Peptides 25 (2004) 115–121 Octreotide ameliorates alendronate-induced gastric injury Göksel ¸ Sener a,∗ , Kübra Paskaloglu a , Caner Kapucu a , Sule Cetinel b , Gazi Contuk b , Gül Ayano˘ glu-Dülger a a Department of Pharmacology, School of Pharmacy, Marmara University, Haydarpa¸ s a, 34668 ˙ I stanbul, Turkey b Department of Histology and Embriology, School of Medicine, ˙ I stanbul, Turkey Received 26 August 2003; accepted 19 November 2003 Abstract Alendronate causes serious gastrointestinal adverse effects. The aim of this study was to investigate whether octreotide, a synthetic somatostatin analogue, improves the alendronate-induced gastric injury. Rats were administered 20mg/kg alendronate by gavage for 4 days, either alone or following treatment with octreotide (0.1 ng/kg, i.p.). On the last day, following drug administration, pilor ligation was performed and 2h later, rats were killed and stomachs were removed. Gastric acidity and tissue ulcer index values, lipid peroxidation (as assessed by malondialdehyde, MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity as well as the histologic appearance of the stomach tissues were determined. Chronic oral administration of alendronate induced significant gastric damage, increasing lipid peroxidation (37.1±3.2 nmol/g) and myeloperoxidase activity (57.6±3.7 U/g), while tissue glutathione levels (0.9±0.1 mol/g) decreased. Treatment with octreotide prevented this damage as well as the changes in biochemical parameters (MDA: 23.4 ± 1.3 nmol/g; MPO: 31.68 U/g; GSH: 1.5 ± 0.1 mol/g). Findings of the present study suggest that alendronate induces oxidative gastric damage by a local irritant effect, and that octreotide ameliorates this damage by inhibiting neutrophil infiltration and reducing lipid peroxidation. Therefore, its therapeutic role as a “ulcer healing” agent must be further elucidated in alendronate-induced gastric mucosal injury. © 2004 Elsevier Inc. All rights reserved. Keywords: Alendronate; Octreotide; Lipid peroxidation; Glutathione; Myeloperoxidase 1. Introduction Bisphosphonates (BPs) are widely used in the treatment of postmenopausal osteoporosis and Paget’s disease of bone. Alendronate sodium (AL) is a primary amino bisphospho- nate and one of the most commonly used member of this group [26]. However, oral administration of BPs have been associated with gastrointestinal adverse effects including gastritis, gastric ulcer, and erosive esophagitis. It was re- ported that rate of acute mucosal injury due to AL was com- parable to that observed with NSAIDs [23]. Generally these GI side effects were attributed to high local concentrations of the drug in patients who do not follow dosing instructions properly, or do have esophageal or gastric disease [11,19,23]. However, even when taken as directed, amino BPs have the capacity to irritate the GI mucosa [1]. Lanza et al. have pro- posed that 40 mg/kg AL may be associated with gastric le- sions similar to those seen with aspirin treatment, including gastric ulcers [19]. ∗ Corresponding author. Tel.: +90-216-414-29-62; fax: +90-216-345-29-52. E-mail address: gokselsener@hotmail.com (G. ¸ Sener). Various GI adverse effects of BPs were also demonstrated in animal studies, and different mechanism have been pro- posed as the cause of this damage. Marshall et al. [25] conducted a randomized controlled trial to investigate the effect of AL on gastric mucosal prostaglandin (PG) syn- thesis; but they did not find any association between the AL-induced gastric mucosal damage and gastric mucosal PGE 2 synthesis. Based on dog studies, it was hypothesized that the esophageal irritation with BPs in humans is most likely due to reflux of acidic stomach contents and drug, and that esophageal irritation potential can be minimized by proper dosing [30]. Elliot et al. have studied the effect of AL in rats and rabbits and observed that the damaging effects of the drug were not attributable to changes in gastric acid secretion, blood flow or PG synthesis; they concluded that the damaging effects of AL on the stomach were due to a topical irritant effect [8]. Using an ex vivo gastric chamber model, Wallace et al. [42] have reported that both AL and pamidronate cause a widespread epithelial injury and infil- tration of neutrophils into the mucosa, concluding that these drugs directly damage the gastric epithelium. BPs were ob- served to act as local topical irritants to decrease the hy- drophobic barrier of the gastric mucosa. Since they have 0196-9781/$ – see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.peptides.2003.11.017