Mark A. Wingertzahn

A preliminary study of growth hormone therapy for Crohn's disease.

BACKGROUND Crohns disease is a chronic inflammatory disorder of the bowel. In a preliminary study, we evaluated whether the administration of growth hormone (somatropin) as well as a high-protein diet would ameliorate the symptoms of the disease. METHODS We randomly assigned 37 adults with moderate-to-severe active Crohns disease to four months of self-administered injections of growth hormone (loading dose, 5 mg per day subcutaneously for one week, followed by a maintenance dose of 1.5 mg per day) or placebo. We instructed all patients to increase their protein intake to at least 2 g per kilogram of body weight per day. Patients continued to be treated by their usual physicians and to receive other medications for Crohns disease. The primary end point was the change in scores on the Crohns Disease Activity Index from base line to month 4. Scores can range from 0 to 600, with higher scores indicating more disease activity. RESULTS At base line, the mean (+/-SD) score on the Crohns Disease Activity Index was somewhat higher among the 19 patients in the growth hormone group than among the 18 patients in the placebo group (287+/-134 vs. 213+/-120, P=0.09). Three patients in the placebo group withdrew before their first follow-up visit and were not included in the data analysis. At four months, the Crohns Disease Activity Index score had decreased by a mean of 143+/-144 points in the growth hormone group, as compared with a decrease of 19+/-63 points in the placebo group (P=0.004). Side effects in the growth hormone group included edema (in 10 patients) and headache (in 5) and usually resolved within the first month of treatment. CONCLUSIONS Our preliminary study suggests that growth hormone may be a beneficial treatment for patients with Crohns disease.

Effect of gum arabic in an oral rehydration solution on recovery from diarrhea in rats

BACKGROUND It has been shown that gum arabic, a soluble fiber, enhances water, electrolyte, and glucose absorption from oral rehydration solutions in jejunal perfusion of healthy rats and in animals with theophylline-induced secretion or chronic osmotic-secretory diarrhea. This report concerns a study of the effectiveness of an oral rehydration solution supplemented with gum arabic, during recovery from chronic osmotic secretory diarrhea in free-living rats. METHODS Chronic diarrhea was induced in 60- to 80-g juvenile rats by providing a magnesium citrate-phenolphthalein solution as the sole fluid source for 7 days. This led to diarrhea characterized by dehydration, soft stools, increased cecal volume, decreased food and fluid intake and failure to gain weight. After 7 days of diarrhea, rats recovered for 24 hours with either tap water or an oral rehydration solution (90 mM Na, 111 mM glucose, 20 mM K, 80 mM chloride, 20 mM citrate) with or without 2.5 g/l gum arabic. RESULTS Although all three solutions improved the diarrhea, optimal recovery from diarrhea was achieved with the gum arabic-supplemented oral rehydration solution. After 4 hours and 24 hours, rats drinking the gum arabic-supplemented solution gained more weight and had lower fecal output than rats receiving water or the rehydration solution without gum arabic. All three solutions normalized plasma osmolality after 24 hours. CONCLUSIONS The positive effects of the gum arabic-supplemented rehydration solution on fluid and electrolyte absorption seen during jejunal perfusion also occurred during recovery from chronic osmotic secretory diarrhea, when free-living animals drank the solution ad libitum.

Proabsorptive action of gum arabic: regulation of nitric oxide metabolism in the basolateral potassium channel of the small intestine.

Background Gum arabic, a high–molecular-weight natural polysaccharide, has been shown to have proabsorptive properties in animal models of gastrointestinal disease that involve nitric oxide (NO). Gum arabic may indirectly regulate NO metabolism by creating an outward NO gradient, thus altering other intracellular NO–dependent mechanisms such as gating of the potassium (K + ) channel. This hypothesis was further investigated using the K + channel blocker, glybenclamide. Methods Following intraperitoneal injection of 4.5 mg/kg glybenclamide or saline, the jejunum of anesthetized rats was perfused with a standard oral rehydration solution in the presence or absence of 2.5 g/L gum arabic, as well as 1 mmol/L l -arginine to enhance NO production. Sodium, net water, and glucose absorption and unidirectional water movement were determined. Results Gum arabic showed regulatory capacity for NO–dependent metabolism by reducing net water absorption in the absence of arginine, and sodium absorption after arginine stimulation, in the absence of glybenclamide. Addition of gum arabic to oral rehydration solution, in glybenclamide pretreated animals, and in the absence of arginine, normalized sodium absorption, but was less effective in restoring net water transport. Injection of glybenclamide sharply decreased all absorption markers in arginine supplemented oral rehydration solution, which were at least partially restored by addition of gum arabic to the oral rehydration solution. In the presence of glybenclamide, the effects of arginine became antiabsorptive, as had those observed in preceding studies with high arginine concentration. Gum arabic partially or fully reversed alterations produced by perfused 1 mmol/L arginine. Conclusions Some of the effects of gum arabic on the small intestine are likely caused by its ability to remove NO as it diffuses into the lumen, thus reducing NO concentration in the enterocyte and indirectly affecting the absorptive/secretory response of the gut, which leads to normalization of absorptive function. These findings are consistent with the previously shown gum arabic–scavenging properties of NO and support a potential therapeutic role for this product.

Modified starch enhances absorption and accelerates recovery in experimental diarrhea in rats

Rice gruels have been used as home remedies to treat dehydration associated with diarrheal illness in developing countries. These preparations have produced conflicting results, most likely due to the heterogeneity of starch used. We investigated whether the modified tapioca starch, Textra™ (TX), at 5.0 or 10.0 g/L added to a 90 mmol/L Na+-111 mmol glucose oral rehydration solution (ORS) enhanced water and electrolyte absorption in two models of diarrhea. To induce a secretory state (model A), the jejunum of juvenile rats was perfused with 10 mmol/L theophylline (THEO) under anesthesia and then perfused with the solutions indicated above. To produce chronic osmotic-secretory diarrhea (model B), rats had a magnesium citrate-phenolphthalein solution as the sole fluid source for 1 wk, and then were perfused as the THEO-treated rats. Water, electrolyte, and glucose absorption were measured during both perfusions. As an extension of the perfusion studies, we compared how fast rats recovered from chronic osmotic diarrhea by offering them either water, ORS, or ORS containing 5.0 g/L TX along with solid food. Recovery rate markers were measured after 24 h and included weight gain, food and fluid intake, and stool output. In model A, addition of 5.0 g/L TX to ORS reversed Na+ secretion and improved net water as well as K+ and glucose absorption, compared with THEO-treated rats perfused with ORS without TX. In model B, addition of TX to ORS increased water, Na+, K+, and glucose absorption, compared with rats perfused without TX. Increasing TX from 5.0 to 10.0 g/L had no additional benefit. In recovery experiments, animals with free access to ORS with TX had significantly greater weight gain and decreased stool output compared with animals recovering with water or ORS without TX. Our experiments suggest that TX may be a useful additive to standard ORS to promote fluid and electrolyte absorption and may provide additional energy without increasing ORS osmotic load.

CELLULOSE DERIVATIVES AND INTESTINAL ABSORPTION OF WATER AND ELECTROLYTES:POTENTIAL ROLE IN ORAL REHYDRATION SOLUTIONS

Abstract The physicochemical and structural characteristics of several types of carboxymethylcellulose (CMC) and of methylcellulose (MC) were examined in relation to their capacity to modify water and sodium absorption in oral rehydration solutions (ORS) at various concentrations, using a jejunal perfusion procedure in rats. Comparison of intrinsic low-viscosity CMC of various degrees of substitution (DS) revealed that net water absorption increased as the DS was augmented. A stimulatory effect on sodium absorption occurred only at a low (2.5 g/l) CMC concentration. With products of medium DS, stimulation of net water and sodium absorption was observed only with low-viscosity CMC at 2.5 g/l, but not at 5.0 g/l. In perfusions with CMC of medium and high DS there was a reduction of water and sodium absorption, ultimately resulting in net sodium secretion with 5.0 g/l high-DS CMC. MC perfused at 5.0 or 10.0 g/l reduced net water absorption and reversed sodium transport from absorptive to secretory status. These results show that while low-viscosity-grade, low-DS CMC in low concentrations may facilitate solute uptake and concurrent water absorption from ORS by the jejunum, high intrinsic viscosity and possible chemical interaction of solutes with the modified celluloses tend to block water uptake and produce fluid stasis and electrolyte secretion. Thus, the data suggest that only certain types of CMC may be proabsorptive when added to ORS, while high-viscosity and high-DS CMC or MC induce electrolyte malabsorption and eventual catharsis.

Zinc as a Potential Enteroprotector in Oral Rehydration Solutions: Its Role in Nitric Oxide Metabolism

Zinc has been recognized as an antioxidant with potential for chronic and acute effects. Oxidative damage produced by free radicals, including nitric oxide (NO), is responsible for certain types of intestinal malabsorption syndromes and diarrhea. Under physiologic or mildly stimulatory conditions for NO synthesis, the small intestine characteristically is in a proabsorptive state; however, an excessive production of NO triggers formation of cyclic nucleotides, which cause secretion and malabsorption. In this study, we hypothesized that low-molecular-weight, soluble zinc chelates could modulate the effects of induced NO excess on the small intestine. In vitro experiments demonstrated that zinc-citrate or zinc-histidine at ≥0.66 mM, as well as a known NO scavenger, 2-[carboxyphenyl]-4,4,4,4-tetramethylimidazoline-1-oxyl-3-oxide, at 2 μM, were effective at removing chemically generated NO. In vivo jejunal perfusions, conducted in healthy rats under anesthesia, showed that c-PTIO reduced the proabsorptive effects produced by 1 mM l-arginine, the precursor of NO. In a standard oral rehydration solution, 1 mM zinc-citrate partially reversed the antiabsorptive effects on potassium caused by an excess of NO generated from 20 mM l-arginine but did not alter sodium or water absorption. The data are consistent with the view that soluble zinc compounds incorporated into an oral rehydration solution may deserve further attention as a means to scavenge NO with fluids used for the treatment of chronic or acute diarrhea, especially in malnourished children who are often zinc deficient.

Changes in Ryanodine Receptor-Mediated Calcium Release During Skeletal Muscle Differentiation. II. Resolution of a Caffeine-Ryanodine Paradox:

Our previous study demonstrated a disparity of action between two established pharmacological modulators of the same calcium (Ca2+) release channel, the ryanodine receptor (RyR). Specifically, we observed that caffeine sensitivity was elicited at earlier stages of development than that of ryanodine. In the present study, we offer a hypothesis to resolve this paradox. We provide evidence that ryanodine acts as a pure uncompetitive inhibitor of Ca2+ transport, with respect to Ca2+ itself. This explains why little ryanodine inhibition was observed at low Ca2+ concentrations, while maximal ryanodine inhibition was observed at saturating Ca2+ concentrations. In order to exclude the possibility of nonspecific ryanodine actions as an alternative explanation, we established the phenomenon of capacitative calcium entry (CCE) for L6 cells. Since it is known that CCE is inversely correlated with [Ca2+] of the ER/SR lumen, the extent of CCE is therefore an indirect measure of Ca2+ concentration within the SR. We also demonstrated the functional pathway for Ca2+ entry. Employing pharmacological inhibitors, we found that a T-type plasma membrane channel was predominant in the myoblasts, while an L-type channel was predominant in the adult myotubes. Our data using these inhibitors made nonspecific ryanodine actions an unlikely explanation of the disparity in action between ryanodine and caffeine. Moreover, we found no evidence that inositol trisphosphate, a proposed regulator of CCE for other cells, could influence CCE in L6 cells. We conclude that the disparity between caffeine and ryanodine can be explained by Ca2+ dependence of ryanodine action. This study may also offer an explanation of other studies showing unclear actions of ryanodine binding and action.

Proabsorptive effects of modified tapioca Starch as an additive of oral rehydration solutions

BACKGROUND Partially hydrolyzed starches from staple cereals, obtained by heat or by enzymatic treatment, are often used in the formulation of homemade or extemporaneously used oral rehydration solutions used in developing countries. Conflicting or anecdotal results obtained thus far could be clarified with a standardized preparation tested under well-controlled laboratory conditions. METHODS A modified commercial tapioca starch was tested. Textra (National Starch and Chemical Co. Bridgewater, NJ, U.S.A.) added at 0, 5 or 10 g/l to an oral rehydration solution with 90 mM sodium and 111 mM glucose, in 30 rats malnourished by a protein-deficient diet for 3 weeks and in 26 well-fed control animals, using a one-pass jejunal perfusion. RESULTS In protein-deficient rats, Textra stimulated sodium absorption at 5 and 10 g/l (mean +/- SEM); 0 g/l Textra: 160 +/- 13 nmol/min x cm; 5 g/l Textra: 406 +/- 31 (p < 0.0001); and 10 g/l Textra 230 +/- 27 (p < 0.02). Potassium absorption was comparably increased. Textra also improved net water absorption and the water influx:efflux ratio. Glucose absorption was increased only at 10 g/l Textra. In control rats, Textra improved sodium and net water absorption at 5 g/l, but not at 10 g/l Textra; but the influx:efflux ratio and potassium absorption were unaltered. CONCLUSIONS These data, obtained in normal and protein-deficient rats, support the view that modified starch is a potentially useful, energy-rich additive for oral rehydration solution, which does not introduce an osmotic penalty.

Proabsorptive effect of glycerol as a glucose substitute in oral rehydration solutions

We hypothesized that glycerol, a readily diffusable hydrophilic substance, may effectively substitute for glucose and enhance intestinal water and sodium absorption in an oral rehydration solution (ORS). This was evaluated using a low osmolality (230-240 mOsm/kg) ORS containing 75 mmol/L sodium and a combination of glucose:glycerol (in mmol/L) 75:0, 50:25; 37.5:37.5, 25:50, 10:65, or 0:75 during 3-hour long in vivo rat jejunal perfusions. Water, sodium, potassium, glucose and glycerol absorption, and unidirectional fluid movement (J(in), J(eff)) were determined. Sodium and net water absorptions were maximal at glucose:glycerol ratios between 37.5:37.5 and 10:65 mmol/L. In the absence of glucose (0:75), absorption of water and electrolytes was lower than at any other concentration. The greater net rehydration seemed to be due to a higher J(in) as glycerol was increased up to 65 mmol/L. Potassium absorption followed a similar pattern. With 50 mmol/L glycerol and 25 mmol/L glucose, there was a marked expansion of the lamina propria extracellular space and increased intercellular expansion between enterocytes. These results indicate that glycerol may be an effective partial substitute for glucose in ready-to-use ORS by producing an improved rate of water and electrolyte absorption.

SECRETORY DIARRHEA IN AN ANIMAL MODEL: REVERSAL BY GUM ARABIC-CONTAINING ORAL REHYDRATION SOLUTIONS (ORS). 756

SECRETORY DIARRHEA IN AN ANIMAL MODEL: REVERSAL BY GUM ARABIC-CONTAINING ORAL REHYDRATION SOLUTIONS (ORS). 756