Cimetidine inhibits salivary gland tumor cell adhesion to neural cells and induces apoptosis by blocking NCAM expression

<p>Abstract</p> <p>Background</p> <p>Cimetidine, a histamine type-2 receptor antagonist, has been reported to inhibit the growth of glandular tumors such as colorectal cancer, however the mechanism of action underlying this effect is unknown. Adenoid cystic carcinoma is well known as a malignant salivary gland tumor which preferentially invades neural tissues. We demonstrated previously that human salivary gland tumor (HSG) cells spontaneously express neural cell adhesion molecule (NCAM), that HSG cell proliferation may be controlled via a homophilic (NCAM-NCAM) binding mechanism and that NCAM may be associated with perineural invasion by malignant salivary gland tumors. We further demonstrated that cimetidine inhibited NCAM expression and induced apoptosis in HSG cells. Here, we investigated the effects of cimetidine on growth and perineural/neural invasion of salivary gland tumor cells.</p> <p>Methods</p> <p>In this study, we have examined the effect of cimetidine on cancer cell adhesion to neural cells <it>in vitro</it>, one of the critical steps of cancer invasion and metastasis. We have also used an <it>in vivo </it>carcinogenesis model to confirm the effect of cimetidine.</p> <p>Results</p> <p>We have demonstrated for the first time that cimetidine can block the adhesion of HSG cells to neural cell monolayers and that it can also induce significant apoptosis in the tumor mass in a nude mouse model. We also demonstrated that these apoptotic effects of cimetidine might occur through down-regulation of the cell surface expression of NCAM on HSG cells. Cimetidine-mediated down-regulation of NCAM involved suppression of the nuclear translocation of NF-κB, a transcriptional activator of NCAM gene expression.</p> <p>Conclusion</p> <p>These findings suggest that growth and perineural/neural invasion of salivary gland tumors can be blocked by administration of cimetidine via induction of apoptosis and in which NCAM plays a role.</p

Long-term management of GERD in the elderly with pantoprazole

The prevalence of gastroesophageal reflux disease (GERD) increases with age and elderly are more likely to develop severe disease. Older patients often complain of less severe or frequent heartburn than younger patients and they may present with atypical symptoms such as dysphagia, weight loss, or extraesophageal symptoms. Proton pump inhibitors (PPIs) are central in the management of GERD and are unchallenged with regards to their efficacy. They are considered safe and more effective than histamine receptor antagonists for healing esophagitis and for preventing its recurrence using a long term maintenance treatment. PPI have minimal side effects and few slight drug interactions and are considered safe for long term treatment. Pantoprazole is significantly effective both for acute and long-term treatment with excellent control of relapse and symptoms. It is well tolerated even for long-term therapy and its tolerability is optimal. Pantoprazole shows to have minimal interactions with other drugs because of a lower affinity for cytocrome P450 than older PPIs. Although the majority of elderly has concomitant illnesses and receive other drugs, this does not adversely effect the efficacy of pantoprazole because of its pharmacokinetics, which are independent of patient age. Clinical practice suggests that a low dose maintenance of PPIs should be used in older patients with GERD

Appropriateness of treatment recommendations for PPI in hospital discharge letters

International audienc

Severe and Refractory Peptic Ulcer Disease: The Diagnostic Dilemma

The recognition of Helicobacter pylori infection as a cause of peptic ulcer disease, medical regimens to eradicate the organism, and the widespread use of proton pump inhibition to suppress gastric acid secretion have revolutionized the management of peptic ulcer disease. As a result, successful medical management of peptic ulcer disease has largely supplanted the need for gastric surgery by general surgeons. Surgery is reserved for complications of the disease, refractory disease, or rare causes of ulcer disease such as gastrinoma and Zollinger–Ellison syndrome. In this report, we describe a case of intractable peptic ulcer disease that progressed to gastric outlet obstruction despite maximal medical therapy. We review the diagnostic studies utilized to evaluate the potential etiologies of peptic ulcer disease and the difficulty in diagnosing gastrinoma and Zollinger–Ellison in the setting of potent medical acid suppression therapy.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44437/1/10620_2005_Article_2999.pd

Laparoscopic correction of perforated peptic ulcer: first choice? A review of literature

Background Perforated peptic ulcer (PPU), despite antiulcer medication and Helicobacter eradication, is still the most common indication for emergency gastric surgery associated with high morbidity and mortality. Outcome might be improved by performing this procedure laparoscopically, but there is no consensus on whether the benefits of laparoscopic closure of perforated peptic ulcer outweigh the disadvantages such as prolonged surgery time and greater expense. Methods An electronic literature search was done by using PubMed and EMBASE databases. Relevant papers written between January 1989 and May 2009 were selected and scored according to Effective Public Health Practice Project guidelines. Results Data were extracted from 56 papers, as summarized in Tables 1-7. The overall conversion rate for laparoscopic correction of perforated peptic ulcer was 12.4%, with main reason for conversion being the diameter of perforation. Patients presenting with PPU were predominantly men (79%), with an average age of 48 years. Onethird had a history of peptic ulcer disease, and one-fifth took nonsteroidal anti-inflammatory drugs (NSAIDs). Only 7% presented with shock at admission. There seems to be no consensus on the perfect setup for surgery and/or operating technique. In the laparoscopic groups, operating time was significant longer and incidence of recurrent leakage at the repair site was higher. Nonetheless there was significant less postoperative pain, lower morbidity, less mortality, and shorter hospital stay. Conclusion There are good arguments that laparoscopic correction of PPU should be first treatment of choice. A Boey score of 3, age over 70 years, and symptoms persisting longer than 24 h are associated with higher morbidity and mortality and should be considered contraindications for laparoscopic intervention

Proton Pump Inhibitors Inhibit Metformin Uptake by Organic Cation Transporters (OCTs)

Metformin, an oral insulin-sensitizing drug, is actively transported into cells by organic cation transporters (OCT) 1, 2, and 3 (encoded by SLC22A1, SLC22A2, or SLC22A3), which are tissue specifically expressed at significant levels in various organs such as liver, muscle, and kidney. Because metformin does not undergo hepatic metabolism, drug-drug interaction by inhibition of OCT transporters may be important. So far, comprehensive data on the interaction of proton pump inhibitors (PPIs) with OCTs are missing although PPIs are frequently used in metformin-treated patients. Using in silico modeling and computational analyses, we derived pharmacophore models indicating that PPIs (i.e. omeprazole, pantoprazole, lansoprazole, rabeprazole, and tenatoprazole) are potent OCT inhibitors. We then established stably transfected cell lines expressing the human uptake transporters OCT1, OCT2, or OCT3 and tested whether these PPIs inhibit OCT-mediated metformin uptake in vitro. All tested PPIs significantly inhibited metformin uptake by OCT1, OCT2, and OCT3 in a concentration-dependent manner. Half-maximal inhibitory concentration values (IC50) were in the low micromolar range (3–36 µM) and thereby in the range of IC50 values of other potent OCT drug inhibitors. Finally, we tested whether the PPIs are also transported by OCTs, but did not identify PPIs as OCT substrates. In conclusion, PPIs are potent inhibitors of the OCT-mediated metformin transport in vitro. Further studies are needed to elucidate the clinical relevance of this drug-drug interaction with potential consequences on metformin disposition and/or efficacy