Cardiopulmonary events during hemodialysis: effects of dialysis membranes and dialysate buffers.

Adverse cardiac and pulmonary events are frequently observed during hemodialysis and contribute to significant morbidity and mortality. The temporal relationship between these events during the intradialytic period has not been well defined. To examine the event rate and timing of silent ischemia, cardiac ectopy, and hypoxemia, we conducted a prospective, single-blind, randomized study of 10 subjects undergoing maintenance hemodialysis with four contiguous combinations of dialysis membranes (cuprammonium or polysulfone) and dialysates (acetate or bicarbonate). The frequency of oxygen desaturation events peaked during the first 2 hours, whereas silent myocardial ischemia and supraventricular ectopies occurred more often in the later hours. Ventricular ectopy occurred steadily throughout the intradialytic period. The combination of acetate dialysis and cuprammonium membrane is associated with the most frequent events. We conclude that cardiopulmonary events can occur frequently during hemodialysis, and the frequency is dependent on the type of dialysis membrane and dialysate buffer used.

Fanconi's syndrome due to ifosfamide.

Although renal wasting of phosphate is relatively common, Fanconi's syndrome following ifosfamide chemotherapy is rare. This case illustrates the possibility of developing Fanconi's syndrome despite the apparent lack of toxicity during previous ifosfamide exposure. As the use of high-dose ifosfamide-containing regimens prior to BMT increases, the occurrence of this adverse effect may become more frequent. Morbidity due to Fanconi's syndrome can be decreased by close monitoring and aggressive management of fluid and electrolytes.

Clinical pharmacology and economics of recombinant human erythropoietin in end-stage renal disease: the case for subcutaneous administration.

The clinical pharmacology of human recombinant erythropoietin (epoetin) was studied in order to compare the effectiveness of various routes and dosing schedules in dialysis patients. Thirty-six patients received epoetin beta three times a week i.v. for at least 12 wk. The mean dose needed to achieve target hemoglobin was 225 +/- 36 U/kg per week (median dose, 180 U/kg per week). Twenty-eight of 36 patients who were converted to a once-a-week i.v. schedule increased their requirements to 429 +/- 50 U/kg per week in order to maintain a target hematocrit of 33 to 40 vol%. Twelve of 28 patients could maintain their target hematocrit when dosed once a week s.c. at 84 +/- 10 U/kg. The other 16 patients required 137 +/- 15 U/kg per week divided into two doses. In the entire group of 28 patients, the weekly requirement for epoetin was reduced by 50% when the s.c. route was used two or three times a week. Pharmacokinetic studies performed during chronic therapy indicated rapid clearance of erythropoietin (t1/2 of 6.8 +/- 0.3 h). Single i.v. doses greater than 150 U/kg were required to increase basal erythropoietin by 30 mU/mL at 44 h postdosing. With s.c. dosing, such increments in erythropoietin levels frequently persisted beyond 60 h because of prolonged and slow absorption. Pharmacokinetic simulations in conjunction with clinical correlation of the erythropoietic response suggest that the duration that the erythropoietin levels are maintained, and not the absolute peaks, is the primary determinant of efficacy. This may result from nonlinearity in the dose response. Pharmacokinetic simulation also indicated that i.v. dosing could not maintain adequate interdialytic erythropoietin levels, whereas s.c. dosing could. Cost analysis indicated that the use of s.c. dosing two or three times a week at an average total weekly dose of 110 to 120 U/kg is effective treatment of anemia in most dialysis patients.

Probenecid enhances central nervous system uptake of 2',3'-dideoxyinosine by inhibiting cerebrospinal fluid efflux.

The effects of probenecid on the pharmacokinetics of 2',3'-dideoxyinosine (ddl) and on the distribution of ddl to cerebrospinal fluid (CSF) and brain tissue were determined in rats during and after a 2-hr i.v. infusion of ddl, 125 mg/kg/hr. Probenecid-treated rats received a loading dose of probenecid followed by an i.v. infusion of probenecid initiated 1 hr before and continued during and for 2 hr after termination of the ddl infusion. Plasma concentrations of probenecid averaged 221 +/- 34 micrograms/ml upon termination of the ddl infusion and 258 +/- 34 micrograms/ml (mean +/- S.D., n = 4) 1 hr later. In the probenecid-treated animals, ddl concentrations were higher in plasma (1.5-fold), brain (1.5-fold) and CSF (5.4-fold) at the termination of the ddl infusion and postinfusion concentrations declined more slowly compared to controls. Postinfusion, the CSF/plasma and brain/plasma ratios steadily increased to a greater extent in the probenecid-treated rats compared to control animals. The time course of plasma, CSF and brain tissue concentrations were analyzed by nonlinear least-squares regression using two different compartmental models, one which neglected the direct exchange of drug between the CSF and brain parenchyma, whereas the other allowed for such exchange to occur and neglected direct vascular transfer of drug to brain tissue. Allowing exchange between the CSF and brain tissue gave slightly improved fitting of the data from both probenecid-treated and control rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Erythropoietin life span in rats with hypoplastic and hyperplastic bone marrows.

The metabolic fate of erythropoietin (EPO) remains unknown. Urinary excretion does not appear to play a major role and liver catabolism has been shown to occur only after terminal sugars on the hormone have been removed. However, it has been proposed that EPO is eliminated by consumption in the bone marrow. In order to examine the extent of such consumption we measured the half-life of radioidinated recombinant EPO injected intravenously (IV) to rats with bone marrows suppressed by cyclophosphamide or hypertransfusion and marrows stimulated by phenylhydrazine or bleeding. The mean half-life or erythropoietin in normal rats was 179 +/- 16 min, with similar half-lives found in the other rats regardless of decreased or increased bone marrow activity. The results indicate that it is unlikely that erythroid activity determines EPO life span and catabolism.

Pharmacokinetics and erythropoietic response to human recombinant erythropoietin in healthy men.

To assess the safety, pharmacokinetics, and erythropoietic responses to human recombinant erythropoietin (epoetin beta), single intravenous doses (10, 50, 150, and 500 IU/kg) were administered at monthly intervals to 16 healthy subjects in a two-panel, placebo-controlled, double-blind ascending-dose trial. A 1000 IU/kg dose was subsequently administered in an open manner. Epoetin concentrations were determined in serum and urine by radioimmunoassay. Reticulocyte, hemoglobin, and hematocrit values were serially measured after each dose. Mean epoetin apparent half-lives ranged from 4.42 to 11.02 hours. The apparent volume of distribution was between 40 and 90 ml/kg, consistent with plasma water, and the apparent clearance values ranged from 4 to 15 ml/kg/hr, with both parameters having the highest values at the 10 IU/kg dose level. Clearance tended to decrease as a function of dose. Maximum reticulocyte counts were dose-dependent and occurred 3 to 4 days after the epoetin dose. Epoetin was well tolerated, and no antibodies were detected.

Clinical pharmacology of recombinant human erythropoietin (r-HuEPO).

Recombinant human erythropoietin reverses the severe anemia associated with end-stage renal disease. Mean half-life values after a single intravenous bolus dose range from 4-13 hours. Renal clearance is not a significant route of elimination. Dosing schedules in chronic renal failure involve a single intravenous bolus dose administered three times weekly after hemodialysis. Subcutaneous dosing has been approved and may be used in patients without intravenous access. Reticulocyte counts and hematocrit levels exhibit dose-dependent increases; improved hematocrit levels can be sustained with maintenance doses.

Epoetin: human recombinant erythropoietin.

The chemistry, pharmacology, pharmacokinetics, clinical uses and efficacy, adverse effects, drug interactions, dosage and administration, and formulary considerations of epoetin are described. Erythropoietin, a glycoprotein hormone primarily synthesized in the kidney, is the chief regulator of red blood cell production. Erythropoietin concentrations increase in response to a hypoxic state, resulting in increased red blood cell formation, accelerated hemoglobin production, and premature movement of reticulocytes into the circulation. The human gene responsible for the production of erythropoietin recently was cloned, and the recombinant product--epoetin--has been made available through mass production. The apparent volume of distribution of i.v. epoetin approximates the assumed plasma volume both in healthy volunteers and in patients with chronic renal failure. Little is known about the metabolism and route of elimination of epoetin and erythropoietin. Epoetin recently was approved by the FDA for treatment of anemia associated with chronic renal failure. Clinical trials in patients receiving hemodialysis or peritoneal dialysis and in predialysis patients with renal dysfunction demonstrate epoetin's efficacy. Other potential indications include augmentation of blood production in patients enrolled in autologous blood donation programs and treatment of anemias associated with rheumatoid arthritis, sickle cell disease, acquired immunodeficiency syndrome, cancer, and premature birth. The most frequent adverse effect associated with epoetin therapy is the worsening or development of hypertension. Other adverse effects include thrombocytosis, hyperkalemia, rise in serum urea concentration, iron deficiency, and flu-like symptoms. No drug interactions with epoetin have been reported in humans. The recommended starting epoetin dosage in patients with chronic renal failure is 50-100 IU/kg three times weekly. Epoetin is available only as an injection for i.v. or s.c. administration. Epoetin provides a new therapeutic approach to the treatment of anemia associated with chronic renal failure in hemodialysis, peritoneal dialysis, and predialysis patients. Benefits of epoetin therapy include reduced need for blood transfusions, the amelioration of anemic symptoms, and an improved quality of life.

Hepatotoxicity associated with amiodarone therapy.

Amiodarone has been reported to cause asymptomatic increases in liver function tests in 15-55% of patients. Clinically apparent, symptomatic hepatic disease occurs less frequently, but patients have been reported to have hepatomegaly, jaundice, cirrhosis, or chronic active hepatitis. Less well recognized is the fact that amiodarone has been attributed to six deaths. We cared for a patient with amiodarone hepatotoxicity, which led us to review the literature associated with this serious condition.