Abstract
An oral sulfate salt solution (OSS), under development as a bowel cleansing agent for colonoscopy in humans, is studied in rats and dogs. In rats, amaximumpractical oral OSS dose (5 g/kg/d) is compared with an oral sodium phosphate (OSP) solution, both at about 7 times the clinical dose. OSS induces the intended effects of loose stools and diarrhea. In rats, higher urine sodium and potassium accompany higher clearance rates, considered adaptive to the osmotic load of OSS. OSS for 28 days is well tolerated in rats and dogs. In contrast, OSP causes increased mortality, reduced body weight and food consumption, severe kidney tubular degeneration, and calcium phosphate deposition in rats. These are accompanied by mineralization in the stomach and aorta, along with cardiac and hepatic degeneration and necrosis. The greater safety margin of OSS over OSP at similarmultiples of the clinical dose indicates its suitability for human use.
Sodium sulfate (Glauber’s salt) and magnesium sulfate (Epsom salts) have been used as osmotic laxatives since the 17th century. Their mechanism of action relies on the saturability of the intestinal sulfate transporters, allowing sulfate levels to obligate water retention in the lumen of the intestine. 1 Depending on the dose and its timing, a laxative action follows when there is sufficient unabsorbed sulfate in the intestines. Cocchetto and Levy 2 found that 5 of 5 subjects who consumed 18 g of sodium sulfate (5.4 g of sulfate) as a single dose experienced diarrhea over 24 hours. The same amount split over 4 doses produced no diarrhea or diarrhea of only short duration. Half this amount in 2 equal hourly doses produced loose stools but no diarrhea. 3
Single sulfate salts for bowel cleansing pose risks of hypernatremia or hypermagnesemia, attributable to the ready absorption of their cation components. Indeed, 200 g of magnesium sulfate produced significant hypermagnesemia and hypophosphatemia after its ingestion. 4 However, a bowel cleansing preparation for colonoscopy consisting of sodium sulfate combined with polyethylene glycol in a balanced salt solution caused minimal electrolyte absorption and fluid shifts and no changes in hemoglobin, hematocrit, or serum electrolytes. 1 Excellent colon cleansing and safety, despite the large volumes (4 L), advanced these “lavage” bowel preparations to become the comparator of new agents that have been developed over the ensuing years.
A bowel cleansing regimen using oral sodium phosphates (OSP) ascended in popularity because of greater patient acceptance of the lower total fluid volumes (2.4 L) coupled with adequate bowel cleansing. Earlier researchers recognized the electrolyte shifts that followed OSP use. Although hypernatremia, hypocalcemia, and hyperphosphatemia occurred, they were viewed as transient. The accompanying clinical signs were considered rare and manageable with proper dosage and hydration. This acceptance began to change after Ayala and associates 5 reported a patient who developed persistent renal insufficiency and hyperphosphatemia after the use of OSP. Haase 6 reviewed clinical and animal experiences from the prior 20 years that linked the administration of phosphate salts with nephropathy, and the author advanced the understanding of the potential risks by showing histological evidence of renal tubular calcium phosphate deposition in animals. Furthermore, electrolyte balance studies in people have estimated that absorbed phosphate (calculated as the amount not present in the stool after an OSP dose) is about 35%, more than twice the fractional absorption of sulfates. 7 The amount of absorbed phosphate leads to hyperphosphatemia, which contributes to precipitation of calcium phosphate crystals in the kidney, a condition that Markowitz et al 8 termed acute phosphate nephropathy.
Therefore, today there is the need for an improved formulation that is similarly effective in colon cleaning prior to colonoscopy procedures. The product should be of low volume to improve patient compliance and willingness to undergo a colonoscopy. It should produce clinically insignificant fluid or electrolyte shifts and should minimize the risks of adverse effects. In this regard, the OSS formulation may have advantages because sulfates have higher relative solubility compared with phosphates and therefore do not promote calcium phosphate precipitation in the urine of patients, as has been reported with OSP. 7 Because the toxicology literature on sulfates consists of “legacy” studies, usually performed with few animals and never approaching modern designs, we examined the safety and efficacy of the OSS formulation in animals to provide support for its phase III clinical development.
Materials and Methods
Physical, Chemical, and Pharmaceutical Properties of the Formulation
OSS contained 0.26 g, 0.046 g, and 0.024 g of sodium, potassium, and magnesium anhydrous salts, respectively, per 1 mL of deionized water. This matched the types and proportions of the OSS (SuPrep; Braintree Laboratories Inc., Braintree, Massachusetts) that was used in phase III clinical studies (J. DiPalma et al, unpublished data, 2009). The solubility of the sulfate salts limited the maximum dose to 5.0 g/kg/d at a dosing volume of 15 mL/kg, the highest practical dose and volume for once-daily oral administration to rats and dogs for a repeated-dose study. Observations were compared with an OSP solution (Fleet Phospho-Soda; C.B. Fleet, Lynchburg, Virginia) that has been used in bowel cleansing for preparation of patients before colonoscopy. This formulation contains 0.43 g/mL of NaH2PO4 and 0.095 g/mL of Na2HPO4 as anhydrous salts. It was diluted for administration to rats in a 15-mL dose of 5.13 g/kg/d. To place these doses into clinical perspective, they are both approximately 7-fold greater on a weight basis (assuming a 60-kg person) than that which would be consumed prior to colonoscopy.
Animals
Male and female Sprague Dawley rats, Crl:CD (SD), were obtained from Charles River Laboratories International, Inc (Wilmington, Massachusetts). The rats were approximately 7 to 8 weeks old at the initiation of dose administration. Male and female beagle dogs were obtained from Ridglan Farms (Mt Horeb, Wisconsin). Dogs were 5.5 to 6.5 months old when received. At the initiation of dosing, males weighed 7.1 to 8.8 kg and females weighed 6.0 to 8.0 kg.
All animals were housed individually in species-appropriate, stainless steel cages with wire mesh floors. They were maintained in accordance with the Guide for the Care and Use of Laboratory Animals. 9 The Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC International) accredits the animal facilities at WIL Research Laboratories, LLC. The 28-day studies were conducted in compliance with the United States Food and Drug Administration (FDA) Good Laboratory Practice (GLP) Regulations (21 CFR Part 58), October 5, 1987.
Toxicity Studies in Rats
7-day study
A preliminary 7-day maximum dose study was undertaken to determine the tolerance of rats when administered OSS and OSP in doses of 5.0 g/kg/d and 5.13 g/kg/d, respectively. The dose of OSP was about 9% lower than OSS on an osmotic load basis. Administration of formulations by oral gavage was conducted in male and female rats in groups of 3 animals/sex. The study was non-GLP.
28-day study
OSS was administered orally by gavage, once daily, to groups of 10 rats/sex/dose at dose levels of 1.25, 2.5, and 5.0 g/kg/d (25.3, 50.5, and 101 mmol/kg/d, respectively). The study was conducted according to GLP guidelines. OSP was administered as a positive control to 10 rats/sex at a dose of 5.13 g/kg/d (91 mmol/kg/d). A concurrent control group received the vehicle (deionized water) on a comparable regimen. The dosage volume was 15 mL/kg for all groups. All animals were observed twice daily for clinical observations, mortality, and moribundity. Clinical examinations were performed 3 times daily, and detailed physical examinations, individual body weights, and food consumption were assessed weekly. Ophthalmic examinations were performed during study weeks −1 and 4 for males and during study weeks −2 and 3 for females. Clinical pathology evaluations (hematology, coagulation, serum chemistry, and urinalysis) were performed on all surviving rats at the scheduled necropsy on study day 28. The following renal function parameters were calculated: creatinine, potassium, and sodium excretion rate; creatinine, potassium, sodium, and free water clearance; and fractional excretion rate of sodium. 10–12 Complete necropsies were conducted on all animals. Tissues were collected and fixed in 10% neutral buffered formalin for histological examination.
Toxicity Studies in Dogs
7-day study
A preliminary 7-day maximum dose study was undertaken to evaluate a dosage level of 5.0 g/kg/d OSS. Three dogs were administered OSS by oral gavage. The study was non-GLP.
28-day study
OSS or its vehicle was administered orally by gavage, daily to groups of 3 male and 3 female dogs. Dosage levels were 1.25, 2.5, and 5.0 g/kg/d at 15 mL/kg/d. The study was conducted according to GLP guidelines. Clinical examinations were performed daily, with weekly detailed physical examinations, body weight, and food consumption assessments. Clinical pathology evaluations (hematology, serum chemistry, and urinalysis) were performed and renal function parameters were calculated prior to the initiation of dose administration (study day −6) and on study day 28. Ophthalmic examinations were performed during study weeks −2 and 3. Electrocardiograms (ECGs) and heart rates were recorded and interpreted qualitatively 1week prior to initiating dosing and approximately 4 hours after dosing during week 3. Because the animals were observed to experience diarrhea and loose stools during this interval, it was considered appropriate for ECGs. Complete necropsies were performed on all animals on study day 28.
Histology
Tissues for microscopic examination were fixed in 10% neutral buffered formalin. After fixation, tissues from all animals were trimmed and processed into paraffin blocks, sectioned at 7 microns, and stained with hematoxylin and eosin. Polarized light microscopy was used to assess birefringence of crystal formation in the kidneys. In the 7-day range-finding rat study, kidneys were also stained by the von Kossa method 13 to identify whether mineral deposits were calcium phosphate.
Tissues examined microscopically from all animals included adrenals, aorta, bone with marrow (femur with articular surface and sternum, brain (cerebrum, cerebellum with medulla/pons), cervix, epididymides, exorbital lacrimal gland, eyes with optic nerve, gastrointestinal tract (esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, rectum), harderian glands, heart, kidneys, liver, lungs, lymph nodes (mandibular, mesenteric), ovaries with oviducts, pancreas, sciatic peripheral nerve, pituitary, prostate, mandibular salivary gland, seminal vesicles, skeletal muscle (rectus femoris), skin with mammary gland, spinal cord (cervical, midthoracic, lumbar), spleen, testes, thymus, thyroid with parathyroids, tongue, trachea, urinary bladder, uterus, and vagina. Gross lesions were also collected.
Statistical Methods
Analyses were conducted using 2-tailed tests (except as noted otherwise) for minimum significance levels of 1% and 5%, comparing each test article–treated group to the control group by sex. Each mean is presented with the standard deviation (SD) and the number of animals used to calculate the mean. Statistical analyses and SD calculations were not conducted when the number of animals was 2 or less. Individual animals’ results are shown in this case. Body weight, body weight change, food consumption, clinical pathology, renal function parameters, and organ weight data were subjected to a parametric 1-way analysis of variance 14 (ANOVA) to determine intergroup differences. If the ANOVA revealed statistically significant (P < .05) intergroup variance, Dunnett’s test 15 was used to compare the test article– treated groups to the control group.
Results
Studies in Rats
7-Day Preliminary Study
The 7-day preliminary study showed that OSS was well tolerated in male and female rats based on body weight, food consumption, and clinical signs at a dose of 5.0 g/kg/d. There were no histological alterations in the animals’ kidneys (Figures 1A and 1B). Rats dosed with 5.13 g/kg/d OSP had lower mean body weights at the end of the week 1 (14% less than controls). They had pronounced mineralization in renal tubules in the outer medulla with tubule degeneration and infiltration of low numbers of inflammatory cells (Figures 1C and 1D). The mineralization was negative for birefringence under polarized light but was positive with von Kossa stain (Figure 2B). There was no mortality. These doses were considered satisfactory for the maximum level in 28-day studies.
28-Day Toxicity Study
Clinical observations and survival
There were no adverse clinical observations in rats administered OSS, and they all survived to the scheduled necropsy after 28 days of dosing. In the OSP group, 75% (8 males and 7 females) were found dead or were euthanized in extremis prior to the scheduled necropsy. Mortality began in the second week of the study. Clinical observations associated with OSP included dermal atonia, hypoactivity, impaired equilibrium, intermittent tremors, and decreased respiration. Test article–related soft feces and diarrhea were attributed to the intended pharmacologic osmotic action of the agents.
Body weights
There were no effects on body weights in the OSS groups. Lower mean cumulative body weights were observed in the OSP males and reached statistical significance at study weeks 2 and 3 (288 and 310 g, respectively) in comparison to the controls (332 and 372 g, respectively). The 2 OSP male rats that survived had 17.3% lower final body weight on day 27 compared with the control group. There was no effect of OSP on body weight in the females. A statistically significant (P < .05) lower mean body weight gain occurred from study week 1 to 2 in females dosed with OSP when compared with the control female group and was considered associated with OSP administration. However, compared with the control group females, the weight gain did not result in a difference in the final mean body weight of the 3 female animals in the 5.13 g/kg/d OSP group that survived to scheduled necropsy.
Food consumption
There was no decrease in food consumption in the OSS groups. Compared with the controls, the OSP group consumed statistically significantly (P < .01) less food during study weeks 0 to 3 for the males and during study week 0 to 1 for the females.
Organ weights
Test article–related decreases in thymus weight were noted in the 5.0 and 5.13 g/kg/d OSS and OSP groups, respectively, compared with the control group. The decrease in absolute thymus weight and its weight relative to body and brain weights reached statistical significance for the OSS males only. There were no other test article–related (OSS or OSP) effects on organ weights.
Hematology and coagulation
Malerats in the 5.0 g/kg/d OSS group showed approximately 19% higher white blood cell counts (not statistically significant) associated with higher neutrophil counts (P < .01) and monocyte counts (P < .05) and approximately 8% lower eosinophil counts (not statistically significant). Female rats administered 5.13 g/kg/d OSP showed higher absolute white blood cell counts; higher absolute neutrophils, lymphocytes, and monocytes; and decreased (44%) absolute number of eosinophils (not statistically significant).
Serum chemistry
Alterations in serum chemistry parameters are summarized in Table 1. Significantly lower (P < .01) serum chloride and potassium were observed in all male and female rats in the 2.5 and 5.0 g/kg/d OSS animals. The surviving 5 OSP-treated rats (2 males and 3 females) also had lower chloride and potassium. The 2.5 and 5.0 g/kg/d OSS females had lower (P < .01) mean serum sodium levels compared with the control group. The 3 surviving females in the OSP group also showed lower serum sodium (not significant). Only the OSS group females showed a lower calculated serum osmolality when compared with the control group (Table 1). These OSS-treated females also showed a dose-related trend (not statistically significant) toward higher serum bicarbonate levels. The 5.13 g/kg/d OSP group females and both the 2.5 and 5.0 g/kg/d OSS group males showed significantly higher serum bicarbonate. The OSP group females had significantly lower serum calcium and significantly higher serum phosphorus. The serum calcium was 35% lower in the OSP group males compared with 11% lower in female rats. The serum phosphorus was 177% higher in the OSP males than in the control group males (compared with 19% higher in the 5.13 g/kg/d OSP group females). These differences could not be analyzed by Dunnett’s test because there were only 2 surviving males, but they were considered OSP-related effects. Serum urea nitrogen was 89% higher in the OSP group males (n = 2), and there was a corresponding increase in the creatinine levels (250% higher). These alterations were indicative of test OSP-related uremia in these male rats and were associated with renal damage. There were no signs of uremia in the rats administered OSS (Table 1).
Urinalysis and renal function tests
No crystals were detected in the urine by direct microscopic examination in any of the groups. Alterations in urinalysis parameters and renal function tests that were considered to be related to test article administration are summarized in Tables 2 and 3, respectively. Urine sodium values were significantly higher in the OSS group males. This was accompanied by significantly higher sodium excretion and clearance rates in the 2.5 and 5 g/kg/d OSS males and females groups (Table 3). The urine sodium elevation reached significance in the OSP group females and was similarly higher in the OSP group males. Urine potassium was significantly higher in the 2.5 g/kg/d OSS group males and in the 2.5 and 5.0 g/kg/d females, as was the potassium clearance rate (P < .01) in the 2.5 and 5.0 g/kg/d OSS group males. The potassium clearance rates in the 2.5 and 5.0 g/kg/d OSS group females were higher, although not statistically significant. In contrast, urine potassium was lower in the OSP group (29% lower in females and 50% lower in males). Free water clearance rate was negative in all groups administered OSS or OSP. Values were statistically significant in the OSP group females, a 109% negative value. The 2 males from the OSP group at the scheduled necropsy showed a 145% decrease in the free water clearance rate. The 5.0 g/kg/d OSS group males showed a similar 139% negative value. The negative free water clearance rate was consistent with higher urine sodium and potassium excretion relative to water.
No alterations in the calculated creatinine clearance rate were observed in any of the groups, with the exception that female rats administered 5.0 g/kg/d OSS showed low calculated creatinine clearance rate. The OSP-treated males and females had similarly lower creatinine clearance rates, but this did not reach statistical significance in light of the few animals that survived to the scheduled sampling time. However, examination of individual animals’ data showed 2 OSS females with very low calculated creatinine clearance rates and a small urine volume. The remaining rats in the 5.0 g/kg/d female group had creatinine clearance rates and urine volumes that were comparable to several individual control female rats. Therefore, in the absence of gross or histological correlates, the normal blood urea nitrogen and normal blood creatinine values in male and female rats administered 5.0 g/kg/d OSS and the lower calculated creatinine clearance rate in female rats administered 5.0 g/kg/d OSS were considered spurious, or possibly adaptive.
Ophthalmic examinations
No ophthalmic lesions indicative of toxicity were observed in any of the test article–treated groups.
Histopathology
Table 4 summarizes the histologic findings. Rats dosed with OSS showed no histological changes in the kidney (Figures 3A and 3B). There was no birefringence in their kidneys assessed by polarized light. All male and female rats administered OSP showed kidney damage with renal tubular degeneration and mineralization (Figures 3C and 3D). Mineral deposition occurred in renal tubules, particularly in straight tubules in the outer medulla, and along the loop of Henle, particularly in the distal tubules. The mineral deposition was negative by birefringence using polarized light microscopy. Rats dosed with OSP also showed mineral deposition in the glandular mucosa of the stomach, particularly in males. In the heart, focal and locally extensive multiple areas of myofiber degeneration were scattered throughout the myocardium, particularly in the left ventricle, with acute inflammatory cell infiltration, predominately neutrophils, and low numbers of macrophages. Some hearts showed individual myofibers with mineralization within areas of degenerating myofibers. The myocardial degeneration was more pronounced inmales compared with females administered 5.13 g/kg/d OSP. There was also mineralization in the media of the aorta. None of these mineralization changes were found in any of the OSS-treated rats.
Dilation of the jejunum and colon was noted in histologic sections and occurred in a dose-related manner in the OSS male and female groups and in male and female rats in the OSP-treated group (Table 5). The dilated intestines were attributed to the pharmacological action of OSS and OSP osmotic effects, drawing water into the lumen of the intestines. This is the intended application of the agents, and these observations demonstrated efficacy.
Studies in Dogs
7-Day Preliminary Study
A 7-day dose-ranging study in groups of dogs established that a dosage level of 5.0 g/kg/d OSS was well tolerated based on clinical observations, macroscopic examination, and histological evaluation of the kidneys.
28-Day Toxicity Study
In the 28-day study, all animals survived to the scheduled necropsy. There was no alteration in body weight or food consumption in dogs dosed with OSS and no changes in organ weights. Test article–related clinical findings included emesis, wet clear or white frothy material around the mouth, excessive salivation, excessive drinking of water, and abnormal excreta (soft and/or mucoid feces and/or diarrhea). These clinical findings showed a dose-related incidence (Table 4) starting on study day 0 (first day of dosing) and as early as 15 minutes postdosing. These findings persisted up until the 4-hour postdose observation for the remainder of the study. Based on the absence of test article–related effects on body weights or food consumption over the course of the study, and because the expected physiological response of soft stools and diarrhea was produced at all dose levels, emesis was not considered adverse or dose-limiting.
Ophthalmic and electrocardiographic examinations
No ophthalmic lesions or alterations in the ECG indicative of toxicity were observed. All findings observed were typical and within normal limits in prevalence and appearance for laboratory dogs of this age and breed.
Hematology and clinical chemistry
There were no test article–related alterations in hematology, coagulation parameters, or serum chemistry parameters. The dogs administered OSS had normal serum bicarbonate on day 28. This indicated that renal (and other) buffer mechanisms were adequate to maintain homeostasis and that the test article was well tolerated.
Urinalysis and renal function tests
Dogs administered OSS had higher (but not significant by Dunnett’s test) calculated values for sodium and potassium excretion rates (Table 6), which may reflect increased renal excretion of these electrolytes in the OSS formulation. Creatinine clearance, although insignificantly lower in males treated with OSS, was unchanged in the females. Because overnight urine collection in the OSS-treated groups most likely contained increased amounts of fecal matter, some of these small changes could have been attributable to urine contamination rather than a physiological response to treatment. Administration of OSS did not adversely affect the renal physiology in the treated animals.
Histopathology
There were no histological OSS related alterations in the organs examined. In addition, all kidneys were negative for birefringence-positive material when examined under polarized light microscopy.
Discussion
Oral administration of OSS in rats and dogs for 28 consecutive days at doses of up to 5.0 g/kg/d was well tolerated with regard to morbidity, mortality, body weight, and food consumption. Changes observed in clinical chemistry and urine analytic parameters were consistent with adaptive physiological mechanisms to retain fluid and electrolyte balance. OSS effectively caused osmotic diarrhea, which was the intended pharmacologic action. There were no abnormal renal microscopic findings associated with OSS administration in rats or dogs, including no evidence of mineral deposition in the kidney. The OSS salt solution formulation has properties of high solubility and poor absorption. It is therefore retained in the lumen of the intestinal tract where it obligates fluid accumulation in the intestine to promote a bowel cleansing action. The salt solution does not precipitate at neutral pH in the intestinal tract, as shown by macroscopic examination of the bowel in these studies in rats and dogs. Furthermore, retention of the OSS agent in the intestine promotes efficacy whereas the poor systemic absorption from the intestinal tract minimizes the risk of systemic or renal toxicity.
Alterations in serum chemistry and renal function in rats dosed with OSS were considered adaptive physiologic responses. The reduced serum potassium in the 2.5 and 5.0 g/kg/d OSS groups was accompanied by increased urinary potassium (Table 2). In contrast, the OSP groups had lower serum potassium and decreased urinary potassium excretion. Although all groups treated with OSS or OSP had increased urine sodium, only the female rats receiving 2.5 and 5.0 g/kg/d of OSS had decreased serum sodium. These differences may arise from the adaptation to the potassium load in OSS, which is absent from OSP.
The lower thymus weights noted in rats in the 5.0 g/kg/d OSS groups and the 5.13 g/kg/d OSP appear to be a secondary stress effect because the hematology results showed a stress leukogram in these rats. However, in OSP rats, higher absolute leukocyte counts in the peripheral blood were associated with inflammatory cell infiltrate responses to degenerative changes, particularly in the kidney, heart, and liver.
Administration of OSP to rats at 5.13 g/kg/d was not well tolerated and resulted in significant morbidity and mortality. Female rats were less susceptible to the effects of OSP compared with males as shown by gender differences in effects on body weight, survival, and clinical chemistry parameters. The primary target organ of OSP was the kidney, with adverse toxic effects of mineral deposition (most likely calcium phosphate) and associated renal tubule degeneration. There was also mineralization in the stomach and aorta and cardiac myofiber degeneration and mineralization. These were considered secondary to alterations in serum calcium and phosphorus. The primary cause of death in the rats dosed with OSP was renal insufficiency. Staining of kidney sections with the von Kossa method demonstrated calcium phosphate deposits. These results therefore confirm and extend those of earlier investigators 6 who reported adverse effects associated with OSP. We believe this is the first report to show these changes in an animal model following administration of a commercially available OSP bowel cleansing preparation. The rapid and reliable onset of mineralization in rats without surgically induced uremia may provide a useful model for human vascular calcification. 16 Considering the large doses applied, the results demonstrated a wide safety margin for the OSS formulation in these animal studies. This indicates a potential for lessened, if any, risk of renal damage when OSS is used as a bowel-cleansing agent.
OSS was well tolerated in dogs as shown by no changes in body weights, food consumption, ocular findings, or electrocardiographic or renal function parameters, even at doses that produced significant diarrhea. OSS at doses of up to 5.0 g/kg/d showed no adverse renal histologic alterations in dogs. Clinical findings of soft and/or mucoid feces were observed throughout the course of the study in dogs dosed with OSS. Even if some of the OSS that was voided resulted in a slightly diminished exposure to test article, the primary pharmacodynamic effects (diarrhea and soft feces) were achieved in a dose-related manner consistently over the entire course of the study. Furthermore, neither food consumption nor body weights were affected, suggesting that the amount of emesis was not significant.
Nephrocalcinosis after phosphate administration to animals has been recognized since as early as the 1930s and occurs at doses that are 3- to 5-fold lower 6 than reported in this study. The present study could be criticized on the basis that the OSP dose was too high and produced significant morbidity and mortality. This dose was chosen as a positive control with an osmotic load equal to the OSS formulation when administered at its maximum feasible level. Although the dose of OSP was 6.5% higher on a weight basis compared with a 5.0 g/kg/d OSS, it was about 9% lower than OSS on an osmotic load basis.
During the preparation of this article, the United States FDA announced that it was recommending that OTC OSP products not be used for bowel preparation and required that prescription OSP products carry a boxed warning covering the risks of phosphate nephropathy. 17
At the doses of OSS used in this study by oral gavage, in both rats and dogs, the formulation caused primarily the intended intestinal effects of diarrhea and loose stools associated with physiologic responses to the osmotic load of the hyperosmolar sulfate OSS solution that was administered. In rats, OSP produced severe renal damage caused by mineral deposition in tubules. The kidney damage resulted in severe renal insufficiency and mortality. The results of this study demonstrated a wide safety margin for the OSS formulation.
Footnotes
Figures and Tables
Acknowledgements
Drs Pelhamand Cleveland are employees of Braintree Laboratories, Inc, which fully funded these studies. Dr Reno is a consultant to Braintree Laboratories; Drs Padgett and Russell are employees of WIL Research Laboratories, LLC.