Increase In Intestinal Absorption Research Articles

The Role of Arginine in Disease Prevention, Gut Microbiota Modulation, Growth Performance and the Immune System of Broiler Chicken – A Review

Abstract The effect of dietary arginine on disease prevention, immune system modulation, the gut micro-biota composition and growth of broiler chicken was reviewed. The main aim of poultry production is the maximization of profit at the least possible cost. This objective can mainly be achieved by ensuring that there is no interference in growth or disease outbreak and by feeding chicken with the best possible level of nutrients. With the ban on antibiotic growth promoters, attention is shifted towards other nutrition methods to prevent diseases and promote growth. More attention is therefore given to protein diets in animal nutrition due to their importance as essential part of active biological compounds in the body, assisting in the breakdown of body tissue and helping in the physiological processes of the animal. Arginine plays important function in serving as building blocks of proteins and polypeptides. It performs other roles during the regulation of important biochemical functions such as maintenance, growth, reproduction and immunity. Arginine cannot be synthesized by the body so it has to be supplemented in the diet. When arginine is supplemented above the recommended level, the gut mucosa is protected, immunosuppression is alleviated, diseases like necrotic enteritis, infectious bursal disease and coccidiosis in broiler chickens are prevented. There is an improvement in growth resulting from the increase in intestinal absorption, barrier function and microbiota composition.

Small‐Bowel Adaptation: A Case of Morphological Changes Induced by Teduglutide in Short‐Bowel Syndrome With Intestinal Failure

Teduglutide (TED) reduces the need for parenteral support (PS) in patients with short-bowel syndrome with intestinal failure (SBS-IF). It is a glucagon-like peptide-2 analog that improves absorption, induces the expansion of the absorptive epithelium in the small intestine, and may be used in patients with SBS-IF after a 6- to 12-month adaptation period, if PS is always necessary. We described the functional and morphological effect of TED in a 40-year-old female patient with SBS-IF due to Crohn's disease who underwent terminal jejunostomy after 12 months of drug exposition. Marked hypertrophy of the villi was detected by endoscopic capsule and confirmed by histological measurements. This is the first publication demonstrating an increase in intestinal absorption in an SBS-IF patient treated with TED because of a morphological adaptation of the small bowel, with hyperplasia confirmed by capsule endoscopy and histology. The capsule endoscopy, a noninvasive exploration of the gut, could be evaluated to monitor the real efficacy of treatments with growth factors in SBS patients.

Repeated Metabolic Balance Studies in Patients With Short Bowel Syndrome.

Weaning from parenteral support is considered indirect evidence of intestinal adaptation in patients with short bowel syndrome (SBS), but direct evidence is lacking. The objective of this study was to examine if intestinal adaptation could be demonstrated as increase in intestinal absorption of energy and wet weight over time measured by repeated metabolic balance studies (MBSs) and to examine whether adaptation was determined by the anatomy of the remnant bowel. We retrospectively analyzed data from 48 repeated MBSs performed in 13 adult patients with SBS. Results were presented graphically and interpreted. The interpatient and intrapatient heterogeneity was compared based on anatomy of the remnant bowel. The number of repeated MBSs ranged from 2 to 7, and time between last intestinal resection and MBS from 5 months to 18.1years. In 6 patients, the first MBS was performed within 2years after last resection, but only 1 patient had repeated MBSs within this period. Nine patients had an end jejunoileostomy, and 4 patients had a jejuno-colonic or ileo-colonic anastomosis. None of the patients had jejunoileal anastomosis with a preserved ileocecal valve. Interpatient and intrapatient heterogeneity of wet weight and energy absorption was larger in patients without colon in continuity. The wet weight and energy absorption data showed no tendency toward intestinal adaptation in any anatomical group. We observed no signs of late-phase intestinal adaptation in this selected group of patients with SBS. Future prospective MBSs are needed to understand the time course and magnitude of intestinal adaptation.

Modeling of the Nanoparticles Absorption Under a Gastrointestinal Simulated Ambient Condition.

Proanthocyanidins (PAs) have several bioactivities, but they are unstable in the digestive tract and possess low bioavailability. Nanoencapsulation stabilizes these compounds for oral administration. The intestinal absorption of grape seed and skin extracts, and the poly-lactic acid (PLA) nanoparticles loaded with such extracts was modeled, taking into consideration physicochemical process parameters, evaluating the PAs concentration profile in the human small intestine. Density (ρ), solubility, viscosity (μ), diffusion coefficient (D), and the global mass transfer coefficient (K) for both substrates were estimated, simulating their passing from the intestine into the blood at 37°C. For the seed and skin extracts encapsulated in PLA the physicochemical parameters were: D=1.81×10^-5 and D=5.72×10^-5cm2/s; K=3.4×10^-3 and K=2.47×10^-4cm/s, respectively. Lower resistance was offered by the seed extract than by skin extracts (nanoencapsulated), which was explained by differences in structural composition, and average molecular weight of the two kinds of extracts, which should be more favorable to the mass transfer in comparison to the raw extracts. The concentration profile of grape extracts in the small intestine was modeled through a pure convection model, and the encapsulated extract on PLA nanoparticles using a mixed regime model, which described the process of dissolution and absorption of the grape extracts from the intestine to the blood stream. The absorbed fraction predicted by the model was 42.7 and 24.2% for seed and skin extracts, respectively. Those values increased to 100% for both extracts after the simulation with the nanoencapsulated extracts. Consequently, extract encapsulation should produce a significant increase in intestinal absorption.

Mineral Metabolism in Singleton and Twin-pregnant Dairy Goats.

During pregnancy, the maternal body undergoes significant physiological changes. The present study assessed the changes on calcium (Ca), phosphorus (P), magnesium (Mg), sodium (Na) and potassium (K) metabolism in singleton and twin-pregnant dairy goats. The 42 goats used (49.5 kg±7.6 body weight [BW]) were assigned at random to treatments that were factorially arranged to account for 2 breeds (Oberhasli and Saanen), 2 pregnancy types (singleton and twin) and 3 gestation periods (80, 110, and 140 days). Digestibility trials were performed at 80, 110, and 140 days of gestation. Mineral retention during pregnancy was determined in the maternal body, femur, uterus, mammary gland, fetus and fetal fluid. Blood samples were taken during pregnancy before and after a meal, and Ca, P, Mg, Na, K ions and alkaline phosphatase activity determined in serum. Bone mineral density was determined in the right femur. Statistical analyses were performed using the SAS MIXED procedure. Dry matter intake decreased linearly up to 140 days of gestation. Maternal BW gain, and Ca, P, and Mg retention (g/kg) decreased linearly with the advance of gestation days. Macromineral retention in maternal body (g/kg) was greater in Oberhasli than Saanen goats, and their fetuses had higher Ca, P, and Mg deposition (mg/g). Mineral retention (mg/g) increased in fetuses according to pregnancy development, with no differences between singleton and twin pregnancy. In the mammary gland, the retention of all minerals (g) increased with the days of pregnancy. In conclusion, related to Ca, P, and Mg metabolism can be divided into two stages. Up to 80 days of gestation, was characterized by the preparation of the maternal body reserves for future mineral demands. From 80 days of gestation onward, was characterized by the transfer of maternal body reserves for fetal development and colostrum production. Na and K supply was provided by adjustments in endogenous excretion and an increase in intestinal absorption. Finally, mineral metabolism was specific to each genotype and, except for Na, was not affected by the number of fetuses.

Reduced Renal Calcium Excretion in the Absence of Sclerostin Expression

The kidneys contribute to calcium homeostasis by adjusting the reabsorption and excretion of filtered calcium through processes that are regulated by parathyroid hormone (PTH) and 1α,25-dihydroxyvitamin D3 (1α,25[OH]2D3). Most of the filtered calcium is reabsorbed in the proximal tubule, primarily by paracellular mechanisms that are not sensitive to calcium-regulating hormones in physiologically relevant ways. In the distal tubule, however, calcium is reabsorbed by channels and transporters, the activity or expression of which is highly regulated and increased by PTH and 1α,25(OH)2D3. Recent research suggests that other, heretofore unrecognized factors, such as the osteocyte-specific protein sclerostin, also regulate renal calcium excretion. Clues in this regard have come from the study of humans and mice with inactivating mutations of the sclerostin gene that both have increased skeletal density, which would necessitate an increase in intestinal absorption and/or renal reabsorption of calcium. Deletion of the sclerostin gene in mice significantly diminishes urinary calcium excretion and increases fractional renal calcium reabsorption. This is associated with increased circulating 1α,25(OH)2D3 levels, whereas sclerostin directly suppresses 1α-hydroxylase in immortalized proximal tubular cells. Thus, evidence is accumulating that sclerostin directly or indirectly reduces renal calcium reabsorption, suggesting the presence of a novel calcium-excreting bone-kidney axis.

Enhancing the intestinal absorption of poorly water-soluble weak-acidic compound by controlling local pH

Recently, the number of poorly water-soluble drug candidates has increased and has hindered the rapid improvement of new drugs with low intestinal absorption; however, the intestinal absorption of pH-dependent poorly water-soluble compounds is expected to be markedly improved by changing the pH in the vicinity of the absorption site. The aim of this study is to clarify the effect of local pH change in the intestinal tract by magnesium oxide on the intestinal absorption of hydrochlorothiazide, a model poorly water-soluble weak-acid compound. The application of hydrochlorothiazide granule containing magnesium oxide to the rat intestinal loop increased the pH in the vicinity of the dosing site to more than 8.5 for 90 min without any mucosal damage. As a result, absorption of hydrochlorothiazide increased by the addition of magnesium oxide to the granule. Intraintestinal administration of a suspension prepared from hydrochlorothiazide granules with magnesium oxide increased the intestinal absorption and the AUC value was 3-fold higher than that without magnesium oxide. To further increase the intestinal absorption of hydrochlorothiazide, we prepared granules containing magnesium oxide and chitosan as a mucoadhesive and tight junction opening material. Chitosan showed a marked increase of intestinal absorption, and the AUC value after the administration of suspensions of chitosan granules was more than 5-fold higher than that of granules containing hydrochlorothiazide alone, respectively. In summary, it has been clarified that the intestinal absorption of weak-acidic poorly water-soluble compound can be enhanced by increasing local pH, mucoadhesion and opening tight junction.

Alterações moleculares associadas à hemocromatose hereditária

A hemocromatose hereditária (HH) é a mais comum doença autossômica em caucasianos e caracteriza-se pelo aumento da absorção intestinal de ferro, o qual resulta em acúmulo progressivo de ferro no organismo. A classificação da HH é realizada de acordo com a alteração genética encontrada, sendo os casos divididos em tipos 1, 2A, 2B, 3 e 4, quando a sobrecarga de ferro for associada aos genes HFE, HJV, HAMP, TFR2 e SLC40A1, respectivamente. Não existem estudos brasileiros que avaliaram a presença de mutações em genes relacionados à fisiopatologia da HH (genes HJV, HAMP, TFR2 e SLC40A1), além da pesquisa das três mutações no gene HFE (C282Y, H63D e S65C). Porém, está descrito, nos estudos realizados no Brasil, que alguns pacientes com sobrecarga de ferro primária não são portadores da HH tipo 1 (associada ao gene HFE). Portanto, é de suma importância a identificação das características genéticas dessa população, uma vez que outras mutações nos genes HJV, HAMP, TFR2 e SLC40A1 podem estar associadas à fisiopatologia da doença, podendo haver interações entre os genes alterados, de forma que possa auxiliar no entendimento da fisiopatologia da HH em pacientes brasileiros.

Enhanced oral bioavailability of paclitaxel by d-α-tocopheryl polyethylene glycol 400 succinate in mice

Paclitaxel is widely used to treat several types of solid tumors. The commercially available paclitaxel formulation contains Cremophor/ethanol as solubilizers. This study evaluated the effects of d-α-tocopheryl polyethylene glycol 400 succinate (TPGS 400) on the oral absorption of paclitaxel in mice. Mice were given an intravenous (18 mg/kg) or oral (100 mg/kg) dose of paclitaxel solubilized in Cremophor/ethanol or in TPGS 400/ethanol formulations. Paclitaxel plasma concentrations and pharmacokinetic parameters were determined. The maximal plasma concentrations of paclitaxel after an oral dose were 1.77 ± 0.17 and 3.39 ± 0.49 μg/ml for Cremophor/ethanol and TPGS 400/ethanol formulations, respectively, with a similar time at 40–47 min to reach the maximal plasma concentrations. The oral bioavailability of paclitaxel in TPGS 400/ethanol (7.8%) was 3-fold higher than that in Cremophor/ethanol (2.5%). On the other hand, the plasma pharmacokinetic profiles of intravenous paclitaxel demonstrated a superimposition for the two formulations. Furthermore, TPGS 400 concentration-dependently increased the intracellular retention of Rhodamine 123 in Caco-2 cells and enhanced paclitaxel permeability in monolayer Caco-2 cultures. TPGS 400 at concentrations up to 1 mM did not inhibit testosterone 6β-hydroxylase, a cytochrome P450 isozyme 3A in liver microsomes metabolizing paclitaxel. Our results indicated that TPGS 400 enhances the oral bioavailability of paclitaxel in mice and the enhancement may result from an increase in intestinal absorption of paclitaxel.

Pharmacokinetics of a New, Orally Available Ceftriaxone Formulation in Physical Complexation with a Cationic Analogue of Bile Acid in Rats

Oral administration of ceftriaxone associated with a bile acid-based new oral carrier, cholylethylenediamine, in 50% propylene glycol to rats at doses of 25 and 50 mg/kg of body weight resulted in a significant increase in intestinal absorption, as evidenced by 55% improvement in the bioavailability, whereas ceftriaxone alone showed a bioavailability of less than 1%.

Magnesium deficiency: effect on bone and mineral metabolism in the mouse.

Insufficient dietary magnesium (Mg) intake has been associated in humans with low bone mass. Mg deficiency in the rat has suggested bone loss is due to increased bone resorption and/or inadequate bone formation during remodeling. The purpose of this study was to assess the effect of a low Mg diet on bone and mineral metabolism in the young and mature BALB/c mouse and explore the hypothesis that inflammatory cytokines may contribute to Mg deficiency-induced osteoporosis. Using an artificial diet, we induced targeted Mg depletion (0.002% Mg) with all other nutrients maintained at the normal level. In all Mg-depleted mice, hypomagnesemia developed and skeletal Mg content fell significantly. The serum Ca in Mg-deficient mice was higher than in control mice; however, serum PTH levels were not significantly different. Osteoprotegerin (OPG) in dosages that inhibit osteoclastic bone resorption did not prevent hypercalcemia in Mg-deficient animals. No significant difference in serum Ca was observed between groups when dietary Ca was reduced by 50%, suggesting that a compensatory increase in intestinal absorption might account for the hypercalcemia. Growth plate width decreased 33% in young Mg-deficient animals and chondrocyte columns decreased in number and length, suggesting that Mg deficiency reduced bone growth. Trabecular bone volume in the metaphysis of the tibia in these animals was decreased and osteoclast number was increased by 135%. Osteoblast number was significantly reduced. Immunohistochemistry revealed that substance P increased 230% and 200% in megakaryocytes and lymphocytes, respectively, after 1 day of Mg depletion. IL-1 increased by 140% in osteoclasts by day 3 and TNF alpha increased in osteoclasts by 120% and 500% in megakaryocytes on day 12. This study demonstrates a profound effect of Mg depletion on bone characterized by impaired bone growth, decreased osteoblast number, increased osteoclast number in young animals, and loss of trabecular bone with stimulation of cytokine activity in bone.

Sarcoidosis of the Thyroid and Kidneys and Calcium Metabolism

In sarcoidosis, the thyroid and the kidneys are infrequently affected. Clinically recognizable thyroid involvement occurs in < 1% of sarcoidosis patients. Hyperthyroidism, myxodema, and thyroid occur with an equal frequency. It is important to distinguish sarcoidosis of the thyroid from other infections and disorders of the gland. Renal involvement may present as granulomatous infiltration of the renal parenchyma, glomerulonephritis, renal arteritis, and nephrocalcinosis or renal stones. The latter are due to abnormalities of calcium metabolism. Hypercalcemia occurs in about 10 to 13% of sarcoidosis patients; hypercalciuria is three times more frequent. Calcium abnormalities may precede, follow, or occur at any time during the course of sarcoidosis. An endogenous overproduction of 1,25-dihydroxyvitamin D [1,25-(OH (2))-D (3)] by granulomatous tissue and activated macrophages results in an increase of intestinal absorption of calcium. Corticosteriods, chloroquine, and hydroxychloroquine subdue 1,25-(OH (2))-D (3) production and correct hypercalcemia and hypercalciuria.

Inherited iron overload disorders.

Iron is an essential nutrient that is highly toxic in excess. Normal iron balance is maintained primarily by regulation of intestinal absorption of the metal from the diet. Iron overload generally results from a chronic increase in intestinal absorption. During the past 5 years, it has become apparent that there are at least eight inherited disorders of iron metabolism characterized by the toxic accumulation of iron. This review provides an update for pediatricians on the clinical features and pathogenesis of these disorders.

Estrogen regulation of intestinal calcium absorption in the intact and ovariectomized adult rat.

Studies were carried out to examine the mechanism of action of estrogen on intestinal calcium absorption in the rat. Three-month-old Wistar rats were sham-operated or ovariectomized (OVX). They were fed a diet containing 0.4% Ca, 0.4% P, and 2000 IU vitamin D3/kg. Eight weeks after operation, both OVX and sham-operated rats were randomly assigned to eight treatment groups. Five groups received per 100 g of body weight 12.5 ng calcitriol (1, 25-dihydroxyvitamin D3); 7.5 microg of estradiol-benzoate; 7.5 microg of estradiol-benzoate and 0.1 mg of ICI 182780; 12.5 ng of calcitriol and 0.1 mg of ICI 182780; and 0.1 mg of ICI 182780, respectively. Three groups received the various vehicles used. Intestinal calcium absorption was measured in vivo using single pass perfusion of the duodenum. OVX did not change intestinal calcium absorption. A pharmacological dose of estradiol-benzoate caused a significant increase in intestinal absorption of calcium, which was comparable to that of a pharmacological dose of calcitriol in both OVX and sham-operated rats. Estrogen-induced rise in intestinal calcium absorption was completely blocked to basal level by the pure estrogen receptor (ER) antagonist ICI 182780. In contrast, ICI 182780 did not antagonize calcitriol-enhanced intestinal calcium absorption. Our findings suggest that estrogen stimulates intestinal calcium absorption via an ER.

Bisphosphonates in the treatment of osteoporosis

The bisphosphonates are synthetic compounds characterized by a P-C-P bond and therefore analogues of the normally occurring substances containing P-0-P. By substituting the hydrogens on the C atom. it is possible to sythesize a variety of bisphosphonates, each of them with its distinct physical-chemical, biological, therapeutic and toxicological characteristics. The first description of their action on calcium phosphate was published by our group in 1968–69.The bisphosphonates are characterized by a strong affinity to calcium phosphates and hence to bone mineral. Once bound they inhibit both formation and dissolution of the crystals. The former effect explains why, when given in large amounts. bisphosphonates can inhibit mineralization in vivo.Many of the bisphosphonates inhibit bone resorption, the newest compounds being 10000 times more active in this respect than the first ones described. In contrast to the effect on mineralizion, the antiresorbing effect is cell mediated. the exact mechanism being still unknown. It seems likely that part of the action is due to a direct effect on the osteoclasts which become inhibited after engulfing the compounds during the process of dissolution of drug-containing mineral. Another part of the effect appears to be mediated throug the osteoblasts, which are induced to produce an inhibitor of osteoclast recruitment. Bisphosphonates have been investigated extensively in animals in view of a possible use in diseases with increased bone resorption. In the growing rat, the inhibition of resorption is accompanied by an increase in intestinal absorption and an increased balance of calcium. They also prevent various types of experimental osteoporosis. such as after immobilization. ovariectomy, orchidectomy, administration of corticosterids, or low calcium diet. Furthermore, bisphosphonates prevent bone destruction induced by various tumor models.The P-C-P bond of the bisphosphonates is completely resistant to enzymatic hydrolysis. The bisphosphonates studied up to now. such as alendronate, clodronate, etidronate, pamidronate, risedronate and tiludronate, are absorbed. stored and excreted unaltered.In humans, bisphosphonates are used successfully in diseases with increased bone turnover. such as Paget's disease. tumoral bone disease, as well as in osteoporosis. They are today the therapy of choice in the former two and are becoming an important addition in the treatment of the latter.Indeed, various bisphosphonates, among them alendronate, clodronate, etidronate. ibandronate and pamidronate not only prevent the loss of bone, but induce an increase in bone mineral density in postmenopausal. as well as in elderly women. Furthermore they prevent the bone loss during corticosteroid treatment. Of great clinical relevance is the fact that. at least alendronate, also decreases the occurence of vertebral and non vertebral fractures. The main bisphosphonates clinically available are alendronate and etidronate.Lastly, etidronate is used with more or less success in prevention of ectopic mineralization and ossification.In humans, the side effects of bisphosphonates depend upon the compound and the amount given. In the case of etidronate. practically the only one is an inhibition of mineralization at high doses, but not at those given in osteporosis. At the beginning of treatment, the amino-derivatives, when given intravenously in larger doses, induce for a period of 2–3 days a syndrome with pyrexia, which resembles an acute phase reaction. Again this effect is not seen at the oral doses used in osteoporosis. Lastly, bisphosphonates, especially the amino-derivatives, can induce gastrointestinal disturbances. especially when given orally in too high doses or with too little water.

Effect of aging and caloric restriction on intestinal sugar and amino acid transport.

The incidence of intestinal nutrient malabsorption increases with age. Therefore, an important question is whether there are age-related changes in intestinal nutrient absorption which may contribute to a decline in absorptive capacity. Sugar and amino acid transport per mg intestine generally decreases with age. The proximate mechanism underlying this age-related decrease in transport activity is a decrease in number of transporters per mg. This reduction in transporter number can be caused by age-related changes in cell proliferation rates which, in turn, can alter the ratio of absorptive to nonabsorptive cells. The age-related change in proliferation rates typically increases intestinal mass. There seems to be no age-related changes in the steady state levels of transporter mRNA. Aging also modestly impairs the ability of intestinal nutrient transport systems to adapt to changes in dietary conditions. Caloric restriction is the only procedure known to consistently increase the lifespan of mammals. Chronic caloric restriction markedly enhances intestinal nutrient transport per mg without affecting intestinal mass. Since body weight decreases with caloric restriction, there is a dramatic increase in intestinal absorptive capacity normalized to body weight. This suggests that an increase in intestinal nutrient absorption may be a critical adaptation to caloric restriction. There is a need to perform in vivo transport studies during senescence, to distinguish between acute and chronic effects of caloric restriction, and to identify hormones that may mediate aging and caloric restriction effects on intestinal nutrient transport.

Bisphosphonates: Preclinical Aspects and Use in Osteoporosis

The bisphosphonates are synthetic compounds characterized by a P-C-P bond. They have a strong affinity to calcium phosphates and hence to bone mineral. In vitro they inhibit both formation and dissolution of the latter. Many of the bisphosphonates inhibit bone resorption, the newest compounds being 10, 000 times more active than etidronate, the first bisphosphonate described. The antiresorbing effect is cell mediated, partly by a direct action on the osteoclasts, partly through the osteoblasts, which produce an inhibitor of osteoclastic recruitment. When given in large amounts, some bisphosphonates can also inhibit normal and ectopic mineralization through a physical-chemical inhibition of crystal growth. In the growing rat the inhibition of resorption is accompanied by an increase in intestinal absorption and an increased balance of calcium. Bisphosphonates also prevent various types of experimental osteoporosis, such as after immobilization, ovariectomy, orchidectomy, administration of corticosteroids, or low calcium diet. The P-C-P bond of the bisphosphonates is completely resistant to enzymatic hydrolysis. The bisphosphonates studied up to now, such as etidronate, clodronate, pamidronate, and alendronate, are absorbed, stored, and excreted unaltered. The intestinal absorption of the bisphosphonates is low, between 1% or less and 10% of the amount ingested. The newer bisphosphonates are at the lower end of the scale. The absorption diminishes when the compounds are given with food, especially in the presence of calcium. Bisphosphonates are rapidly cleared from plasma, 20%-80% being deposited in bone and the remainder excreted in the urine. In bone, they deposit at sites of mineralization as well as under the osteoclasts. In contrast to plasma, the half-life in bone is very long, partially as long as the half-life of the bone in which they are deposited. In humans, bisphosphonates are used successfully in diseases with increased bone turnover, such as Paget's disease, tumoural bone disease, as well as in osteoporosis. Various bisphosphonates, such as alendronate, clodronate, etidronate, ibandronate, pamidronate, and tiludronate, have been investigated in osteoporosis. All inhibit bone loss in postmenopausal women and increase bone mass. Furthermore, bisphosphonates are also effective in preventing bone loss both in corticosteroid-treated and in immobilized patients. The effect on the rate of fractures has recently been proven for alendronate. In humans, the adverse effects depend upon the compound and the amount given. For etidronate, practically the only adverse effect is an inhibition of mineralization. The aminoderivatives induce for a period of 2–3 days a syndrome with pyrexia, which shows a similitude with an acute phase reaction. The more potent compounds can induce gastrointestinal disturbances, sometimes oesophagitis, when given orally. Bisphosphonates are an important addition to the therapeutic possibilities in the prevention and treatment of osteoporosis.

Jejunal Glucose Absorption Is Enhanced by Epidermal Growth Factor in Mice

The effects of epidermal growth factor on intestinal glucose transport were examined in mice. Glucose transport measurements were performed using an in vitro assay system that estimated the rate of accumulation of [3H]3-O-methyl-D-glucose. In Experiment 1, two-mo-old male and female mice were subcutaneously injected once daily with 0, 150 or 300 micrograms epidermal growth factor/kg body weight for 3 d. Jejunal glucose active transport was increased in a dose-dependent manner. There were no gender-related differences in intestinal glucose transport or the response to exogenous epidermal growth factor. In Experiment 2, 2-, 10- and 18-mo-old mice were administered 0 or 300 micrograms epidermal growth factor/kg body weight using a treatment similar to that used in Experiment 1. Active intestinal glucose transport was 30% greater in response to epidermal growth factor in each of the three age groups. Ouabain-sensitive and -insensitive jejunal oxygen consumption was increased in response to epidermal growth factor such that total jejunal respiration was stimulated 15 to 31%. The epidermal growth factor related percentage increase in glucose absorption was similar to the percentage increase in oxygen consumption such that the apparent energetic efficiency of glucose transport was unaffected. In both experiments, the active component of glucose transport was increased by epidermal growth factor while passive transport was not affected. Jejunal morphology and mucosal DNA and protein concentration were not altered by epidermal growth factor treatment. Epidermal growth factor-induced increases in intestinal absorption was not attributable to mucosal hyperplasia.

In vivo effect of 17 β-estradiol on intestinal calcium absorption in rats

Previously we reported that intestinal cells contain estrogen receptors, and that 17 β-estradiol enhanced calcium uptake by these cells in vitro. The current study was undertaken to examine the in vivo effects of 17 β-estradiol on intestinal absorption of calcium and phosphorus. Three groups of rats were studied. Group 1 received solvent vehicle. Groups 2 and 3 received 5 μg and 40 μg 17 β-estradiol/kg body weight/day, respectively, for 21 days. Hormone and solvent vehicle injections were given subcutaneously. Rats were fed a Teklad diet containing 0.4% Ca, 0.3% P and 3.0 U vitamin D/g during the study. Intestinal absorption of calcium and phosphorus was assessed over a 5-day period from day 15–19. Carmine red (25 mg/100 g diet) was added to the rat feed to mark the beginning and end of fecal collections. Administration of 17 β-estradiol caused an increase in intestinal absorption of calcium and phosphorus. The increase was significant only for calcium, and in the animals that received high-dose 17 β-estradiol ( P < 0.05). Serum calcium and phosphorus levels were significantly greater in 17 β-estradiol treated than in control animals. The urinary excretion of calcium and phosphorus was also increased in a dose-dependent manner by 17 β-estradiol, and was significant for both calcium and phosphorus in animals that received high-dose 17 β-estradiol ( P < 0.05). In contrast, 17 β-estradiol treatment did not significantly alter the serum levels of parathyroid hormone and l,25(OH) 2vitamin D. These findings indicate that estrogen administration promotes intestinal absorption of calcium in vivo. The enhanced calcium absorption, in spite of unaltered serum l,25(OH) 2vitamin D levels, suggests that estrogen does not promote calcium absorption mainly by increasing the circulating levels of l,25(OH) 2vitamin D.

New bisphosphonates in osteoporosis.

Bisphosphonates are non-biodegradable compounds characterized by a phosphorus-carbon-phosphorus bond. By substituting the hydrogens on the carbon atom, a variety of bisphosphonates can be synthesized, each with distinct physical-chemical, biologic, therapeutic, and toxicologic characteristics. Bisphosphonates have in general a strong affinity to calcium phosphates, both in vitro and in vivo. They inhibit bone resorption through a cellular mechanism that is not yet completely understood. When given in large amounts, some bisphosphonates can inhibit normal and ectopic mineralization through a physical-chemical mechanism. The main difference among the various compounds appears to be their potency in inhibiting bone resorption, which can vary from 1 to 10,000. The potential efficacy of bisphosphonates in osteoporosis has been investigated extensively in animals. In the growing rat, they induce an increase in intestinal absorption and body retention of calcium. Various types of experimental osteoporosis, such as induced by immobilization, ovariectomy, administration of corticosteroids, or low calcium diet, can be prevented. Bisphosphonates are rapidly cleared from plasma, with 20%-60% deposited in bone and the remainder excreted in the urine. The half-life in bone is, however, very long. The toxicity of bisphosphonates is low, probably because of their rapid plasma and soft tissue clearance. It varies greatly from compound to compound. Bisphosphonates are used successfully in diseases with increased bone turnover, such as Paget's disease of bone, tumoral bone disease, and recently, osteoporosis. Most results in osteoporosis have been obtained with etidronate and pamidronate. Both of these compounds, as well as other bisphosphonates, such as tiludronate, alendronate, and clodronate, inhibit bone loss and sometimes even increase bone mass.(ABSTRACT TRUNCATED AT 250 WORDS)