ABSTRACT
Aspirin is an effective analgesic and antiplatelet drug that in addition to its ability to reduce pain, inflammation and fever, appears to have efficacy in the prevention/treatment of a range of diseases including heart disease, numerous cancers and Alzheimer's. It is important to understand the bioavailability of aspirin and its major metabolite, salicylic acid, since dosage and route of administration can vary for treating differing diseases, and the major side-effects of aspirin, upper gastrointestinal ulceration and bleeding, are dose-dependent. We examined the time course for gastroduodenal uptake of aspirin and the appearance of its major metabolite salicylic acid in blood and lymph after intragastric (to simulate oral) and intraduodenal (to simulate enteric-coating) dosing in rats. Results show that after intragastric dosing, intact aspirin is absorbed primarily by the gastric mucosa and to a lesser extent by the duodenal mucosa. When aspirin is dosed intragastrically or intraduodenally, a much greater concentration of aspirin enters the lymph than the blood. In contrast, the concentration of salicylic acid was higher in blood than in lymph. Lymph levels of both aspirin and salicylic acid were sufficiently high so as to perform a pharmacologic function there, possibly as a chemopreventive agent against colon cancer and potentially the metastatic spread of non-gastrointestinal cancers.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anticarcinogenic Agents/pharmacokinetics , Aspirin/pharmacokinetics , Intestinal Mucosa/metabolism , Lymphatic System/metabolism , Salicylic Acid/pharmacokinetics , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/blood , Anticarcinogenic Agents/administration & dosage , Anticarcinogenic Agents/blood , Aspirin/administration & dosage , Aspirin/blood , Biological Availability , Drug Administration Routes , Male , Rats , Rats, Sprague-Dawley , Salicylic Acid/administration & dosage , Salicylic Acid/bloodABSTRACT
OBJECTIVES: Breast feeding protects infants from many diseases, including necrotizing enterocolitis, peptic ulceration and infectious diarrhea. Conversely, maternal separation stress and Non-Steroidal Anti-Inflammatory Drugs (NSAID's) can induce intestinal injury and bleeding. This study aimed to evaluate in suckling rats if maternal separation/formula feeding leads to increased intestinal sensitivity to indomethacin (indo)-induced intestinal injury and to look at potential mechanisms involved. METHODS: Nine-day-old rats were dam-fed or separated/trained to formula-feed for 6 days prior to indo administration (5 mg/kg/day) or saline (control) for 3 days. Intestinal bleeding and injury were assessed by measuring luminal and Fecal Hemoglobin (Hob) and jejunal histology. Maturation of the intestine was assessed by measuring luminal bile acids, jejunal sucrase, serum corticosterone, and mRNA expression of ileal Apical Sodium-Dependent Bile Acid Transporter (ASBT). RESULTS: At 17 days, formula-fed indo-treated pups had a 2-fold increase in luminal Hb compared to formula-fed control pups and had evidence of morphological injury to the small intestinal mucosa as observed at the light microscopic level, whereas indo had no effect on dam-fed littermates. In addition, formula-fed rats had significant increases in luminal bile acid, sucrase specific activity, serum corticosterone, and expression of ASBT mRNA compared to dam-fed rats. CONCLUSION: Maternal separation stress may cause early intestinal maturational changes induced by corticosteroid release, including increased epithelial exposure to bile acids. These maturational changes may have a sensitizing rather than protective effect against indo-induced injury in the new-born.
ABSTRACT
BACKGROUND: Infectious endocarditis in children requires prolonged antibiotic therapy. In adults, antibiotics administrated subcutaneously such as teicoplanin are an alternative to intravenous treatment. CASE REPORT: We report the use of subcutaneous teicoplanin, after an initial antibiotic treatment administrated intravenously, for 2 children treated for infectious endocarditis following an initial cardiac surgery. Serum concentrations of teicoplanin were within the target range after the adaptation in the teicoplanin subcutaneous dosages. The treatment was effective for both cases. No specific side effects related to the treatment were reported. DISCUSSION: Subcutaneous administration could be used for prolonged antibiotic therapy for the treatment of infectious endocarditis in children, after an initial intravenous treatment. Variability of the bioavailability of antibiotics administrated subcutaneously requires regular testing. Prospective, randomized trials comparing intravenous and subcutaneous administration of teicoplanin should be conducted to assess the efficacy and safety of this treatment.
Subject(s)
Anti-Bacterial Agents/administration & dosage , Endocarditis, Bacterial/drug therapy , Prosthesis-Related Infections/drug therapy , Teicoplanin/administration & dosage , Child , Child, Preschool , Drug Therapy, Combination , Humans , Infusions, Intravenous , Injections, Subcutaneous , Male , Prosthesis-Related Infections/microbiology , Streptococcal Infections/drug therapyABSTRACT
Clinical evidence suggests that aspirin and particularly enteric-coated aspirin induce significant injury to the lower gut. We have reported that NSAID injury to the small bowel is exacerbated by bile acids and that phosphatidylcholine (PC) can protect against this damage. Using a recently described method, we intra-duodenally administered either: saline, aspirin or aspirin pre-associated with PC. The rats were euthanized 90 minutes later at which time we assessed: tissue injury morphologically, vascular permeability with i.v. administered Evan's blue and intestinal bleeding by measuring luminal hemoglobin. In a separate experiment, aspirin-induced injury was studied in rats whose bile duct was ligated either alone or in the presence of rat bile (collected from donor animals). Intra-duodenal administration of aspirin induced mucosal injury (observed histologically), an increase in vascular permeability and blood loss into the intestinal lumen, all of which could be attenuated if the NSAID was pre-associated with PC. Furthermore, using 100 mg/kg dose of aspirin it was determined that bile duct ligation (BDL) significantly reduced aspirin-induced intestinal bleeding which was not different from control rats. Lastly, it was determined that intestinal bleeding was significantly increased in rats with BDL if the aspirin was administered in rodent bile. Aspirin-induced intestinal injury and bleeding in the rat is dependent on the presence of luminal bile, which is likely attributable to it's constituent bile acids. Pre-association of aspirin with PC provides a novel therapeutic approach to significantly reduce aspirin-induced small intestinal injury and bleeding, as may occur with enteric-coated aspirin.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Aspirin/adverse effects , Bile , Gastrointestinal Hemorrhage/prevention & control , Intestine, Small/drug effects , Phosphatidylcholines/administration & dosage , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Aspirin/administration & dosage , Bile/chemistry , Bile Acids and Salts/adverse effects , Dose-Response Relationship, Drug , Gastrointestinal Hemorrhage/chemically induced , Gastrointestinal Hemorrhage/pathology , Intestinal Mucosa/drug effects , Intestinal Mucosa/injuries , Intestinal Mucosa/pathology , Intestine, Small/injuries , Intestine, Small/pathology , Male , Rats , Rats, Sprague-DawleyABSTRACT
BACKGROUND AND PURPOSE: Indomethacin is a non-steroidal anti-inflammatory drug (NSAID) that is limited in its enteral or parenteral use by side effects of gastroduodenal bleeding and ulceration. We have investigated the ability of phosphatidylcholine associated with indomethacin to form a therapeutically effective drug (INDO-PC) with reduced gastrointestinal (GI) toxicity for parenteral use. EXPERIMENTAL APPROACH: Rats were treated acutely by intravenous or chronically with subcutaneous injection of vehicle, indomethacin or INDO-PC using three related protocols. We then evaluated the following properties of these parenterally administered test drugs: (i) GI toxicity (luminal and faecal haemoglobin; intestinal perforations and adhesions; and haematocrit); (ii) bioavailability (plasma indomethacin); and (iii) therapeutic efficacy (analgesia from sensitivity to pressure; anti-inflammatory from ankle thickness; cyclo-oxygenase (COX) inhibition from synovial fluid prostaglandin E(2) concentration) in rats with adjuvant-induced joint inflammation. KEY RESULTS: Acute and chronic dosing with INDO-PC produced less GI bleeding and intestinal injury than indomethacin alone, whereas the bioavailability, analgesic, anti-inflammatory and COX inhibitory activity of INDO-PC were comparable to indomethacin. CONCLUSIONS AND IMPLICATIONS: The chemical association of phosphatidylcholine with indomethacin appears to markedly reduce the GI toxicity of the NSAID while providing equivalent therapeutic efficacy in a parenteral INDO-PC formulation.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Gastrointestinal Hemorrhage/chemically induced , Indomethacin/therapeutic use , Models, Animal , Phosphatidylcholines/chemistry , Stomach Ulcer/chemically induced , Animals , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Chromatography, High Pressure Liquid , Dinoprostone/analysis , Drug Administration Routes , Indomethacin/adverse effects , Indomethacin/blood , Radioimmunoassay , RatsABSTRACT
UNLABELLED: We have been developing a family of phosphatidylcholine (PC)-associated NSAIDs, which appear to have improved GI safety and therapeutic efficacy in both rodent model systems and pilot clinical trials. As naproxen has been demonstrated to be associated with the lowest cardiovascular adverse events in comparison with both COX-2 selective inhibitors and conventional NSAIDs, we have been developing a Naproxen-PC formulation for evaluation in animal models and clinical trials. We have determined that an oil-based formulation of naproxen and triple strength soy lecithin provides excellent GI protection in both: 1) an acute NSAID-induced intestinal bleeding model in rats pretreated with L-NAME that are intragastrically administered a single dose of naproxen (at a dose of 50 mg/kg) vs the equivalent dose of Naproxen-PC; and 2) a more chronic model (at a naproxen dose of 25 mg/kg BID) in rats that have pre-existing hindpaw inflammation (induced with a intradermal injection of Complete Freund's Adjuvant/CFA). Both models demonstrate the superior GI safety of Naproxen-PC vs naproxen while this novel formulation had significant anti-inflammatory efficacy to reduce hindpaw edema and the generation of PGE(2) in the collected joint synovial fluid. CONCLUSION: Naproxen-PC appears to induce significantly less GI injury and bleeding in two rodent model systems while maintaining anti-inflammatory and COX-inhibitory activity.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Inflammation/drug therapy , Lecithins/chemistry , Naproxen/administration & dosage , Animals , Anti-Inflammatory Agents, Non-Steroidal/toxicity , Cyclooxygenase Inhibitors/administration & dosage , Cyclooxygenase Inhibitors/toxicity , Dinoprostone/metabolism , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Administration Schedule , Edema/drug therapy , Edema/physiopathology , Gastrointestinal Hemorrhage/chemically induced , Gastrointestinal Hemorrhage/prevention & control , Inflammation/physiopathology , Naproxen/toxicity , Rats , Glycine max/chemistry , Synovial Fluid/metabolismABSTRACT
BACKGROUND: Chronic use of NSAIDs is associated with gastrointestinal (GI) toxicity that increases with age. AIM: To evaluate the GI safety and therapeutic efficacy of ibuprofen chemically associated with phosphatidylcholine (PC) in osteoarthritic (OA) patients. METHODS: A randomized, double-blind trial of 125 patients was performed. A dose of 2400 mg/day of ibuprofen or an equivalent dose of ibuprofen-PC was administered for 6 weeks. GI safety was assessed by endoscopy. Efficacy was assessed by scores of analgesia and anti-inflammatory activity. Bioavailability of ibuprofen was pharmacokinetically assessed. RESULTS: Ibuprofen-PC and ibuprofen provided similar bioavailability/therapeutic efficacy. In the evaluable subjects, a trend for improved GI safety in the ibuprofen-PC group compared with ibuprofen that did not reach statistical significance was observed. However, in patients aged >55 years, a statistically significant advantage for ibuprofen-PC treatment vs. ibuprofen in the prevention of NSAID-induced gut injury was observed with increases in both mean Lanza scores and the risk of developing >2 erosions or an ulcer. Ibuprofen-PC was well tolerated with no major adverse events observed. CONCLUSION: Ibuprofen-PC is an effective osteoarthritic agent with an improved GI safety profile compared with ibuprofen in older OA patients, who are most susceptible to NSAID-induced gastroduodenal injury.
Subject(s)
Analgesics, Non-Narcotic/adverse effects , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Ibuprofen/adverse effects , Osteoarthritis/drug therapy , Phosphatidylcholines/adverse effects , Adolescent , Adult , Aged , Aged, 80 and over , Analgesics, Non-Narcotic/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Double-Blind Method , Drug Therapy, Combination , Female , Gastrointestinal Hemorrhage/chemically induced , Gastrointestinal Hemorrhage/prevention & control , Humans , Ibuprofen/pharmacology , Male , Middle Aged , Phosphatidylcholines/pharmacology , Stomach Ulcer/chemically induced , Stomach Ulcer/prevention & control , Treatment OutcomeABSTRACT
BACKGROUND AND PURPOSE: Clinical studies demonstrate that aspirin consumption reverses the gastrointestinal (GI) benefits of coxibs, by an undefined mechanism. EXPERIMENTAL APPROACH: Rodent models were employed to investigate the effects of combinations of celecoxib and aspirin on gastric ulcerogenesis, bleeding, surface hydrophobicity (by contact angle analysis) and ulcer healing. We also evaluated the effects of phosphatidylcholine (PC)-associated aspirin in these rodent models and confirmed its cyclooxygenase (COX)-inhibitory activity by measuring mucosal prostaglandin E(2) (PGE(2)) concentration. We present evidence that aspirin's ability to induce gastric injury and bleeding in rats, was exacerbated in the presence of a coxib and was dependent on its ability to reduce gastric surface hydrophobicity. In contrast, co-administration of phosphatidylcholine (PC)-associated aspirin and celecoxib induced little or no gastric injury/bleeding and maintained the stomach's hydrophobic properties. Interestingly, aspirin and aspirin/PC equally inhibited gastric mucosal PGE(2) concentration. Aspirin in combination with a coxib retarded the healing of experimentally induced gastric ulcers, whereas healing rates of rats treated with celecoxib in combination with aspirin/PC were comparable to controls. CONCLUSIONS AND IMPLICATIONS: Aspirin's gastric toxicity in combination with a coxib can be dissociated from its ability to inhibit COX-1 and appears to be dependent, in part, on its ability to attenuate the stomach's surface hydrophobic barrier. This adverse drug interaction between aspirin and coxibs, which impacts the treatment of osteoarthritic and cardiac patients requiring cardiovascular prophylaxis, can be circumvented by the administration of phosphatidylcholine (PC)-associated aspirin, to maintain the stomach's hydrophobic properties.
Subject(s)
Aspirin/administration & dosage , Cyclooxygenase Inhibitors/administration & dosage , Phosphatidylcholines/administration & dosage , Pyrazoles/administration & dosage , Stomach Ulcer/prevention & control , Sulfonamides/administration & dosage , Animals , Aspirin/adverse effects , Celecoxib , Dinoprostone/metabolism , Drug Interactions , Gastric Mucosa/drug effects , Gastric Mucosa/metabolism , Gastric Mucosa/pathology , Hydrophobic and Hydrophilic Interactions , Male , Pyrazoles/adverse effects , Rats , Rats, Sprague-Dawley , Stomach Ulcer/chemically induced , Stomach Ulcer/metabolism , Stomach Ulcer/pathology , Sulfonamides/adverse effectsABSTRACT
The murine gastric mucosa possesses very high secretory type phospholipase A2 activity. Northern and Western blots indicated that the pancreatic-type, sPLA2-IB represents the predominant form of sPLA2 enzymes present in the gastric mucosa. Both sPLA2-IB mRNA and protein in the gastric mucosa exceeded levels found in the pancreas, and in contrast to the pancreatic enzyme it was present primarily in the active state. The sPLA2-IB gene is not expressed in the murine small intestine and colon. Infection by the gastritis-inducing bacteria, Helicobacterfelis (H. felis) dramatically and time dependently decreased the PLA2 activity in the glandular stomach of the mouse strain, C57BL/6, sensitive to the organism, which appeared to be related to a decrease in the percentage of sPLA2-IB present in the active form. This bacterial-induced reduction in PLA2 activity was not observed in BALB/c mice that fail to develop gastritis in response to H. felis infection. C57BL/6 mice do not, while BALB/c mice express, the PLA2-II enzyme. The H. felis-induced reduction in sPLA2-IB activity may weaken the gastric barrier by reducing the local concentration of arachidonic and linoleic acid, liberated from membrane phospholipids, the major precursors of 'cytoprotective' prostaglandins. Data presented here suggest that both sPLA2-IB and sPLA2-II enzymes may contribute to the gastric response to Helicobacter infection.
Subject(s)
Gastric Mucosa/enzymology , Helicobacter Infections/enzymology , Phospholipases A/biosynthesis , Phospholipases A/metabolism , Animals , Blotting, Northern , Blotting, Western , Female , Group II Phospholipases A2 , Helicobacter Infections/genetics , Ileum/enzymology , Intestines/enzymology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Phospholipases A/genetics , Phospholipases A2 , RNA, Messenger/biosynthesis , Species Specificity , Time FactorsABSTRACT
We investigated whether chemical association of phosphatidylcholine (PC) to ibuprofen enhances the anti-inflammatory/analgesic activity of the nonsteroidal anti-inflammatory drug (NSAID) and whether any change in therapeutic action is due to alterations in drug bioavailability and cyclooxygenase (COX) inhibitory activity. Acute/chronic joint inflammation was induced in rats, by injection of Complete Freund's Adjuvant. In the acute study, rats were administered saline, ibuprofen, or PC-ibuprofen (at NSAID doses of 10, 25, and 50 mg/kg), and 2 h later the pain threshold of the affected joint to pressure was measured. PC-ibuprofen increased the pain threshold at all NSAID doses, whereas unmodified ibuprofen demonstrated analgesic activity at only the highest dose. In the chronic study, we investigated the effects of saline, PC-ibuprofen, and ibuprofen (administered at 15 and 25 mg/kg/day) on ankle thickness and pain threshold, and demonstrated that PC-ibuprofen had significantly greater anti-inflammatory and analgesic activity than ibuprofen, over a 30- to 60-day period. PC association resulted in reduced uptake (decreased Cmax), a modest increase in the area under the curve, and a longer t(1/2) of ibuprofen. We also demonstrated that PC-ibuprofen was a comparable or a more effective inhibitor of both 6-keto-prostaglandin F1alpha concentration of fluid collected from tissue in and around the inflamed stifle joint, and COX-2 activity in activated human umbilical vein endothelial cells. In conclusion, we have demonstrated that PC association results in increases in ibuprofen's anti-inflammatory and analgesic activity in rodent models of acute and chronic joint inflammation, and this effect may relate to alterations in drug bioavailability and COX-inhibitory potency.
Subject(s)
Analgesics, Non-Narcotic/therapeutic use , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Arthritis, Experimental/drug therapy , Cyclooxygenase Inhibitors/therapeutic use , Ibuprofen/therapeutic use , Phosphatidylcholines/therapeutic use , Analgesics, Non-Narcotic/blood , Animals , Anti-Inflammatory Agents, Non-Steroidal/blood , Arthritis, Experimental/blood , Biological Availability , Chemistry, Pharmaceutical , Cyclooxygenase Inhibitors/blood , Drug Combinations , Drug Synergism , Ibuprofen/blood , Male , Phosphatidylcholines/blood , Rats , Rats, Sprague-DawleyABSTRACT
In this commentary, we take a critical look at the concept that the gastrointestinal (GI) side-effects of nonsteroidal anti-inflammatory drugs (NSAIDs) are due to the ability of these drugs to inhibit cyclooxygenase-1 (COX-1) that is constitutively expressed in the GI mucosa. Indeed, development of the new "super aspirins," such as Celebrex and Vioxx, that selectively inhibit the inducible COX-2, expressed in areas of inflammation, is a direct outgrowth of this concept. We discuss evidence from both the laboratory and the clinic that appears to be inconsistent with the above concept, and cite a number of examples where the depletion of mucosal prostaglandin levels and the development of GI injury can be dissociated. Instead, we revisit the possibility that NSAID-induced GI side-effects are mostly due to the ability of these drugs to topically injure the GI mucosa. We devote the remainder of the commentary to presenting evidence from our and other laboratories that NSAIDs can directly attenuate the surface hydrophobic barrier of the GI mucosa due to their ability to bind to zwitterionic phospholipids, and that even systemically administered NSAIDs that are secreted into the bile may induce GI ulceration and/or bleeding due to phospholipid interactions and the development of topical mucosal injury.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Gastrointestinal Diseases/chemically induced , Intestinal Mucosa/drug effects , Isoenzymes/metabolism , Prostaglandin-Endoperoxide Synthases/metabolism , Celecoxib , Cyclooxygenase 1 , Cyclooxygenase 2 , Gastrointestinal Diseases/enzymology , Humans , Intestinal Mucosa/injuries , Isoenzymes/antagonists & inhibitors , Membrane Proteins , Pyrazoles , Sulfonamides/pharmacologyABSTRACT
Intrinsic factor is produced primarily by chief cells in rat and mouse, but 4 to 11% of isolated rat parietal cells also contain intrinsic factor. To test whether local conditions could alter the distribution of intrinsic factor expression, two rodent models of chronic lymphocytic gastric inflammation were examined. Immunocytochemistry was performed using antiserum against human intrinsic factor and H/K ATPase (a parietal cell marker), counting the percent of intrinsic factor-positive parietal cells. HLA-B27 transgenic rats develop chronic gastritis at age 3 months. Congenic controls expressed intrinsic factor in 8.9 +/- 3.8% (mean +/- SD) of parietal cells; in inflamed areas of transgenic rats 21 +/- 5.2% (P < 0.0001) of parietal cells were positive. In adjacent areas without inflammatory infiltrate 16 +/- 3.6% of parietal cells contained intrinsic factor. C57BL/6 mice inoculated with Helicobacter felis develop gastritis by 4 weeks. After 4 and 8 weeks of infection, intrinsic factor-positive parietal cells increased from 7.8 +/- 2.8% in the congenic controls to 17.6 +/- 4.1% in the inflamed gastric body (P < 0.0001). Isolated rat parietal cells incubated with interleukin-1beta demonstrated a twofold increase in intrinsic factor-positive parietal cells. These studies are consistent with the concept that intrinsic factor expression is both predetermined in chief cells and can be expressed in parietal cells in response to local inflammatory factors. The differences between inflamed and adjacent noninflamed areas in the rat model suggest a tissue gradient of soluble inducer(s), possibly cytokines.
Subject(s)
Gastric Mucosa/metabolism , Gastritis/metabolism , Intrinsic Factor/metabolism , Animals , Animals, Genetically Modified/genetics , Cell Line , Cell Separation , Female , Gastric Mucosa/cytology , Gastric Mucosa/immunology , Gastric Mucosa/pathology , Gastritis/immunology , Gastritis/microbiology , Gastritis/pathology , HLA-B27 Antigen/genetics , HLA-B27 Antigen/physiology , Helicobacter Infections , Immunohistochemistry , Interleukin-1/pharmacology , Mice , Mice, Inbred C57BL , Parietal Cells, Gastric/metabolism , Rats , Rats, Inbred LewABSTRACT
Bisphosphonates are a family of chemically related zwitterionic molecules that are used clinically to retard bone resorption in individuals with osteoporosis and associated skeletal diseases. Inflammation and ulceration of the upper gastrointestinal tract by a mechanism that relates to a topical irritant action is associated with the consumption of some bisphosphonates. In the present study, we investigated the effects of three bisphosphonate molecules, pamidronate, alendronate, and risedronate on the surface hydrophobicity and phosphatidylcholine (PC) concentration of the antral mucosa. We also examined how these surface changes related to mucosal injury in an established rat model, in which the test compounds were administered in combination with indomethacin. We initially determined that a combination of pamidronate (300 mg/kg) and indomethacin (40 mg/kg) induced a significant reduction in mucosal surface hydrophobicity and macroscopic lesion formation by 15 min and mucosal PC concentration by 30 min, with the magnitude of these changes increasing over the 4-hr study period. An equivalent dose of alendronate or risedronate in combination with indomethacin produced modest or no macroscopic injury, respectively, to the antral mucosa over the 4-hr study, although the bisphosphonates clearly induced surface injury and some glandular necrosis when examined at the light microscopic level. These bisphosphonates also induced modest decreases in antral surface hydrophobicity and mucosal PC concentration that appeared to be related to their injurious potential. In conclusion, the variable toxicity of bisphosphonates to the antral mucosa appears to be associated with their ability to compromise the surface hydrophobic phospholipid barrier of the tissue, with pamidronate > > > alendronate > risedronate. This bisphosphonate effect on the surface barrier may trigger the development of mucosal injury and possible ulceration.
Subject(s)
Diphosphonates/pharmacology , Etidronic Acid/analogs & derivatives , Gastric Mucosa/drug effects , Phosphatidylcholines/metabolism , Alendronate/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Etidronic Acid/pharmacology , Gastric Mucosa/metabolism , Gastric Mucosa/physiology , Indomethacin/pharmacology , Male , Pamidronate , Rats , Rats, Sprague-Dawley , Risedronic Acid , Surface PropertiesABSTRACT
The rare, genetically based disorder, Williams syndrome (WMS), produces a constellation of distinctive cognitive, neuroanatomical, and electrophysiological features which we explore through the series of studies reported here. In this paper, we focus primarily on the cognitive characteristics of WMS and begin to forge links among these characteristics, the brain, and the genetic basis of the disorder. The distinctive cognitive profile of individuals with WMS includes relative strengths in language and facial processing and profound impairment in spatial cognition. The cognitive profile of abilities, including what is 'typical' for individuals with WMS is discussed, but we also highlight areas of variability across the group of individuals with WMS that we have studied. Although the overall cognitive abilities (IQs) of individuals with WMS are typically in the mild-to-moderate range of mental retardation, the peaks and valleys within different cognitive domains make this syndrome especially intriguing to study across levels. Understanding the brain basis (and ultimately the genetic basis) for higher cognitive functioning is the goal we have begun to undertake with this line of interdisciplinary research.
Subject(s)
Cognition/physiology , Nervous System Physiological Phenomena , Williams Syndrome/physiopathology , Williams Syndrome/psychology , Child , Humans , Intelligence , Language DevelopmentABSTRACT
Altered gastrin expression associated with Helicobacter pylori infection may contribute to the pathogenesis of peptic ulcer disease or gastric cancer in man, but gastrin has not been investigated in a murine model of Helicobacter infection. C57BL/6 mice were inoculated with Helicobacter felis and examined after 4-21 weeks for G and D cell numbers, antral gastrin and somatostatin mRNA, and luminal pH. In H. felis-infected mice, gastrin mRNA declined at four and six weeks after infection to 57% and 23%, respectively, of uninfected control values. Concurrently, somatostatin mRNA showed no change at four weeks and a modest 25% decrease at six weeks after infection. Similar reductions were noted in G and D cell numbers, resulting in a decrease in the G/D cell ratio after mice were infected with H. felis. Infected animals also showed a loss of parietal and chief cells, and an increased gastric pH. H. felis infection in C57BL/6 mice leads to an early suppression of G cell number and gastrin mRNA. These changes precede an alteration in somatostatin cell number and mRNA and, coupled with reductions in parietal and chief cells, may contribute both to severe impairment of gastric acid output and the potential for carcinogenic processes.
Subject(s)
Gastrins/metabolism , Helicobacter Infections/metabolism , Animals , Cell Count , Gastric Mucosa/metabolism , Gastric Mucosa/pathology , Gastrins/genetics , Helicobacter Infections/pathology , Hydrogen-Ion Concentration , Mice , Mice, Inbred C57BL , Organ Size , Parietal Cells, Gastric/pathology , RNA, Messenger/metabolism , Reference Values , Somatostatin/genetics , Time FactorsABSTRACT
BACKGROUND & AIMS: We explored the role of biliary phosphatidylcholine (PC) in protection of the intestinal mucosa against bile salt (BS)-induced intestinal injury and how this property may be blocked by indomethacin (Indo), a nonsteroidal anti-inflammatory drug (NSAID) that is secreted into the bile. METHODS: We performed in vivo studies in which bile was collected over a 2-hour period after rats were intragastrically administered Indo (25 mg/kg) or an equivalent volume of saline (controls). The bile samples (some of which were supplemented with PC) were then instilled into a loop of distal ileum of anesthetized rats. After a 30-minute exposure period, we measured the hemoglobin concentration of the ileal loop fluid, as an index of bleeding, and mucosal contact angles, as an index of surface hydrophobicity. A similar in vivo experiment was performed in which model bile containing 5 mmol/L each of the BS, sodium deoxycholate, PC, or Indo, alone and in combination, was instilled into ileal loops. In our in vitro test system, human erythrocytes were exposed to the above biliary constituents, and hemolysis was measured spectrophotometrically. RESULTS: Bile from Indo-pretreated rats decreased the surface hydrophobicity and induced bleeding of ileal loops in comparison with control bile, and both NSAID-induced changes were reversed if PC was added to the bile. Similarly, synthetic BS caused gastrointestinal bleeding, decreased ileal contact angles, and induced erythrocyte hemolysis, all of which were reversed by addition of equimolar PC. This protective role of PC in both the in vivo and in vitro systems was partially blocked by Indo, although the NSAID had no effect on these properties on its own. CONCLUSIONS: These findings support the hypothesis that PC protects the intestinal mucosa against injurious actions of BS, possibly by forming less toxic mixed micelles. Indo and perhaps other NSAIDs that enter the bile may damage the mucosa, not by a direct action, but by competing for the available protective PC molecules.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Bile Acids and Salts/toxicity , Ileum/pathology , Indomethacin/pharmacology , Phosphatidylcholines/metabolism , Animals , Bile Acids and Salts/metabolism , Erythrocytes/drug effects , Hemolysis , Ileal Diseases/chemically induced , Ileal Diseases/metabolism , Ileal Diseases/pathology , Ileum/metabolism , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Male , Micelles , Rats , Rats, Sprague-DawleyABSTRACT
Recombinant human lactoferrin possesses in-vitro antibiotic and anti-inflammatory activity similar to the native form. It was tested for in-vivo activity in mice infected with the gastritis-inducing bacterium Helicobacter felis. A two-week course of treatment with lactoferrin was sufficient to partially reverse both infection-induced gastritis and the infection rate, and fully reverse gastric surface hydrophobicity changes. A comparison of lactoferrin with amoxicillin and standard triple therapy revealed no differences in infection rate. These results show that recombinant human lactoferrin is effective in a mouse model of Helicobacter infection, and support further testing of this promising agent for this application.
Subject(s)
Gastritis/drug therapy , Helicobacter Infections/drug therapy , Helicobacter/drug effects , Lactoferrin/pharmacology , Amoxicillin/pharmacology , Animals , Body Weight/drug effects , Dose-Response Relationship, Drug , Gastritis/etiology , Helicobacter Infections/complications , Helicobacter Infections/microbiology , Humans , Mice , Mice, Inbred C57BL , Organ Size/drug effects , Penicillins/pharmacology , Recombinant Proteins/pharmacology , Stomach/drug effects , Stomach/pathology , Time FactorsABSTRACT
OBJECTIVE: In previous studies on rats, we have shown that aspirin (ASA)-induced injury to the gastric mucosa is markedly reduced or completely abolished if ASA is chemically associated with the phospholipid, phosphatidylcholine (PC). We have also shown that the protective effect of PC does not influence the ability of ASA to inhibit mucosal cyclooxygenase (COX) activity in the stomach and other tissues. We therefore sought to assess the effect of PC-associated ASA (ASA/PC) on the gastric mucosa of normal volunteers and to compare the results with the use of ASA alone. METHODS: Sixteen normal healthy subjects were administered ASA or ASA/PC in a randomized, double-blind, crossover study. The subjects received ASA in a dose of 650 mg three times a day for 3 days or an equivalent dose of ASA chemically associated with PC. Endoscopy was performed at baseline and again on the morning of day 4, after the subjects had taken the final dose of the test drug. On both occasions, antral biopsy specimens were obtained for the assessment of mucosal COX activity and prostaglandin concentration. RESULTS: The number (mean +/- SD) of gastric erosions seen with the ASA/PC formulation was significantly less than when ASA was used alone (8.7 +/- 10.7 vs 2.9 +/- 4.3; p < 0.025). A similar trend was seen in the duodenum but the difference was statistically not significant. The antral mucosal COX activity, as well as the level of prostaglandin 6-keto PGF1alpha, were reduced significantly (80-88%) and to a similar extent by both ASA and ASA/PC. CONCLUSIONS: The present study shows that acute aspirin-induced damage to the gastric mucosa can be reduced by chemically associating ASA with PC. The mechanism of mucosal protection provided by this compound is not related to any alteration in the ability of ASA to inhibit mucosal COX activity. We believe this protection is attributable to the maintenance of the defensive hydrophobic barrier of the gastric mucosa.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/toxicity , Aspirin/toxicity , Gastric Mucosa/drug effects , Phosphatidylcholines/administration & dosage , 6-Ketoprostaglandin F1 alpha/metabolism , Adult , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Aspirin/administration & dosage , Cross-Over Studies , Double-Blind Method , Female , Gastric Mucosa/metabolism , Humans , Male , Prostaglandin-Endoperoxide Synthases/metabolism , SuspensionsABSTRACT
BACKGROUND: Helicobacter pylori has become recognized as a fundamental pathogen in the development of gastritis and peptic ulcer disease. Bismuth compounds in combination with antibiotics are widely used to treat H. pylori associated peptic ulcer disease. METHODS: In this study we measured and analysed the inhibitory effect of ranitidine bismuth citrate (RBC, Pylorid, Tritec) on the activity and kinetics of phospholipase A2 (PLA2) (E.C.3.1.1.4) of commercial cobra (Naja naja) venom and H. pylori (French press lysates) using L-alpha-dipalmitoyl-(2[1-14C]palmitoyl)-phosphatidylcholine as substrate. RESULTS: Our data suggest that RBC might exert a dose-dependent uncompetitive inhibition on PLA2 activity of both H. pylori and Naja naja venom. the inhibitory effect of RBC on the PLA2 activity cannot be abolished by the optimal concentration of calcium (10 mM), indicating its mechanism to be unrelated to the displacement of calcium from the activation site of the enzyme. CONCLUSION: Our results suggest that one of the mechanisms by which bismuth compounds are therapeutically effective in the treatment of H. pylori associated gastritis is by inhibiting the activity of the degradative PLA2 enzyme secreted by H. pylori. As a consequence of the inhibitory action of RBC on PLA2 of the bacteria, the extracellular and/or intracellular phospholipid components of the gastric mucosal barrier are preserved.
Subject(s)
Anti-Ulcer Agents/pharmacology , Bismuth/pharmacology , Elapid Venoms/enzymology , Helicobacter pylori/drug effects , Helicobacter pylori/enzymology , Histamine H2 Antagonists/pharmacology , Phospholipases A/drug effects , Ranitidine/analogs & derivatives , Animals , Anti-Ulcer Agents/therapeutic use , Bismuth/therapeutic use , Dose-Response Relationship, Drug , Gastritis/drug therapy , Gastritis/microbiology , Helicobacter Infections/drug therapy , Histamine H2 Antagonists/therapeutic use , Humans , Phospholipases A2 , Ranitidine/pharmacology , Ranitidine/therapeutic useABSTRACT
Williams syndrome (WMS) is a rare sporadic disorder that yields a distinctive profile of medical, cognitive, neurophysiological, neuroanatomical and genetic characteristics. The cognitive hallmark of WMS is a dissociation between language and face processing (relative strengths) and spatial cognition (profound impairment). Individuals with WMS also tend to be overly social, behavior that is opposite to that seen in autism. A genetic hallmark of WMS is a deletion on chromosome band 7q11.23. Williams syndrome is also associated with specific neuromorphological and neurophysiological profiles: proportional sparing of frontal, limbic and neocerebellar structures is seen using MRI; and abnormal functional organization of the neural systems that underlie both language and face processing is revealed through studies using event-related potentials. The non-uniformity in the cognitive, neuromorphological and neurophysiological domains of WMS make it a compelling model for elucidating the relationships between cognition, the brain and, ultimately, the genes.