Use of magnesium hydroxide and low magnesium dialysate does not permit reduction of aluminum hydroxide during continuous ambulatory peritoneal dialysis

In an effort to reduce the ingestion of aluminum in phosphate-binding antacids, we treated seven patients on continuous ambulatory peritoneal dialysis (CAPD) with low magnesium dialysate and phosphate binders containing both aluminum and magnesium hydroxide. The total amount of phosphate binders prescribed was adjusted to maintain the serum phosphorus at normal levels. The dose of magnesium hydroxide was limited by intolerable gastrointestinal side effects in six of the seven patients. One patient also developed symptomatic hypermagnesemia. When magnesium hydroxide was prescribed in tolerable doses, the mean aluminum dose was not significantly decreased compared with the dose when taking aluminum hydroxide alone. We conclude that substitution of magnesium hydroxide for aluminum hydroxide as a phosphate binder fails to reduce the dose of aluminum in most patients on CAPD.     

Phosphate-binding properties and electrolyte content of aluminum hydroxide antacids

The phosphate-binding capacities of 19 liquid and solid aluminum hydroxide gel antacids were determined in vitro under varying pH conditions. The resulting data provide a basis explaining the phosphate-binding characteristics observed when patients are treated with long-term aluminum hydroxide therapy. No antacid, liquid or solid, showed significant binding at pH 1.0. Maximum phosphate binding (expressed as phosphorus; P) was observed at pH 2.0 and 3.0 for most antacids and decreased markedly at alkaline pH. The liquid antacids showed a significantly greater phosphate-binding capacity than did tablets or capsules (p less than 0.01). At pH 2.0, the liquid antacids bound a mean of 22.3 mg P/5 ml. At pH 8.0 binding was reduced to a mean of 7.3 mg P/5 ml. Significant interbrand differences were observed. At pH 2.0, the solid antacids bound a mean of 15.3 mg P/tablet or capsule. At pH 8.0, binding was reduced to a mean of 5.8 mg P/tablet or capsule. Interbrand differences, while substantial, were less than those observed among the liquid antacids. Variations in sodium and potassium content were clinically insignificant for most of the antacids in this study, while the differences in phosphate-binding properties were sufficient to warrant attention in the patient with renal failure.     

Interactions Between Phosphate Binders and H2 Blockers

Do H₂ blockers (cimetidine, ranitidine) interact with calcium and aluminum phosphate binders in end-stage renal disease patients?     

Phosphate binding gels: balancing phosphate adsorption and aluminum toxicity

The phosphate binding capacity of five commercial aluminum hydroxide phosphate-binding gels and two crystalline forms of aluminum hydroxide was studied by an in vitro procedure which simulated passage through the stomach to the small intestine. The potential for aluminum toxicity was estimated by determining the fraction of the dose which was converted into soluble aluminum species by acid neutralization at pH 3, 37 degrees C. The commercial products varied widely both in phosphate binding capacity and production of soluble aluminum species. The evidence suggests that the ideal phosphate binder will have a surface area small enough to minimize the formation of soluble aluminum species during the gastric residence time but also large enough to adsorb a clinically significant amount of phosphate.     

Pharmacology of the phosphate binder, lanthanum carbonate

Studies were conducted to compare the phosphate-binding efficacy of lanthanum carbonate directly with other clinically used phosphate binders and to evaluate any potential adverse pharmacology. To examine the phosphate-binding efficacy, rats with normal renal function and chronic renal failure received lanthanum carbonate, aluminum hydroxide, calcium carbonate, or sevelamer hydrochloride in several experimental models. Lanthanum carbonate and aluminum hydroxide markedly increased excretion of [(32)P]-phosphate in feces and reduced excretion in urine in rats with normal renal function (p < 0.05), indicating good dietary phosphate-binding efficacy. In rats with chronic renal failure, lanthanum carbonate and aluminum hydroxide reduced urinary phosphate excretion to a greater degree and more rapidly than calcium carbonate, which in turn was more effective than sevelamer hydrochloride. The potential to induce adverse pharmacological effects was assessed systematically in mice, rats, and dogs with normal renal function using standard in vivo models. There was no evidence of any adverse secondary pharmacological effects of lanthanum carbonate on the central nervous, cardiovascular, respiratory, or gastrointestinal systems. These studies indicate that lanthanum carbonate is the more potent of the currently available dietary phosphate binders. No adverse secondary pharmacological actions were observed in vivo in a systematic evaluation at high doses.     

The role of daily dialysis in the control of hyperphosphatemia

The role of daily dialysis in the control of hyperphosphatemia. In patients with end-stage renal disease (ESRD), hyperphosphatemia occurs in the vast majority of patients. The numerous clinical sequelae of hyperphosphatemia include secondary hyperparathyroidism and increased risk of cardiovascular death. Chronic hemodialysis as it is currently practiced in the United States does not remove sufficient phosphate to control serum levels within accepted guidelines. The inadequacy of conventional hemodialysis in removing phosphate mandates the use of phosphate binders in virtually all hemodialysis patients. Despite their proven efficacy, these medications fail to control phosphorous in 70% of hemodialysis patients. Additionally, these medications may have untoward side effects that must be considered since they are typically intended for lifetime use. Quotidian hemodialysis has in previous uncontrolled studies shown promise in reducing serum phosphorus while at the same time reducing or eliminating the need for phosphate binders. Recent results from our group demonstrate for the first time in a controlled fashion the efficacy of short daily dialysis in controlling serum phosphorus.     

Colonic intussusception secondary to a calcium phosphate bezoar in a child receiving calcium carbonate for hyperphosphatemia

We report a case of a calcium phosphate bezoar resulting in colonic intussusception in a boy with chronic renal failure who received calcium carbonate to control hyperphosphatemia. Because of concerns about aluminum-related disease in patients receiving aluminum hydroxide phosphate binders, calcium carbonate is being used more frequently to manage phosphate retention in renal failure. The development of bezoars may complicate this new form of therapy.     

Lanthanum carbonate as a first-line phosphate binder: the "cons"

Controlling serum phosphorus levels in patients with renal failure is critical. The use of oral phosphate-binding agents is universal for patients with end-stage kidney disease to reduce phosphate absorption. The therapeutic goal is to reduce serum phosphorus levels without disturbing calcium homeostasis or promoting accumulation of potentially toxic elements from the medication. Aluminum hydroxide effectively reduces serum phosphorus, but has largely been abandoned as a first-line phosphate binder because of hazards associated with metal absorption and tissue accumulation. Traditional calcium-based phosphate binders tend to promote hypercalcemia and calcium overloading, and are linked to accelerated cardiovascular calcification. Interest in aluminum-free, calcium-free phosphate-binding agents continues to grow. Sevelamer hydrochloride, a metal-free, calcium-free hydrogel, is not absorbed, has been proven safe and efficacious in controlling serum phosphorus, and is associated with attenuated progression of cardiovascular calcification. Lanthanum carbonate is a newer aluminum-free, calcium-free phosphate-binding agent. Lanthanum is a rare-earth trace metal with industrial and agricultural applications. As a therapeutic, this metal-based binder appears effective in reducing serum phosphorus, yet concerns remain about lanthanum accumulation in tissues during long-term oral administration. Similar to the metal aluminum, lanthanum is absorbed in the intestine and accumulates in body tissues, especially in the liver, bone, muscle, kidney, and brain. Moreover, the rate of intestinal absorption of lanthanum is enhanced in chronic renal failure. Our experience with aluminum hydroxide suggests caution regarding the long-term use of another metal-based agent that displays enhanced absorption in the uremic state and progressive tissue accumulation.     

Oral Phosphate Binders: Phosphate Binding Capacity of Iron (III) Hydroxide Complexes Containing Saccharides; and Their Effect on the Urinary Excretion of Calcium and Phosphate in Rats

Phosphate binders that contain aluminum or calcium are frequently prescribed to treat hyperphosphatemia in patients with end-stage renal disease (ESRD), but an accumulation of aluminum can lead to encephalopathy, aluminum related bone disease (ARBD) such as osteomalacia, anaemia, and resistance to erythropoietin, and calcium accumulation can lead to hyperculcaemia. High phosphate concentrations are reducd in vitro and in vivo by a phosphate adsorption pill, which is synthesized by hydrolyzing ferrous sulfate in the presence of saccharides, to form an iron (III)-saccharide complex that is acid resistant anti binds phosphate greater than iron (III) hydroxide alone. Under in vitro conditions, containing 3.26 mg P/dL, the iron (III)-sucrose complex showed the highest phosphate adsorption capacity at pH 2 with artificial gastric juice, 58.9 mg P/g binder. For the 7 day in vivo study, 0% (Group 1), 1% (Group 2), 4% (Group 3), and 8% (Group 4) iron (III)-sucrose complex was admixed into the rodent chow by weight and fed to 15 male Wistar rats. The weight and volume of the feces and urine, and the calcium, iron, and phosphorus excretions in the feces and urine samples were monitored for any signs of irregularity. Total urine outfrow was collected during a 24-h period to determine the amount of phosphate recovered, which indicates the ability of the phosphate binder to reduce gastrointestinal phosphate absorption. The fecal iron excretion was significantly effected by the amount of binder ingested throughout the study for Group 2 (p < 0.001), Group 3 (p < 0.01), and Group 4 (p < 0.001). The urinary calcium excretion (mg/rat/24-h) significantly increased by the 7th day for Group 2 (p < 0.05) and Group 4 (p < 0.01) in comparison to the control. Finally, after 7 days, there was a significant drop in the urinary phosphorus levels (mg P/rat/24-h) in a dose dependant manner for Group 2: from 7.82 ± 1.46 to 1.98 ± 0.10 mg P/rat/24-h (102 mg P/dL/24-h; p < 0.05); Group 3: from 6.70 ± 1.14 to 0.16 ± 0.09 mg P/rat/24-h (6.0 mg P/dL/24-h; p < 0.01); and Group 4: fiom 8.25 ± 0.67 to 0.04 ± 0.01 mg P/rat/24-h (0.9 mg P/dL/24-h; p < 0.01). The results show that this new adsorbent might provide an alternative to conventional aluminum and calcium containing phosphate-binding agents for combating hyperphosphataemia.     

Oral phosphate binders: phosphate binding capacity of iron (III) hydroxide complexes containing saccharides and their effect on the urinary excretion of calcium and phosphate in rats.

Phosphate binders that contain aluminum or calcium are frequently prescribed to treat hyperphosphatemia in patients with end-stage renal disease (ESRD), but an accumulation of aluminum can lead to encephalopathy, aluminum-related bone disease (ARBD) such as osteomalacia, anaemia, and resistance to erythropoietin, and calcium accumulation can lead to hypercalcaemia. High phosphate concentrations are reduced in vitro and in vivo by a phosphate adsorption pill, which is synthesized by hydrolyzing ferrous sulfate in the presence of saccharides, to form an iron (III)-saccharide complex that is acid resistant and binds phosphate greater than iron (III) hydroxide alone. Under in vitro conditions, containing 3.26 mg P/dL, the iron (III)-sucrose complex showed the highest phosphate adsorption capacity at pH 2 with artificial gastric juice, 58.9 mg P/g binder. For the 7 day in vivo study, 0% (Group 1), 1% (Group 2), 4% (Group 3), and 8% (Group 4) iron (III)-sucrose complex was admixed into the rodent chow by weight and fed to 15 male Wistar rats. The weight and volume of the feces and urine, and the calcium, iron, and phosphorus excretions in the feces and urine samples were monitored for any signs of irregularity. Total urine outflow was collected during a 24-h period to determine the amount of phosphate recovered, which indicates the ability of the phosphate binder to reduce gastrointestinal phosphate absorption. The fecal iron excretion was significantly effected by the amount of binder ingested throughout the study for Group 2 (p < 0.001), Group 3 (p < 0.01), and Group 4 (p < 0.001). The urinary calcium excretion (mg/rat/24-h) significantly increased by the 7th day for Group 2 (p < 0.05) and Group 4 (p < 0.01) in comparison to the control. Finally, after 7 days, there was a significant drop in the urinary phosphorus levels (mg P/rat/24-h) in a dose dependent manner for Group 2: from 7.82 +/- 1.46 to 1.98 +/- 0.10 mg P/rat/24-h (102 mg P/dL/24-h; p < 0.05); Group 3: from 6.70 +/- 1.14 to 0.16 +/- 0.09 mg P/rat/24-h (6.0 mg P/dL/24-h; p < 0.01); and Group 4: from 8.25 +/- 0.67 to 0.04 +/- 0.01 mg P/rat/24-h (0.9 mg P/dL/24-h; p < 0.01). The results show that this new adsorbent might provide an alternative to conventional aluminum and calcium containing phosphate-binding agents for combating hyperphosphataemia.     

Effectiveness of intestinal phosphate binders in patients maintained by hemodialysis

Two formulations of aluminum phosphate binders-aluminum hydroxide suspension and aluminum carbonate powder in the form of capsules-were found to be equally effective in lowering the plasma phosphate concentration. The effective dose was 4 g/day given in divided doses before meals and at bedtime. Side effects were negligible with this dosage for both preparations, but aluminum carbonate capsules were preferred by most patients because of the greater convenience of the capsule form. Coincident with the lowering of serum phosphorus concentrations, serum parathyroid hormone concentrations decreased approximately 30% from levels obtained while patients were taking placebo.     

A comparison of clinically useful phosphorus binders for patients with chronic kidney failure

A comparison of clinically useful phosphorus binders for patients with chronic kidney failure. Over the past 30 years it has become apparent that hyperphosphatemia plays a major causative role across the entire spectrum of morbidity associated with advancing kidney dysfunction and failure. A large fraction (60% to 70%) of dietary phosphorus is absorbed and normally excreted by the kidneys. Ideally, as kidney function deteriorates, the net quantity of phosphorus absorbed from the GI tract should be proportionally reduced to match the decrease in kidney function. After initiation of chronic dialysis therapy, the absorbed phosphorus load should match the amount of phosphorus removed via dialysis plus any excreted by residual kidney function. Because it is very difficult to reduce dietary phosphorus to these levels, a variety of oral phosphorus binders have been employed. Currently available binders include alkaline aluminum, magnesium, and calcium salts (primarily calcium carbonate and calcium acetate), various iron salts, and the binding resin sevelamer hydrochloride. Lanthanum carbonate is the newest agent and will probably be released shortly. This review compares the theoretic and in vitro chemistry of these drugs with in vivo data obtained in both normal patients, and in patients with kidney failure. The clinical potency and potential toxicity of the binding agents are compared, and optimal drug administration strategies are also reviewed.     

Long-term suppression of hyperparathyroidism by phosphate binders in uremic children

Forty-five children with stable chronic renal failure, not on dialysis, were treated conservatively with a regimen of mild dietary phosphate restriction and high-dose phosphate binders for up to 5 years. Both aluminum hydroxide and calcium carbonate were used initially, but almost all patients were taking calcium carbonate towards the end of the period. Serum immunoreactive parathyroid hormone concentrations were significantly decreased and were within the normal range after 1 year and remained normal during treatment. There was no significant change in renal function over the same treatment period. We conclude that calcium carbonate should be used as the phosphate binder of choice in the long-term suppression of hyperphosphatemia and hyperparathyroidism in uremic children.     

Novel dosage forms and regimens for sevelamer-based phosphate binders.

Sevelamer, a nonabsorbed, calcium- and metal-free dietary phosphate binder, consists of a polyallylamine polymer backbone with a cationic charge that shows a high capacity for binding anionically charged compounds such as phosphate. The currently licensed form of sevelamer, Renagel, exists as sevelamer hydrochloride, which disassociates in the acidic environment of the stomach and early gastrointestinal tract, exchanging the chloride ions attached to the polymer backbone for phosphate ions. The resulting absorption of these chloride ions has been reported to be accompanied by a reduction in serum levels of bicarbonate in some patients. To minimize the possibility of this effect, a new salt form of sevelamer has been developed in which carbonate replaces the chloride counter ion, thereby providing a source of buffer. The majority of phosphate binders exist only in tablet form and are dosed three times per day with meals. Genzyme has developed sevelamer carbonate in tablet form and also as a powder formulation that can be taken after mixing with water. This allows for an alternate and potentially more palatable way of dosing. Preliminary data exist suggesting that once daily dosing with sevelamer hydrochloride tablets provides similar phosphate control to three times daily dosing. By providing novel dosage forms and regimens for sevelamer-based phosphate binders, Genzyme will be providing patients and health care providers additional choices and flexibility in controlling phosphorus levels in chronic kidney disease. This should translate to increased compliance and improved rates of phosphate control.     

Early absorption of enteral ranitidine after major laparotomy.

Thirty-six patients were studied following abdominal aortic surgery to determine if a commonly used medication could be absorbed from the gastrointestinal (GI) tract in the early postoperative period. Patients were randomized into two groups: Group I received ranitidine elixir 3 mg/kg via nasogastric tube every 12 hours; Group II received intravenous (IV) ranitidine 1 mg/kg every 8 hours. Ranitidine serum levels were measured with high performance liquid chromatography 1 hour after administration of the first three doses. Gastric pH was measured every 4 hours. It was found that serum ranitidine levels generally regarded as clinically effective were achieved in both groups. Although the levels were significantly higher following intravenous (IV) administration (Group II), there were no differences in average gastric pH. The authors conclude that within 24 hours of aortic surgery enterally administered ranitidine is effectively absorbed and provides prophylaxis equivalent to IV administration of the drug at lower cost. Other medications might be deliverable via the GI tract in the early postoperative period.     

Serum concentrations of calcitriol and PTH in hemo-dialysis patients on treatment with calcium carbonate.

The effects of calcium carbonate and aluminium hydroxide as phosphate binders were investigated in nine patients on chronic hemodialysis. Aluminium hydroxide, 1 g X 3, was given during four weeks followed by a period of four weeks without any phosphate binders and after this calcium carbonate, 2.5 g X 3, was introduced for four weeks. Calcium carbonate resulted in lowering of bioactive PTH in serum from 22.4 to 16.4 pM and a rise of serum calcitriol from 8.0 to 11.5 pg/ml with maintained control of phosphate and without significant difference in the calcium-phosphate product. Calcium in serum rose from 2.27 to 2.57 mM and mild hypercalcemia (less than 3.0 mM) in five of the patients could be controlled by dose reduction of calcium carbonate without losing control of serum phosphate levels. We conclude that calcium carbonate offers advantages as a phosphate binder compared to aluminium hydroxide in that it offers equal control of serum phosphate and elevates serum calcium which helps to control the hyperparathyroidism secondary to uremia.     

Calcium alginate, an aluminum-free phosphate binder, in patients on CAPD

Since dialysis solutions in CAPD are now nearly aluminum free, the only source for elevated aluminum levels are aluminum-containing phosphate binders. Elimination with CAPD is insufficient to prevent aluminum accumulation. Therefore, we investigated a phosphate binder consisting of calcium alginate, a natural polyuronic acid, containing 100 mg calcium/g substance in 14 patients on CAPD over a period of one year. The patients had previously been treated with aluminum-containing phosphate binders for a period of 24.3 +/- 21.3 months. During a period of 3 weeks before changing to the new phosphate binder the mean (+/- SD) serum phosphorus concentration was 1.8 +/- 0.4 mmol/l, while at the end of one year of treatment with calcium alginate the concentration was 1.6 +/- 0.4 mmol/l. In order to lower serum phosphorus to this level, it was necessary to increase the mean (+/- SD) amount of calcium alginate from 6.9 +/- 1.3 g per day at the beginning of the study to 8.3 +/- 2.1 g per day at the end. The mean (+/- SD) serum calcium concentration did not change throughout the study period. Serum levels of alkaline phosphatase, 1.25 (OH)2 vitamin D3, and intact parathyroid hormone did not change as well. The mean (+/- SD) serum aluminum level declined from 36.0 +/- 20 to 14.0 +/- 11.3 micrograms/l after 6 months (p less than 0.001). In conclusion, calcium alginate is a good alternative to aluminum-containing phosphate binders and to phosphate binders on a calcium base as it does not lead to hypercalcemia. It prevents aluminum intoxication and has no serious side effects.     

Phosphate-binding effects of sucralfate in patients with chronic renal failure

Sucralfate has been reported to reduce serum phosphate concentration in patients with chronic renal failure. To evaluate whether sucralfate could be used to treat hyperphosphatemia secondary to chronic renal failure and whether this treatment resulted in a reduced exposure to aluminum, an open-label crossover study was designed to determine the efficacy, relative potency, safety, and cost of sucralfate v aluminum hydroxide. Of the 21 hemodialysis patients completing both phases of the crossover study, serum phosphate could be maintained below 4.5 mg/dL (1.45 mmol/L) in 16 with sucralfate and in 14 with aluminum hydroxide. The 16 patients controlled on sucralfate consumed 1,694 +/- 190 mg/d of aluminum to maintain a serum phosphate concentration of 3.91 +/- 0.17 mg/dL (1.27 +/- 0.05 mmol/L) compared with the 14 patients controlled on aluminum hydroxide with an aluminum intake of 2,678 +/- 294 mg/d (P less than 0.025) and a serum phosphate concentration of 3.94 +/- 0.13 mg/dL (1.27 +/- 0.04 mmol/L). Thus sucralfate was an effective, albeit expensive, alternative to aluminum hydroxide for the treatment of hyperphosphatemia associated with chronic renal failure. Although the difference in aluminum intake was significant, use of sucralfate did not result in lower serum aluminum concentrations.     

Upper Gastrointestinal Tract Transit Times of Tablet and Drinkable Solution Formulations of Alendronate: A Bioequivalence and a Quantitative, Randomized Study using Video Deglutition

The bioequivalence and upper digestive tract transit time of a drinkable solution of 70?mg/100?mL alendronate was compared to reference tablets. A randomized, single- dose, two-way crossover study of the rate of urinary recovery of alendronate during 36?h (AE_(0–36?h)) by HPLC, in 104 healthy young male volunteers, showed that AE_(0–36?h) and the maximum excretion rate (R _max) were within the accepted range of bioequivalence 81.8–105.7 and 81.7–106.2, respectively. To characterize the oesophageal passage time of the two alendronate formulations, we performed a randomized, controlled study, in 24 healthy men and women (mean 52?years old), who took the formulations standing or lying down, by an X-ray video deglutition system. When taken in the standing position, both formulations had equal mean transit times from mouth to stomach and tablet disintegration but data dispersion was significantly smaller with the liquid form. When taken in lying position, drinkable alendronate had shorter and less variable median transit times compared to the tablets. These results show that the drinkable alendronate formulation is bioequivalent to the tablets and may be advantageous in patients in whom the transit or disintegration of the tablets is impaired.