients with hepatic disease. It should be unnecessary to modify the dose of famciclovir for subjects with compensated hepatic disease and normal renal function.

Objective: To characterize the pharmacokinetics of a single 500 mg oral dose of famciclovir in subjects with varying degrees of renal impairment.Methods: Twenty-seven subjects were enrolled in an open-label parallel-group study. Eighteen patients had renal impairment (average age [+/-SD], 49 +/- 12 years), and nine subjects were healthy volunteers (average age, 28 +/- 7 years). Patients with renal impairment were stratified into groups based on estimated creatinine clearance (CL(CR)): mild impairment (CL(CR), 60 to 80 ml/min/1.73 m(2)), moderate impairment (CL(CR), 30 to 59 ml/min/1.73 m(2)) and severe impairment (CL(CR), 5 to 29 ml/min/1.73 m(2)). Plasma and urine specimens were analyzed for concentrations of penciclovir, the antivirally active metabolite of famciclovir, by reversed-phase HPLC. Plasma data were analyzed with use of model-independent methods.Results: In subjects with normal renal function (CL(CR) >80), the mean maximum plasma concentration of penciclovir was 2.83 mu g/ml (range, 1.30 to 3.82 mu g/ml) and the mean time to reach maximum concentration was 0.89 hours (range, 1/2 to 1 1/2 hours). The mean apparent terminal elimination half-life was 2.15 hours (range, 1.56 to 2.87 hours). A linear relationship was observed between the plasma elimination rate constant and CL(CR) and between renal clearance and CL(CR). Mean area under the plasma concentration-time curve from zero to infinity was approximately tenfold higher and the plasma elimination rate constant was approximately fourfold lower in patients with severe renal impairment than in subjects with normal renal function.Conclusion: Consideration should be given to modification of the dosing schedule of famciclovir from the usual 8-hour interval to a 12-hour interval for patients with moderate renal impairment (CL(CR) 30 to 59 ml/min/1.73 m(2)) or a 24-hour interval for patients with severe renal impairment (CL(CR) <30 ml/min/1.73 m(2)).

Nonsteroidal antiinflammatory drugs differ with respect to their effects on prostaglandin metabolism in various tissues, a property that may be partly responsible for some of the differences in the pharmacologic activities and side‐effect profiles that are associated with their use. The effects of nabumetone on urinary prostaglandin excretion have not been reported. Fourteen healthy females, age 21–43 years, were treated with nabumetone (NAB) 1000 mg daily, sulindac (SUL) 200 mg every 12 hours, and indomethacin (IND) 50 mg every 12 hours for 7 days in a randomized period‐balanced crossover study. The effects of drug treatment on urinary prostaglandin excretion (PGE 2 , 6‐keto‐PGF 1α , PGF 2α , thromboxane [TX] B 2 ) and platelet function (collagen‐induced whole blood platelet aggregation [CIPA] and template bleeding time) were determined on day 1 and day 7. For each treatment regimen, mean baseline urinary PG excretion values were comparable for each prostanoid, but the pattern of excretion differed in response to each drug. Treatment with NAB significantly increased the urinary excretion rates of PGE 2 and PGF 2α , but 6‐keto‐PGF1 α and TXB 2 excretion were unchanged. IND treatment did not result in a significant change in PGE 2 excretion but did significantly reduce urinary 6‐keto‐PGF 1α and TXB 2 excretion rates. Reduced excretion of PGF 2α was observed on both study days during treatment with IND and SUL. SUL treatment also resulted in increased urinary PGE 2 excretion while significantly reducing 6‐keto‐PGF 1α excretion on day 7. Significant differences were observed between the NAB and SUL regimens with respect to PGF 2α excretion and between the NAB and SUL regimens for PGE 2 , PGF 2α , 6‐keto‐PGF α1 (on day 1 only) and TXB 2 (on day 1 only). Neither NAB nor SUL caused inhibition of CIPA or bleeding time although platelet aggregation was inhibited during IND treatment. That NAB treatment was neither associated with alterations in platelet function nor decreases in the urinary excretion of the vasodilatory prostaglandins, PGE 2 and 6‐keto‐PGF 1α , suggests that NAB possesses renal sparing properties.

Of 13 chronic hemodialysis end-stage renal disease (ESRD) patients undergoing open-heart surgery, 7 received intraoperative hemodialysis (IHD) during cardiopulmonary bypass and 6 received hemodialysis on a routine basis (RHD). Within the groups, IHD patients had significantly lower post-operative mean serum potassium and mean plasma creatinine concentrations compared to mean preoperative values. Postoperative mean BUN tended to decrease and mean serum bicarbonate concentration was unchanged as compared to mean preoperative values. In the RHD group, however, post-operative mean serum potassium concentration tended to increase, mean serum bicarbonate concentration significantly declined and mean BUN was unchanged as compared to mean preoperative values. An average of 2.1 +/- 0.5 liters of fluid was removed from the IHD patients during cardiopulmonary bypass. Post-operatively, 0 of 7 IHD patients versus 4 of 6 RHD patients required parenteral sodium bicarbonate therapy (chi-2, p < 0.01). On average, RHD patients required hemodialysis 1 day after surgery, whereas IHD patients were hemodialyzed 2 days after surgery (p = 0.009). We conclude that IHD lessened postoperative hyperkalemia and metabolic acidosis and delayed postoperative hemodialysis by an additional day. IHD should be considered as an adjunct to RHD therapy in the management of ESRD patients undergoing open-heart surgery.