Oral Indomethacin Research Articles

Effects of esomeprazole on healing of nonsteroidal anti-inflammatory drug (NSAID)-induced gastric ulcers in the presence of a continued NSAID treatment: Characterization of molecular mechanisms

Proton pump inhibitors promote ulcer repair in nonsteroidal anti-inflammatory drug (NSAID)-treated patients with ongoing NSAID-induced gastric toxicity, although the underlying mechanisms remain unclear. We examined the healing mechanisms of esomeprazole on NSAID-induced gastric ulcerations in the presence of a continued NSAID treatment. Ulcerations were induced in rats by oral indomethacin (6 μmol/kg/day) for 14 days. Indomethacin administration was continued, alone or combined with equivalent acid inhibitory doses of esomeprazole (5 μmol/kg/day), lansoprazole (15 μmol/kg/day) or famotidine (20 μmol/kg/day), for additional 7 days. Stomachs were then processed for: histomorphometric analysis of mucosal injury; mucosal levels of prostaglandin E 2 (PGE 2) and malondialdehyde (MDA); expression of vascular endothelial growth factor (VEGF), proliferating cell nuclear antigen (PCNA), caspase-3, and cyclooxygenase-2 (COX-2) (Western blot); expression of Ki-67 (immunohistochemistry). Indomethacin for 14 days elicited mucosal damage, reduced PGE 2 levels and increased MDA. After additional 7 days, indomethacin induced the following effects: further enhancement of mucosal damage and MDA content; decrease in PGE 2 levels; increase in COX-2 and activated caspase-3 expression; decrease in VEGF, PCNA and Ki-67 expression. In the presence of indomethacin, esomeprazole and lansoprazole were more effective than famotidine in promoting resolution of mucosal damage. Concomitantly, esomeprazole and lansoprazole, but not famotidine, restored PCNA and Ki-67 expression, and normalized MDA levels. Moreover, esomeprazole, lansoprazole and famotidine partly counteracted caspase-3 activation, without affecting VEGF expression. The healing activity of esomeprazole on indomethacin-induced gastric ulcerations can be ascribed to two mechanisms: (1) acid-dependent reduction of pro-apoptotic signalling; (2) acid-independent restoration of proliferating/repairing pathways.

The effects of varied intensities of intrasound therapy with indomethacin on the morphology of the healing tendon.

Patients undergoing intrasound therapy are often concurrently on NSAIDs. The effect of varied intensities of intrasound therapy with NSAIDs on tendon healing is yet to be determined. The study investigated the effects of a concurrent admistration of low and high intensity intrasound therapy (LIRT&HIRT) with indomethacin (Indocid) on the morphology of the tendon in the early stage of healing. Thirty five male rats were divided randomly into seven groups; groups 2-6 underwent an induced crush injury. Group 1, nil injury and nil treatment. Group 2: injury but nil treatment. Group 3: Indomethacin only. Group 4: LIRT only, Group 5: Indocidand LIRT, Group 6: HIRT, Group 7: Indocid and HIRT. Intrasound therapy (IRT) commenced 24 hours post-injury and was given alternate days for the first 10 days post injury. Indocid was given at a dosage of 0.4 mg/kg body weight daily. On the 11 day post injury, the animals were sacrificed and the tendons excised and processed for histological study. Indocid significantly (p < 0.05) reduced the tenocyte population when combined with LIRT but marginally increased it when combined with HIRT (p > 0.05). There was significant difference in the tenocyte population between the combined Indocid and LIRT and the combined Indocid and HIRT groups (p < 0.05). High intensity intrasound given concurrently with oral indomethacin resulted in tenoblast proliferation and promoted healing in the injured tendon.

Effects of prophylactic indomethacin treatment on postoperative pericardial effusion after aortic surgery

This prospective, randomized study assessed the prophylactic effects of indomethacin treatment on pericardial effusion after aortic surgery. Eighty-five patients were found eligible to participate in this double-blind study. Patients were assigned to a control group receiving oral placebo or to an indomethacin group receiving 25 mg oral indomethacin 3 times daily for 7 days preoperatively. After aortic surgery, patients were followed up clinically and evaluated for pericardial effusion with transthoracic echocardiography on the first and seventh postoperative days during hospitalization and at the second and sixth weeks after discharge. The demographic and the operative data were similar between groups. The surgical interventions included Bentall procedure in 63 patients, valve-sparing procedures in 7 patients, and supracoronary ascending aorta replacement in 15 patients. Hemiarch replacement was performed in 16 patients. No patient in either group had pericardial effusion after the first postoperative day. At the end of the first week, however, 2 patients had pericardial effusion, at the end of the second week after discharge, 3 patients had pericardial effusion, and at the end of the sixth week after discharge, 4 patients had PEs. One of the patients who had PE at the end of the sixth week received indomethacin; the others were all in the control group, a significant difference (P=.019). Five patients underwent transthoracic echocardiographically guided pericardiocentesis; 4 underwent surgical pericardiocentesis. Indomethacin may have beneficial effects on the outcomes and incidence of postoperative pericardial effusion after aortic surgery.

Exacerbation of Obstructive Sleep Apnea by Oral Indomethacin

Patients with obstructive sleep apnea (OSA) are predisposed to instability in central ventilatory control during sleep. Increased instability, as reflected in an enhanced expired volume in per unit time loop gain, has been associated with a greater predisposition to upper airway collapse. Here, in an otherwise healthy patient with untreated mild OSA, we describe the further exacerbation of OSA after oral indomethacin administration. The subject was a control subject in part of a study to investigate the effects of altering cerebral blood flow (CBF) on ventilatory responses and sleep. He was administered either placebo or 100 mg of indomethacin orally with 20 mL of antacid 2.5 h before sleep on different days. He was studied overnight by polysomnography, arterial blood gases, and transcranial Doppler ultrasound. Administration of 100 mg of oral indomethacin prior to sleep resulted in an almost doubling of the apnea-hypopnea index (14 to 24/h), compared with placebo. This was due to an increase in apneas, rather than hypopneas. Following the indomethacin, changes in arterial blood gases were unremarkable, but both CBF as indexed using transcranial Doppler ultrasound and CBF reactivity to a steady-state change in CO(2) (CBF-CO(2)) reactivity were reduced, and the ventilatory response to CO(2) was elevated. CBF was also further reduced during nonrapid eye movement sleep following the indomethacin when compared with the control night. Indomethacin-induced reductions in CBF and CBF-CO(2) reactivity and related increases in ventilatory instability may lead to a greater predisposition to upper airway collapse and related apnea; these factors may partly explain the exacerbation of OSA.

Effects of proton pump inhibitors on healing of gastric ulcerations induced by a continued non steroidal anti-inflammatory drug (NSAID) treatment

Proton pump inhibitors promote ulcer healing in NSAID-treated patients with ongoing NSAID-induced gastric toxicity. However, the underlying mechanisms are unknown. This study examined the molecular pathways contributing to healing actions of esomeprazole (ESO) and lansoprazole (LAN) on NSAID-induced gastric ulcers after a continued NSAID treatment. Ulcers were induced in male rats by daily oral indomethacin (IND, 6 μmol/kg) for 14 days. Animals were then treated with IND (6 μmol/kg), alone or in combination with equivalent acid inhibitory doses of ESO (5 μmol/kg), LAN (15 μmol/kg) or famotidine (FAM, 20 μmol/kg) for 7 days. Stomachs were processed for: 1) histomorphometric analysis of mucosal injury; 2) mucosal levels of prostaglandin E2 (PGE2) and malondialdehyde (MDA); 3) expression of cyclooxygenase-2 (COX-2), VEGF and cleaved caspase-3 (Western blot); 4) expression of Ki-67 (immunohistochemistry). IND for 14 days induced mucosal damage (5.6±0.6%), reduced PGE2 mucosal levels (54.5±21.4 pg/mg) and increased MDA (8.4±1.0 nmol/mg). IND for additional 7 days enhanced further the mucosal damage and MDA, while PGE2 levels remained low. IND enhanced also the expression of COX-2 and caspase-3, reduced VEGF and Ki-67. In the presence of IND, treatment with ESO, LAN or FAM affected differentially most of the tested parameters. In particular: 1) ESO and LAN were more effective than FAM in reducing mucosal damage and MDA levels; 2) ESO and LAN, but not FAM, restored Ki-67 expression; 3) ESO, LAN and FAM partly counteracted IND-induced caspase-3 activation, without affecting the decrease in VEGF expression. The superiority of ESO and LAN over FAM in promoting ulcer healing in the presence of a continued IND treatment is likely to depend on both acid-dependent reduction of pro-apoptotic signalling and acid-independent restoration of repairing pathways.

Oral prednisolone is more cost-effective than oral indomethacin for treating patients with acute gout-like arthritis

Acute gouty arthritis is often treated with NSAIDs, but recent studies have suggested that treatment with prednisolone has at least equivalent analgesic efficacy and fewer adverse effects. No formal economic analysis has been performed earlier. In this study, we aimed to compare the economic impact of oral indomethacin therapy and oral prednisolone therapy in the treatment of acute gout in patients presenting to an emergency department in Hong Kong. Data from a previously published randomized controlled trial were used to compare the costs of the two treatment options. Direct, incremental costs incurred in the 2 weeks after the initial presentation were considered from the perspective of the healthcare provider. Costs were subdivided into those incurred in the emergency department phase; admission on day 1 to the emergency department's observation ward; admission subsequently to the general medical ward for adverse events and reattendance to the hospital outpatients' or emergency department. The prednisolone strategy resulted in cost savings in the emergency department of HK$5.67 (US$0.73; pound0.37) and in medical admissions of HK$1727.48 (US$221.47; pound111.45) per patient treated. Overall, the average saving with prednisolone was HK$1235 (US$158.33; pound79.68) per patient treated, which was equivalent to one admission bed/day saved for every two patients treated. Treatment for each of the six patients in the indomethacin group admitted for serious adverse effects cost the healthcare provider HK$13 244 (US$1697.95; pound854.45). Treatment of acute gouty arthritis with a 5-day course of prednisolone is significantly more cost-effective than treatment with indomethacin.

A systematic review of oral ibuprofen versus intravenous indomethacin for the treatment of PDA in preterm infants

A systematic review of oral ibuprofen versus intravenous indomethacin for the treatment of PDA in preterm infants

Effects of indomethacin on cerebrovascular response to hypercapnea and hypocapnea in breath-hold diving and obstructive sleep apnea

We tested whether breath hold divers (BHD) and obstructive sleep apnea (OSA) subjects had similar middle cerebral artery velocity (MCAV) responses to hypercapnea and hypocapnea. We analyzed changes in MCAV (cm/s) in response to hypocapnea and hyperoxic hypercapnea during placebo or after 90 min of oral indomethacin (100 mg) in BHD (N=7) and OSA (N=7). During control hypercapnea MCAV increased for 54.4% in BHD and 48.4% in OSA. Indomethacin blunted the MCAV increase in response to hypercapnea in BHD (P=0.02), but not in OSA. Indomethacin attenuated the mean arterial pressure response in BHD, but not in OSA. The blunted MCAV responses to hypercapnea with indomethacin in BHD, but not in OSA patients suggests that (a) the normal contribution of local vasodilating mechanisms to the cerebrovascular responses to hypercapnea is absent in OSA patients and (b) exposure to chronic/repeated apneas is not causal per se in limiting the contribution of vasodilating mechanisms to the cerebrovascular responses to hypercapnea in OSA.

Therapeutic Effectiveness of Various Treatments for Eosinophilic Pustular Folliculitis

Eosinophilic pustular folliculitis is a rare dermatosis. Recently, in addition to oral indomethacin, other treatments have been applied for eosinophilic pustular folliculitis. The aim of this study was to assess the effectiveness of various therapies encompassing conventional to newly applied drugs for eosinophilic pustular folliculitis. Twenty patients with eosinophilic pustular folliculitis seen in our department were investigated. The effectiveness of each treatment was assessed by a severity score index. Eleven patients were treated with oral indomethacin, and the severity scores of all patients were decreased after the treatment. Oral cyclosporine was markedly effective in all 11 patients treated, and topical tacrolimus ointment alleviated eosinophilic pustular folliculitis in 3 of 7 with one patient showing a remarkable reduction in the severity score. In addition to indomethacin or other oral non-steroidal anti-inflammatory drugs, oral cyclosporine and topical tacrolimus may be beneficial choices when patients have been resistant to previous treatments.

Optical Coherence Tomography Findings in a Child with Posterior Scleritis

To present the findings of optical coherence tomography (OCT) in a child with posterior scleritis. A 13-year-old boy was admitted to our clinic with symptoms of low degree of vision and ocular pain. Ophthalmologic examination, ocular ultrasonography, magnetic resonance imaging, fundus fluorescein angiography (FFA), and OCT investigations were carried out and the results were evaluated. Visual acuity was 10/10 in the right eye, and finger counting at 1 meter in the left eye. Anterior segments and vitreous were normal in both eyes. Fundus examination revealed the edema on the macula and the normal disc margins on the left eye, while the right eye was normal. The FFA revealed the leakage on the macula. Posterior scleral thickening, choroidal effusion, and serous retinal detachment were determined in ocular ultrasonography, suggesting posterior scleritis. There were interesting cystic forms underneath the retina and serous macular detachment (SMD) in the first OCT examination. The patient was treated with oral prednisolone for 10 days and then with oral indomethacin for 20 days. Following the systemic treatment the visual acuity of the left eye improved, subjective signs disappeared, and the OCT manifestations returned to normal. In this case report, OCT provided new information about the retinochoroidal structure in posterior scleritis. These findings may be helpful for the diagnosis of this rare condition, but further studies are needed.

The pharmacological treatment of patent ductus arteriosus in premature infants with respiratory distress syndrome: oral ibuprofen vs. indomethacin

Purpose : Indomethacin is widely used for the prophylaxis and treatment of patent ductus arteriosus (PDA); however, it is associated with side effects such as renal failure, intraventricular hemorrhage, and gastrointestinal bleeding. Intravenous ibuprofen has been shown to be as effective as indomethacin in prompting PDA closure. If treatment with oral ibuprofen is as effective as indomethacin, it would have the advantages of greater availability, simpler administration, and lower cost. We conducted this study to compare the efficacy and side effects of indomethacin with those of oral ibuprofen, vis- a-vis on the pharmacological closure of PDA. Methods : As a randomized double-blind study, 34 preterm infants with respiratory distress syndrome and hemodynamically significant PDA were treated with either intravenous indomethacin or oral ibuprofen. Echocardiography was performed by one cardiologist who was blind to the treatment that any given infant received. The rate of ductal closure, the need for additional drug treatment or surgical ligation, clinical outcome, and the side effects of drug treatment were compared. Results : Ductal closure occurred in 16 of 18 patients (88.9%) from the indomethacin group and in 14 of 16 patients (87.5%) from the ibuprofen group (P>0.05). Three patients in the indomethacin group and four in the ibuprofen group required a second drug treatment (P>0.05). Three patients (i.e., one patient in the indomethacin group and two in the ibuprofen group) underwent surgical ligation (P>0.05). Between the two groups, there was no significant difference vis- a-vis in side effects or clinical outcome. Conclusion : Compared to indomethacin, oral ibuprofen has the advantages of simpler administration and lower cost, while being as effective; in addition, there are no differences between the two drug treatments with regards to side effects or clinical outcomes. Therefore, the widespread use of oral ibuprofen should be considered in treating PDA in preterm infants. (Korean J Pediatr 2008;51:956-963)

Intravitreal Pegaptanib Sodium for Irvine-Gass Syndrome

To report the novel use of intravitreal pegaptanib sodium for the treatment of refractory cystoid macular edema (CME) following cataract extraction. A 72-year-old man presented with decreased visual acuity in his right eye 8 months after uncomplicated phacoemulsification cataract extraction and intraocular lens implantation. His bestcorrected visual acuity (BCVA) was 20/125 in the affected eye, and fundus examination revealed CME despite 6 months of oral and topical indomethacin therapy. Fluorescein angiography (FA) showed leakage in the central region with no signs of neovascularization, and optical coherence tomography (OCT) confirmed the diagnosis with thickening of the fovea. Because of his history of glaucoma, the patient chose to be treated with intravitreal pegaptanib sodium 0.3 mg. At the 1-week follow-up, BCVA was 20/25, and the FA and OCT revealed almost total resolution of the CME with no adverse sequelae. Six months postinjection, the patient's BCVA remained 20/25 with no recurrence of CME. Perimetry revealed a stable fixation within 4 degrees with slight reduction of sensitivity. Vascular endothelial growth factor inhibition with intravitreal pegaptanib sodium appears to be of benefit in the treatment of chronic refractory CME with improvement of visual acuity. Studies evaluating pegaptanib''s use in this setting with long-term follow-up are warranted to confirm its efficacy and safety.

Acute and chronic neuroendocrine effects of interferon‐β 1a in multiple sclerosis

Treatment of multiple sclerosis with interferon-beta (IFN-beta) results in variable responses interindividually. Cytokine-hormone interactions may modulate the therapeutic effects of IFN-beta. Since hyperactivity of the hypothalamo-pituitary-adrenal (HPA) axis and other neuroendorine disturbances occur in multiple sclerosis, we determined the detailed neuroendocrine response of patients with multiple sclerosis to IFN-beta. Longitudinal open-label study. Eight patients with relapsing-remitting multiple sclerosis (four women, age 31.9 +/- 1.5 years, EDSS 1.5-2.5). Plasma ACTH, cortisol, prolactin, GH, TSH, LH and FSH were determined in 30-min intervals during 8 h on four occasions: after intramuscular injection of saline; after the first dose of IFN-beta 1a; after the second IFN-beta dose with oral indomethacin pretreatment; and after 3 months of IFN-beta therapy. Dexamethasone-corticotropin-releasing hormone test was performed before and at 3 months on IFN-beta. Compared to saline, IFN injection resulted in marked rise in plasma ACTH (mean, 370% of baseline), cortisol (214%), prolactin (253%) and GH (756%), between 2 and 6 h after injection. With indomethacin, hormone secretion occurred with reduced peak values. Endocrine response adapted partially after 3 months of treatment. HPA axis activity decreased in most patients, but increased in one patient with frequent relapses. Marked neuroendocrine effects occur in response to IFN-beta in multiple sclerosis. Upon prolonged treatment, these effects partially adapt, and HPA axis hyperactivity is reduced. Prospective studies to determine the relation to individual treatment response can be based on these findings.

Mode of Administration-Dependent Brain Uptake of Indomethacin: Sustained Systemic Input Increases Brain Influx

Nonsteroidal anti-inflammatory drugs, including indomethacin, have been found in both epidemiological and clinical studies to reduce the prevalence and severity of Alzheimer's disease. However, long-term use of indomethacin is limited by significant gastrointestinal and renal toxicities. An indomethacin prodrug that delivers low and continuous blood levels of the drug showed a superior safety profile and similar efficacy in comparison to an equivalent dose of free indomethacin because of limited systemic exposure and preferred brain uptake. The purpose of the present investigation was to evaluate whether sustained systemic input causes an increased brain influx in comparison to rapid input of the drug. Oral indomethacin, indomethacin prodrug, or intravenous indomethacin infusion was administered to rats. The infusion was designed to mimic the plasma indomethacin levels resulting from the prodrug. The resultant blood levels and brain indomethacin uptake were evaluated. The brain indomethacin concentrations 8 h following indomethacin administration were 0.45, 0.3, and 0.31 microg/g after the oral indomethacin, oral prodrug, and intravenous infusion, respectively. The corresponding plasma concentrations were 14.1, 4.1, and 4 microg/ml. Therefore, brain versus plasma indomethacin level ratios were 2.5-fold higher after slow systemic input of indomethacin in comparison to rapid drug input. In conclusion, indomethacin brain uptake was found to be mode of administration-dependent, and a sustained input function increases the drug brain uptake. Thus, these unique results indicate that an appropriate indomethacin controlled release delivery system may induce the desirable brain-related pharmacodynamic effects, while avoiding the concentration-dependent adverse effects. These findings may contribute to improved therapy in Alzheimer's disease.

Influence of cerebrovascular function on the hypercapnic ventilatory response in healthy humans

An important determinant of [H(+)] in the environment of the central chemoreceptors is cerebral blood flow. Accordingly we hypothesized that a reduction of brain perfusion or a reduced cerebrovascular reactivity to CO(2) would lead to hyperventilation and an increased ventilatory responsiveness to CO(2). We used oral indomethacin to reduce the cerebrovascular reactivity to CO(2) and tested the steady-state hypercapnic ventilatory response to CO(2) in nine normal awake human subjects under normoxia and hyperoxia (50% O(2)). Ninety minutes after indomethacin ingestion, cerebral blood flow velocity (CBFV) in the middle cerebral artery decreased to 77 +/- 5% of the initial value and the average slope of CBFV response to hypercapnia was reduced to 31% of control in normoxia (1.92 versus 0.59 cm(-1) s(-1) mmHg(-1), P < 0.05) and 37% of control in hyperoxia (1.58 versus 0.59 cm(-1) s(-1) mmHg(-1), P < 0.05). Concomitantly, indomethacin administration also caused 40-60% increases in the slope of the mean ventilatory response to CO(2) in both normoxia (1.27 +/- 0.31 versus 1.76 +/- 0.37 l min(-1) mmHg(-1), P < 0.05) and hyperoxia (1.08 +/- 0.22 versus 1.79 +/- 0.37 l min(-1) mmHg(-1), P < 0.05). These correlative findings are consistent with the conclusion that cerebrovascular responsiveness to CO(2) is an important determinant of eupnoeic ventilation and of hypercapnic ventilatory responsiveness in humans, primarily via its effects at the level of the central chemoreceptors.

Vaginal versus oral indomethacin in a rabbit model for non-infection–mediated preterm birth: An alternate tocolytic approach

We examined the hypotheses that vaginal indomethacin is more effective for prolonging gestation, and mediates its tocolytic actions via changes in cervical matrix metalloproteinase (MMP) activity, compared to oral. Pregnant rabbits induced with mifepristone received oral or vaginal indomethacin; or oral or vaginal vehicle once daily for 2 days. Premature delivery, fetal ductus arteriosus, and cervical MMP activity were assessed. Vaginal indomethacin delayed delivery >72 hours in 100% of the rabbits, extending gestation to 28.2 +/- 0.5 (P < .01) versus 26.4 +/- 0.3, 25.8 +/- 0.5, and 26.5 +/- 0.3 days, for vaginal placebo, oral indomethacin, and oral vehicle, respectively. Fetal ductus arteriosus was patent in all groups. Vaginal indomethacin decreased MMP-1, -8, and -9 activities and increased TIMP-1 levels in the cervix. Vaginal indomethacin is more effective than oral for prolonging gestation in the rabbit. Its tocolytic effects may be mediated, in part, by alterations in cervical MMP activity.

Comparative effects of oral versus vaginal indomethacin on amniotic fluid and fetal membrane cytokines in a rabbit model for RU486-induced preterm birth

Preterm birth is associated with infection-mediated and non-infection-mediated etiologies, both of which are associated with an activation of proinflammatory cytokines in fetal membranes (FM) and amniotic fluid (AF). We examined the hypothesis that vaginal indomethacin suppresses pro-inflammatory cytokines in FM and AF more effectively than oral indomethacin.

Oral vs vaginal indomethacin in a rabbit model of RU486-induced preterm birth: A novel approach to tocolysis

Oral indomethacin is currently used for prevention of preterm birth in humans; however, its use may be associated with premature fetal ductal closure, renal ischemia, and oligohydramnios. We examined the hypothesis that vaginal indomethacin would be more efficacious than oral for prolonging pregnancy in a rabbit model of RU468-induced preterm birth, with fewer side effects.

Vaginal indomethacin increases TIMP-2 levels in amniotic fluid and fetal membranes in a rabbit model for RU486-induced preterm birth

FETAL MEMBRANES IN A RABBIT MODEL FOR RU486-INDUCED PRETERM BIRTH WILBERT FORTSON (F), KAY BEHARRY, STEPHEN NAGEOTTE, AMANDA JAN, TAMEROU ASRAT, HOUCHANG MODANLOU, University of California, Irvine, Maternal Fetal Medicine, Irvine, California, University of California, Irvine, Pediatrics, Orange, California, Miller Children’s Hospital, Women’s Pavilion, Maternal Fetal Medicine, Long Beach, California, Miller Children’s Hospital, Women’s Pavilion, Irvine, California OBJECTIVE: Preterm parturition and rupture of fetal membranes are associated with decreased amniotic fluid tissue inhibitor of metalloproteinases (TIMP-2), an endogenous inhibitor of MMPs. We examined the hypothesis that vaginal indomethacin will increase TIMP-2 levels in a rabbit model for RU468-induced preterm birth in amniotic fluid (AF) and fetal membranes (FM) in a rabbit model for RU468-induced preterm birth. STUDY DESIGN: Pregnant rabbits were induced with a single 50 mg IM dose of RU486 at day 24 of a 32 day gestation. The animals received either oral indomethacin (20 mg in a vehicle suspension, OI), a methylcellulose vehicle suspension (OV), a vaginal suppository of indomethacin (20 mg in cocoa butter, VI), or a vaginal suppository of cocoa butter only (placebo, VP) once daily for 2 days. At delivery (expulsion of at least 1 fetus), AF and FM were collected for MMP-2, and -9 activity; and TIMP-1 and -2 levels. RESULTS: Data are meanGSEM. There were not differences in MMP-9 activity. CONCLUSION: Elevated TIMP-2 levels in the amniotic fluid and fetal membranes with vaginal indomethacin suggest decreased breakdown of extracellular matrix and inhibition of membrane rupture in our model.

Alterations in the intestinal glycocalyx and bacterial flora in response to oral indomethacin

Nonsteroidal anti-inflammatory drugs (NSAIDs), used extensively in clinical medicine, tend to cause adverse effects in the gastrointestinal tract. Earlier work has shown that oral administration of indomethacin produced oxidative damage in the small intestine and attenuation of the glycocalyx layer of the mucosa. The present study assessed, in greater detail, the alterations produced in the glycocalyx of rat small intestinal mucosa in response to indomethacin, with specific reference to surfactant-like particles (SLP) and brush border membranes (BBM). Changes in gut flora in response to the drug were also studied, as it has been shown that luminal bacteria play a role in the pathogenesis of NSAID-induced intestinal damage. The levels of sugars such as sialic acid, fucose, hexose and hexosamine were increased in SLP and decreased in the BBM following indomethacin treatment, with the effects being maximal 24 h after the administration of the drug. The composition of lipids in the SLP was also found to be altered. There was a significant increase in the number of bacteria in the luminal contents of the small intestine and caecum in these animals, as compared with controls. The number of bacteria adherent to the intestinal mucosa was also significantly higher in the drug-treated group. In vitro studies revealed that there was an increased tendency for bacteria to adhere to SLP isolated from indomethacin-treated rats. These results suggest that alterations in glycosylation of SLP and BBM in response to indomethacin, along with qualitative and quantitative changes in the luminal bacterial flora, may facilitate translocation of bacteria into the mucosa. These changes may contribute to the enteropathy observed as a result of NSAID treatment.