Rapid, high-dose intravenous iron sucrose therapy in 2 Jehovah's Witness patients with severe anemia, iron deficiency and chronic kidney disease.

AIMS: Two patients with chronic kidney disease presented with severe anemia and iron deficiency. Because of their religious beliefs, red blood cell transfusions were not possible, and an aggressive therapeutic regimen of iron replenishment was instituted. MATERIAL AND METHODS: The regimen included epoetin, folic acid and high-dose intravenous iron sucrose infusions over multiple successive days (total dosages of 2 and 3.5 g). RESULTS: The patients' iron stores were replenished and an erythropoietic response ensued subsequent to this aggressive and unique therapeutic regimen. There were no side effects observed which could be attributed to iron sucrose, and both patients stabilized and were discharged after 3 - 4 weeks. CONCLUSION: In patients with chronic kidney disease who are severely anemic and iron-deficient and where transfusions are not possible, an aggressive regimen of multiple high-dose iron sucrose infusions may be both safe and effective.

Effect of angiotensin-converting enzyme inhibitors on response to erythropoietin therapy in chronic dialysis patients.

BACKGROUND: Erythropoietin (EPO) therapy is a common and effective treatment for the correction of anemia in patients with end-stage renal disease. Simultaneous treatment with angiotensin-converting enzyme (ACE) inhibitors for the control of hypertension and/or heart failure is often necessary. Recent reports in the literature have raised concern about a potential interaction between these drugs, with a resultant decreased EPO efficacy. METHODS: To investigate whether this interaction occurs in chronic dialysis patients, we retrospectively reviewed the records of 175 patients receiving chronic dialysis. All study patients were treated with EPO for at least 3 months, and had normal iron indices. Patients were treated with ACE inhibitors for at least 3 months, at a constant daily dose for at least 1 month (group 1, n = 32), or did not receive ACE inhibitors (group 2, n = 143). Patients with infections or overt iron deficiency were excluded. Total weekly EPO doses and hematocrit (Hct)/hemoglobin (Hgb) values in the two groups were compared. Variables known to affect response to EPO were compared, including ferritin, transferrin saturation, dialysis dose and serum aluminum. RESULTS: Total weekly EPO dose was 17,358 +/- 6,871 units in group 1 and 17,612 +/- 7,744 units in group 2 (p = 0.854). The achieved Hct was 32.1 +/- 4.4% (group 1) and 30.5 +/- 4.0% (group 2) (p = 0.079). Similarly, Hgb, ferritin, transferrin saturation, Kt/V, and serum aluminum were not different. The dose or duration of ACE inhibitor therapy did not affect Hgb or Hct. Thus, ACE inhibitor therapy does not appear to affect response to EPO in chronic dialysis patients.

Blood disposition and urinary excretion kinetics of methazolamide following oral administration to human subjects.

The pharmacokinetic disposition of methazolamide (MTZ) was studied in five healthy volunteers following administration of a single oral dose. Drug concentrations in blood, plasma, and urine were measured by HPLC. Over the range of plasma concentrations observed in vivo, MTZ free fraction (measured by ultrafiltration) was 0.28. Being a carbonic anhydrase inhibitor, MTZ would be expected to distribute into, and be sequestered by, red blood cells. For this reason, MTZ disposition was characterized utilizing blood concentrations as the reference. Using a two-compartment model, a series of differential equations were simultaneously fitted to blood concentrations and urinary excretion data generating estimates for k10 (0.035 +/- 0.019 h(-1)), k12 (0.200 +/- 0.036 h(-1)), k21 (0.077 +/- 0.046 h(-1)), k(a) (0.304 +/- 0.064 h(-1)), Vc (1.1 +/- 0.18 L) and f(r) (fraction excreted renally, 0.61 +/- 0.14). Total blood clearance was 0.037 +/- 0.020 L h(-1). The model estimate of elimination half-life (126 +/- 61 h) was consistent with drug binding to a high affinity carbonic anhydrase isozyme in the erythocyte. Estimates of MTZ renal clearance and renal excretion ratio were 0.021 +/- 0.010 L h(-1) and 0.16 +/- 0.06, respectively. Overall, the prolonged elimination of MTZ from the blood is the result of extensive erythrocyte distribution and tubular reabsorption by the kidney.

Potential angiotensin-converting enzyme inhibitor-epoetin alfa interaction in patients receiving chronic hemodialysis.

We compared epoetin alfa (EPO) dose requirements and hematocrit response in 17 patients receiving chronic hemodialysis at baseline and after 3 and 12 months of therapy with angiotensin-converting enzyme (ACE) inhibitors (12 enalapril, 5 captopril). No acute processes were present (infection, hemorrhage, inflammation) at time of starting ACE inhibitor therapy. Mean (+/- SD) intravenous EPO dosages at zero, 3, and 12 months were 6012 +/- 2575, 5800 +/- 2026, and 5660 +/- 2285 U 3 times/week (p=0.56), and mean differences were -212 U for 0-3 months (95% CI -1310 to 886) and -713 U for 0-12 months (95% CI -2142 to 716). Mean +/- SD hematocrits were 30.5 +/- 3.9%, 31.6 +/- 3.2%, and 34.2 +/- 3.1% (p=0.01, zero vs 12 mo), and mean differences were 1.7% for 0-3 months (95% CI -1.41 to 4.81) and 3.85% for zero-12 months (95% CI 0.71-7). Our results indicate that ACE inhibitors do not increase EPO dose requirements or reduce hematocrits in these patients.

Hemodialyzability of sertraline.

Sertraline is an antidepressant which selectively inhibits the neuronal uptake of serotonin in the central nervous system. The pharmacokinetics of sertraline in end-stage renal disease (ESRD) and the effect of hemodialysis on sertraline clearance is unknown. A dose of 100 mg sertraline was administered to two anuric hemodialysis patients after hemodialysis. During the next hemodialysis session, simultaneous pre- and post dialyzer blood samples were obtained at the start of and hourly throughout dialysis until completion. All spent dialysate was collected hourly, quantified and an aliquot retained. Additional blood samples were obtained approximately 20 hours after dialysis and prior to the next treatment. Serum and dialysate were assayed for sertraline by gas chromatography-mass spectroscopy. Initial sertraline serum concentrations were similar to those observed in subjects with normal renal function given the same sertraline dose, implying unaltered absorption and distribution. Sertraline was not detected in any dialysate sample. The elimination half-life was 42-92 h (normally 24-36 h), suggesting impaired clearance. Smaller doses of sertraline may be required in ESRD patients, yet post-hemodialysis supplementation is unnecessary.

Acetazolamide toxicity and pharmacokinetics in patients receiving hemodialysis.

Acetazolamide-induced central nervous system toxicity occurred in two patients undergoing hemodialysis. Symptoms of toxicity included fatigue, lethargy, and confusion, which resolved several days after discontinuing acetazolamide. Pharmacokinetic studies showed markedly elevated serum concentrations of the drug during the period of toxicity, which decreased at a slower rate compared with that reported in patients with normal renal function. The effect of hemodialysis on acetazolamide clearance was quantified. The agent should be avoided in patients receiving dialysis unless the dosage is reduced and serum concentration monitoring can be performed in a timely manner. These patients should be monitored closely for central nervous system toxicity if acetazolamide is given.

The effect of sucralfate on serum lipids and lipoproteins in normal volunteers [corrected].

Sucralfate is used in the treatment and prophylaxis of peptic ulcer disease. One possible mechanism of action is the binding of bile acids. Because the absorption of dietary fat and cholesterol is dependent on the presence of bile acids in the small intestines, sucralfate therapy may produce changes in serum lipoprotein composition qualitatively similar to bile acid sequestrants, such as cholestyramine, which reduce serum cholesterol levels. Although changes in total serum cholesterol have not been reported in sucralfate efficacy studies, the effect of sucralfate on serum lipoprotein composition has not been specifically addressed. The purpose of this study was to prospectively examine the effect of sucralfate on serum lipids and lipoproteins in normal volunteers. Eight healthy volunteers (six men, two women) were recruited for this 10-week study. Drugs known to affect cholesterol levels were not permitted before or during the study. Diet composition during the study period was unaltered from before the study. Subjects took 1 g sucralfate orally 1 hour before meals and at bedtime (four times a day) for 8 weeks, followed by a 2-week washout period. Fasting blood samples were obtained at baseline and weekly, and were analyzed for serum total and HDL cholesterol and for triglycerides. Levels of LDL cholesterol were estimated. After eight weeks of sucralfate, HDL cholesterol increased from baseline by 2.5 mg/dL (6.6%, from 37.6 +/- 9.5 to 40.1 +/- 8.69 mg/dL), and LDL cholesterol decreased by 7.6 mg/dL (6.4%, from 134 +/- 28.1 to 125.4 +/- 34.1). Total cholesterol decreased by 3.5 mg/dL (1.8%, from 192.9 +/- 34.3 to 189.4 +/- 37.2 mg/dL.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetics of acetazolamide during CAPD.

Acetazolamide is a carbonic anhydrase inhibitor commonly used to reduce intraocular pressure (IOP). We report the first pharmacokinetic study of acetazolamide in a patient undergoing continuous ambulatory peritoneal dialysis (CAPD). The patient was a Type I diabetic with end-stage renal disease (ESRD) undergoing CAPD who received acetazolamide for elevated IOP after surgery for a detached retina. Serum acetazolamide concentrations were measured prior to a 250 mg oral dose and 12 additional times during a 24-h dosing interval. All dialysate effluent was collected and assayed for acetazolamide. Serum concentrations at the beginning and end of the dosing interval were 18 and 17 mcg/mL, respectively, with a maximum concentration of 27 mcg/mL at 6.5 h (therapeutic range = 5-10 mcg/mL). The elimination half-life was prolonged, 28.5 h, compared to that seen in subjects with normal renal function (5-10 h). CAPD did not remove a clinically significant amount of drug (17.1 mg, or 6.8% of dose recovered in dialysate). The patient was very lethargic during therapy, a possible manifestation of acetazolamide toxicity. Marked reduction in acetazolamide dosage (in this case, 125 mg/day) would be required to prevent drug accumulation and toxicity.

Epoetin enhances erythropoiesis in normal men undergoing repeated phlebotomies.

Epoetin may enhance autologous blood donation, but efficacy and dose response have not been established. This multicenter, double-blind trial compared intravenous placebo (n = 23) with epoetin beta, 250 U/kg (n = 23), 500 U/kg (n = 19), and 1000 U/kg (n = 22), administered three times weekly for 26 days. Normal men (age, 28 +/- 7 years; mean +/- SD) received phlebotomies up to three times weekly as long as the hemoglobin remained greater than or equal to 12 gm/dl. Subjects treated with epoetin donated 32% more units of blood (p less than 0.05) compared with placebo. A dose response was not observed. Platelet counts increased with epoetin compared with placebo, but platelet function and bleeding time did not change. Prothrombin times increased and partial thromboplastin times decreased with both epoetin and placebo. The supernatant of packed red blood cells collected after multiple phlebotomies and stored 42 days had slightly lower glucose concentrations and pH after therapy with epoetin. Blood pressure did not change with epoetin or placebo. These findings support the efficacy and safety of epoetin for enhancing the erythropoietic response of normal subjects during intensive phlebotomy.

New drugs on the horizon.

The agents covered in this article are useful in a wide range of illnesses, including infections, cancers, cardiovascular and gastrointestinal diseases, and others. One of the major forces driving the development of new drugs is the use of biotechnology. Biotechnology encompasses the techniques of recombinant DNA and monoclonal antibody technologies to produce protein drugs that have not been previously available in sufficiently pure form or in adequate quantities. As new drugs are developed, the authors hope that intensified efforts will be geared towards the development of unique drugs that offer important therapeutic gains.

Disposition of roxithromycin in patients with normal and severely impaired renal function.

The disposition of roxithromycin, an investigational macrolide antibiotic, was evaluated in 20 subjects, 10 with normal renal function (creatinine clearance [CLCR] of 116 +/- 17 ml/min [mean +/- standard deviation]) and 10 with severely impaired renal function (CLCR of 10.2 +/- 2.6 ml/min) after a single 300-mg oral dose. Plasma concentration-time data were analyzed in terms of a one- or two-compartment oral absorption model utilizing nonlinear regression analysis. The terminal elimination half-life was significantly prolonged in the group with severely impaired renal function (15.5 +/- 4.7 h) compared with that of the group with normal renal function (7.9 +/- 2.5 h). Apparent total body clearance was significantly reduced in the renally impaired (25.3 +/- 10.5 ml/min) in relation to the group with normal renal function (48.8 +/- 11.1 ml/min). The first-order absorption rate constants and apparent volumes of distribution did not differ between the two groups. These data indicate that the disposition of roxithromycin is significantly delayed in subjects with CLCRs of less than 15 ml/min and suggest that the roxithromycin dosing interval be doubled for these patients.

Recombinant human erythropoietin.

Erythropoietin is produced mainly by the kidneys and stimulates erythropoiesis in the bone marrow. Chronic renal failure is characterized by anemia, which is principally caused by erythropoietin deficiency. Recombinant human erythropoietin (r-hEPO) corrects the anemia of chronic renal disease and improves patient well-being, exercise tolerance, and cognitive function. The clinical pharmacology, efficacy, safety, and tolerance of r-hEPO are presented. Four major studies attest to r-hEPO's efficacy in the treatment of anemia of chronic renal disease and document potential toxicities of hypertension, iron deficiency, thrombosis, and bone pain. Careful attention to the extent of correction of the hematocrit, increased heparinization during hemodialysis therapy, and compliance with dietary restrictions may minimize the incidence and severity of adverse reactions. Resistance to r-hEPO may be due to iron deficiency, aluminum toxicity, or inflammation, including infection. Potential future uses of r-hEPO include the treatment of various other anemias, such as those seen in sickle cell anemia, rheumatoid arthritis, and autologous blood donation. Controlled clinical studies in these areas have not been reported.

Disposition of guanadrel in subjects with normal and impaired renal function.

The disposition of a single 25 mg oral dose of guanadrel was evaluated in 22 subjects with various degrees of renal function. The terminal elimination half-life was significantly prolonged in subjects with a creatinine clearance (ClCr) less than 30 mL/min/1.73 m2 (19.2 +/- 16.8 h) compared to 3.7 +/- 1.9 h in subjects with a ClCr greater than 80 mL/min/1.73 m2. Apparent total body clearance (Clp/F) was also progressively lower in the patients with decreased renal function and the decline was significantly correlated with ClCr (Clp/F = 0.0294 + 0.0236 Clcr, r = 0.74, P = 0.002). Renal clearance and apparent nonrenal clearance also declined as creatinine clearance decreased, and both were significantly correlated with the observed ClCr. Apparent volume of distribution averaged 11.5 +/- 8.9 L/kg and did not differ in patients with decreased renal function compared to those with normal renal function. Thus, the disposition of guanadrel is significantly altered in the presence of renal insufficiency and dosage adjustments may be necessary, especially in patients with ClCr less than 50 ml/min.

Interindividual and intraindividual variability in labetalol pharmacokinetics.

The between-subject and within-subject variability in the pharmacokinetics of labetalol at steady state were determined. Sixteen nonobese normal volunteers (mean age, 27 years) received five different formulations of labetalol orally on five different occasions every 12 hours for five doses. A 7-day washout separated each administration phase. Plasma concentration-time data for labetalol were obtained over the 24-hour period after the fifth dose in each phase. Labetalol concentrations in plasma were measured using high-performance liquid chromatography (HPLC). Pharmacokinetic parameters for each subject after each study phase were estimated. The mean V beta/F, Vdss/F, TBC/F, t1/2 beta, and AUC tau 0 for each subject ranged between 18.1 and 161.9 L/kg, 7.1 and 53.9 L/kg, 1.3 and 5.72 L/hr/kg, 6.9 and 11.0 hours, and 154 and 520 micrograms.hr/L, respectively, indicating large interindividual variability. Considerable intraindividual variability in each of the pharmacokinetic parameters was also observed. These data indicate that a larger number of subjects will be required to detect "significant" differences in the disposition of labetalol.