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RanitidineENDOCANNABINOID SYSTEM AND THE CARDIOVASCULAR CONSEQUENCES OF CIRRHOSIS Sndor Btkai1, 2, Partha Mukhopadhyay2, Judith Harvey-White1, George Kunos1 and Pl Pacher2 Sections on 1Neuroendocrinology and 2Oxidative Stress & Tissue Injury, Laboratory of Physiologic Studies, NIAAA, NIH, Bethesda, MD 20892, USA Advanced liver cirrhosis is associated with hyperdynamic circulation i.e. systemic hypotension, decreased peripheral resistance and cardiac dysfunction termed as cirrhotic cardiomyopathy. We have previously demonstrated the role of endocannabinoids and vascular CB1 receptors in the development of generalized hypotension and mesenteric vasodilation in cirrhosis Batkai et al., Nat. Med. 7: 827, 2001 ; . In this study we explore the pathogenic role of the endocannabinoid system in cardiac dysfunction associated with cirrhosis. Rats with CCl4-induced cirrhosis developed tachycardia, decreased cardiac contractility as documented through the use of the Millar pressure-volume microcatheter system, low blood pressure, decreased peripheral resistance and elevated mesenteric blood flow. Bolus i.v. injection of the CB1 antagonist AM-251 3 mg kg ; acutely increased mean blood pressure as well as cardiac contractility and reduced mesenteric blood flow, whereas no such changes were elicited by AM-251 in control rats. Furthermore, the myocardial content of anandamide increased 2.7-fold in cirrhotic vs. control rats without any change in 2-arachidonoylglycerol 2-AG ; levels, whereas in the cirrhotic liver both 2-AG 6-fold ; and anandamide 3.5-fold ; were markedly increased compared to control. CB1 receptor expression in the heart of cirrhotic animals was not different from the controls, as verified by Western blotting. We conclude that activation of cardiac CB1 receptors by endogenous anandamide contributes to the reduced cardiac contractility in cirrhosis, and CB1 receptor antagonists may be used to improve contractile function in cirrhotic cardiomyopathy and, possibly, in other forms of heart failure. Furthermore, the pro-fibrotic function of hepatic CB1 receptors has been recently documented Teixeira-Clerc et al., Nat. Med. 12: 671, 2006 ; , and the observed marked elevations in hepatic endocannabinoid levels may contribute to the development of cirrhosis in these animals. CB1 receptor blockade may therefore represent a novel strategy in the medical management of cirrhosis, as it could not only slow down the progression of fibrosis, but would also correct the associated cardiac dysfunction. Supported by intramural funds of NIAAA. Six strategies were compared in this model: two test and treat approaches Helicobacter pylori H. pylori ; eradication with triple therapy if H. pylori positive; four weeks of antisecretory therapy with either generic omeprazole 20 mg daily or ranitidine 150 mg twice daily if H. pylori negative ; in the treatment of UD patients four weeks of empirical antisecretory therapy in all patients with either omeprazole 20 mg daily or ranitidine 150 mg twice daily.
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A 74 year old Type 2 diabetic patient with end-stage renal disease on CAPD was admitted to hospital because of painful ischaemic left foot. His usual treatment consisted of frusemide, ranitidine, ascorbic acid, tramadol, morphine sulphate, lactulose and Human Mixtrard 30 Insulin administered morning and evening. His daily CAPD regime comprised two exchanges of 2L of 1.36% glucose solution, one exchange of 2L of Nutraneal and an overnight exchange of 2.5L of Icodextrin 7.5% solution. On the morning of the second day the patient was found unconscious. His capillary glucose result using the POC Advantage glucose meter Roche Diagnostics ; was 13.0mmol L. Assuming that the patient was suffering from an opiate overdose he was treated with an opiate antidote and a glucose infusion. The patient regained consciousness. Two days later the patient had a similar episode during which a POC result of 7.2mmol L was obtained on the Advantage meter. A concentration of 1.0mmol L was reported on a paired venous sample analysed in the laboratory.
It is recommended that the patient's usual medications, except insulin and oral hypoglycemics, be continued until the time of surgery. Antibiotic prophylaxis is important because of increased risk of postoperative wound infection. Published rates of wound infection after gastric operations for obesity are approximately 5% 60 ; , and rates after clean contaminated GI surgery are 2%3% 61 ; . A metaanalysis of open bariatric surgery quoted the infection rate of restrictive procedures VBG, silastic ring vertical gastroplasty, and AGB ; as 3%11%, whereas that of combination procedures RYGB and extended RYGB ; was 5.27% 62 ; . Other authors have quoted wound infection rates of 11.7%15.8% after open gastric bypass 63, 64 ; . In a prospective, randomized study, Nguyen et al. 15 ; found that open RYGB had an approximately 10 times more frequent incidence of wound infection 10.5% versus 1.3% ; when compared with the laparoscopic approach. The increased incidence of wound infection is due to longer incisions, generally longer operative times because of obesity, tissue trauma from excessive traction, difficulty in deadspace obliteration, and inability of adipose tissue to resist infection 65 ; . Antibiotic prophylaxis is, however, also recommended by many practitioners for the laparoscopic approach. Anxiolysis, analgesia, and prophylaxis against both aspiration pneumonitis and DVT should be addressed during premedication. Oral benzodiazepines are reliable for anxiolysis and sedation because they cause little or no respiratory depression. IV midazolam can also be titrated in small doses for anxiolysis during the immediate preoperative period. Pharmacologic intervention with H2-receptor antagonists e.g., cimetidine, ranitidine, famotidine ; and nonparticulate antacids e.g., sodium bicitrate ; and proton pump inhibitors e.g., omeprazole, lansoprazole, rabeprazole ; will reduce gastric volume, acidity, or both, thereby reducing the risk and complications of aspiration. Morbid obesity is a major independent risk factor for sudden death from acute postoperative PE 66, 67 ; . Heparin, 5000 IU subcutaneously, administered before surgery and repeated every 12 h until the patient was fully mobile, reduced the risk of DVT 68 ; . Recently, low molecular weight heparins LMWH ; have gained popularity in thromboembolism prophylaxis because.
Although various schemes preceded it, the 1988 classification of the International Headache Society IHS ; 7 was the first to be widely adopted. This was extensively revised in late 2003 and the new system, the International Classification of Headache Disorders, 2nd edition ICHD-II ; , is the international standard.8 It includes operational diagnostic criteria and classifies headache disorders under 14 headings table I ; .The first four of these cover the primary headache disorders and relafen. Ranitidine 300 mg tablet ivx
On the active ingredient sulcrafat. These drugs stimulate the protection of the gastric mucosa and build a specific kind of protective layer. In the recent Bayer Healthcare Roche OTC Business ; decision however, the Commission stated that there were strong indications for a relevant OTC product market comprising on the ATC 4 level H2 antagonists A2B1 ; and antacids ATC 4 category A2A1 ; .6 Antacids neutralize, in one way or another, excess acids. Although H2 antagonists A2B1 ; may be considered as "stronger" drugs, the lower dosages authorized for OTC sale are indicated for similar gravities of diseases. However, the market definition can be left open for the purpose of this decision since serious competition concerns due to the transaction do not arise whatever market definition is taken. With respect to all OTC drugs in the ATC 3 class A2B the Parties had a combined share of [60-65]% Novartis [0-5]%, Hexal [55-60]% ; . The total volume of OTC drugs in the ATC 3 class A2B amounted to Euro [1.3-1.5] million. The Parties' products are all generics. They are active mainly with H2 antagonists A2B1 ; , which are all based on the active ingredients ranitidine and cimetidine. Only Novartis is active with a sucrafate product "Hexagaston". Other major competitors in this area were GlaxoSmithKline [10-15]% ; with the H2 antagonists Zantac ranitidine ; and Novamed cimetidine ; , Paranova [10-15]% ; with the H2 antagonist Zantac ranitidine ; and Orion [5-10]% ; with Antepsin sucralfate ; . Several other players are on the market with generic H2 antagonists based on the active ingredients ranitidine and cimetidin. Although the notified transaction will strengthen the leadership of Novartis Hexal in Denmark with respect to market share, the limited overlap in terms of market share and value Euro [.] ; does not significantly strengthen the pre-merger position of Hexal. The Parties face strong competition by several originator and generic drugs based on the same active ingredients. Third parties in their replies to the Commission's questionnaire have not revealed substantial competition concerns in this market and no specific entry barriers were mentioned. Hence, the market investigation has found no indication that competition might be significantly impeded as a result of the notified transaction. Based on ATC 4 subgroups, the competitive structure and hence the assessment of the market does not differ significantly. Based on ATC 4 A2B1 H2 antagonists ; , the combined market share would be [60-65]% Hexal: [60-65] %; Novartis [0-5]% ; , the total market volume [1.2-1.4] million Euro. Based on ATC 4 A2A9 there would be no competition concerns as the parties products do not overlap in this category. Adding up antacids ATC 4 category A2A1 ; to the H2 antagonists A2B1 ; would reduce the Parties combined market share significantly to [15-20]% Novartis [0-5]%, Hexal [1015]% ; 7.
In 1997, the EU introduced Sustainable Development in its Treaties as one of its fundamental objectives. It requires the integration of sustainable development into all European policies, so they contribute in an integrated way to meeting economic, environmental and social objectives. Article 2 of the EC Treaty ; . In June 2001, the European Council at Gothenburg discussed `A Sustainable Europe for a better world: A European Strategy for Sustainable Development', proposed by the European Commission. The Gothenburg European Council Conclusions, together with the 2002 Barcelona European Council's Conclusions on the Commission Communication `Towards a global partnership for sustainable development' on the external dimension, formed the first EU SDS. However, combining several documents to form one SDS was somewhat confusing and conflicted with the integrated nature of sustainable development. EEB, variously in coalition with other environmental organisations or with other stakeholders such as trade unions, social groups, consumers, religious organisations, etc, has been instrumental, first, in getting Sustainable Development into the Treaty, next, in convincing the European Council to request a Strategy, and then to press for a meaningful Strategy with the Commission in 2000-2001. EEB was positive about the 2001 Commission proposal, but subsequently concluded that implementation had been rather poor, owing partly to a lack of political will, and partly to a dearth of clear targets, timetables and regular, comprehensive stocktaking and ritalin.
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