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Intestinal Ulcer

Intestinal ulcer

Peptic ulcer is usually a non-malignant ulcer of the stomach (called gastric ulcer) or duodenum (called duodenal ulcer). About 4 % of gastric ulcers are caused by malignant tumour, which is why ulcers of stomach are controlled. Duodenal ulcers are non-malignant. By far most instances are now known to be due to Helicobacter pylori, a spiral-shaped bacterium that lives in the acid environment of the stomach. These ulcers can also be caused or worsened by drugs such as Aspirin and other NSAIDs.

Signs and symptoms

Symptoms of a peptic ulcer can be:
- Abdominal pain;
- Hematemesis (vomiting blood);
- Melena (tarry feces due to oxidised iron from hemoglobin);
- Weight loss;
- Rarely, an ulcer can lead to a gastric or duodenal perforation. This is extremely painful and requires immediate surgery. A history of heartburn, gastroesophageal reflux disease (GERD) and use of certain forms of medication can raise the suspicion for peptic ulcer. Medicines associated with peptic ulcer are NSAID (non-steroid anti-inflammatory drugs) that inhibit cyclooxygenase 1, and most glucocorticoids (e.g. dexamethasone). In patients over 45 with more than 2 weeks of the above symptoms the odds for peptic ulceration are high enough to warrant rapid investigation by EGD (see below). The timing of the symptoms in relation to the meal may differentiate between gastric and duodenal ulcers: A gastric ulcer would give epigastric pain during the meal, as gastric acid is secreted, or after the meal, as the alkaline duodenal contents reflux into the stomach. Symptoms of duodenal ulcers would manifest mostly before the meal — when acid (production stimulated by hunger) is passed into the duodenum.

Diagnosis

In patients in whom peptic ulcer is suspected, esophagogastroduodenoscopy (EGD, a form of endoscopy) is indicated. By direct visual identification, the location and severity of an ulcer can be described. Moreover, if no ulcer is present, EGD can often provide an alternative diagnosis. The diagnosis of Helicobacter pylori can be by:
- Biopsy during EGD;
- Breath testing (does not require EGD);
- Direct culture from an EGD biopsy specimen;
- Direct detection of urease activity in a biopsy specimen;
- Measurement of antibody levels in blood (does not require EGD). It is still slightly controversial whether a positive antibody without EGD is enough to warrant eradication therapy. The possibility of other causes of ulcers, notably malignancy (gastric cancer) needs to be kept in mind. This is especially true in ulcers of the large curvature of the stomach; most are also a consequence of chronic H. pylori infection.

Pathophysiology

Classical causes of ulcers (tobacco smoking, blood groups, spices and a large array of strange things) are of relatively minor importance in the development of peptic ulcers. A major causative factor (90% of gastric and 75% of duodenal ulcers) is chronic inflammation due to Helicobacter pylori, a spirochaete that inhabits the antral mucosa and increases gastrin production. Gastrin, in turn, stimulates the production of gastric acid by parietal cells. Another major cause is the use of NSAIDs (see above). The gastric mucosa protects itself from gastric acid with a layer of prostaglandins. NSAIDs block the function of cyclooxygenase 1 (cox-1), which is essential for the production of these prostaglandins. Newer NSAIDs (celecoxib, rofecoxib) only inhibit cox-2, which is less essential in the gastric mucosa, and roughly halve the risk of NSAID-related gastric ulceration. Glucocorticoids lead to atrophy of all epithelial tissues. Their role in ulcerogenesis is relatively small. Stress in the psychological sense has not been proven to influence the development of peptic ulcers. Burns and head trauma, however, can lead to "stress ulcers", and it is reported in many patients who are on mechanical ventilation. Smoking leads to atherosclerosis and vascular spasms, causing vascular insufficiency and promoting the development of ulcers through ischemia. A family history is often present in duodenal ulcers, especially when blood group O is also present. Inheritance appears to be unimportant in gastric ulcers. Macroscopically: Gastric ulcer is most often localized on the lesser curvature of the stomach. It is a round to oval parietal defect ("hole"), 2 to 4 cm diameter, with a smooth base and perpendicular borders. These borders are not elevated or irreguliar as in gastric cancer - ulcerative form. Surrounding mucosa may present radial folds, as a consequence of the parietal scarring. Microscopically: Gastric peptic ulcer is a mucosal defect which penetrates the muscularis mucosae and muscularis propria, produced by acid-pepsin aggression. Ulcer margins are perpendicular and present chronic gastritis. During the active phase, the base of the ulcer shows 4 zones: inflammatory exudate, fibrinoid necrosis, granulation tissue and fibrous tissue. The fibrous base of the ulcer may contain vessels with thickened wall or with thrombosis. [http://www.pathologyatlas.ro/Peptic%20ulcer.html 1]

Epidemiology

In Western countries the prevalence of Helicobacter pylori infections roughly matches age (i.e., 20% at age 20, 30% at age 30, 80% at age 80 etc). Prevalence is higher in third world countries. Transmission is by food and human contact, sharing food utensils etc. A minority of cases of Helicobacter infection will eventually lead to an ulcer and a larger proportion of people will get non-specific discomfort, abdominal pain or gastritis.

Treatment

Younger patients with ulcer-like symptoms are often treated with antacids or H2 antagonists before EGD is undertaken. Bismuth compounds may actually reduce or even clear organisms. When H. pylori infection is present, the most effective treatments are combinations of 2 antibiotics (e.g. Erythromycin, Ampicillin, Amoxicillin, Tetracycline, Metronidazole) and 1 proton pump inhibitor (PPI). An effective combination would be Amoxicillin + Metronidazole + Pantoprazole (a PPI). In the absence of H. pylori, long-term higher dose PPIs are often used. Treatment of Helicobacter usually leads to clearing of infection, relief of symptoms and eventual healing of ulcers. Recurrence of infection can occur and retreatment may be required, if necessary with other antibiotics. However, there is mounting evidence of the fact that H. pylori may be protective against certain diseases of the esophagus and cardia, including GERD, Barrett's esophagus, and esophageal adenocarcinoma (a particularly deadly form of cancer). Therefore, a more cautious approach to its eradication may be necessary.

External links

- [http://www.pathologyatlas.ro/Peptic%20ulcer.html Image of Gastric ulcer]
- http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11380319&dopt=Abstract
- http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=14755326 Category:Gastroenterology simple:Gastric ulcer

Ulcer

An ulcer (from Latin ulcus) is an open sore of the skin, eyes or mucous membrane, often caused by an initial abrasion and generally maintained by an inflammation and/or an infection.

Description

Ulcers are non-healing wounds that develop on the skin, mucous membranes or eye. Although they have many causes, they are marked by: # Loss of integrity of the area # Secondary infection of the site by bacteria, fungus or virus # Generalized debilitation of the patient # A lengthy healing time

Skin ulcers

The skin is the largest organ of the human body. Classification systems are used to communicate the severity and depth of an ulcer. It is an easy way to communicate changes for the better, or worse.

Merck Manual classification

- Stage 1: The skin is red. The underlying tissue is soft. The redness disappears with minor pressure.
- Stage 2: There is redness, swelling and hardening of the skin around the area. Sometimes there is blistering. Sometimes there is loss of the superficial skin.
- Stage 3: The skin becomes necrotic. There may be exposure of the fat beneath the skin. The skin may be lost through all its layers.
- Stage 4: There is more loss of fat and more necrosis of the skin through to the muscle beneath.
- Stage 5: Continuing loss of fat and necrosis of muscle below.
- Stage 6: Bone destruction begins with irritation of the bone, erosion of the bone cortex progressing to osteomyelitis. There may be sepsis of a joint, pathologic fracture or generalized body infection, septicemia.

National Pressure Ulcer Advisory Panel (NPUAP)

- Stage I - There is erythema of intact skin which does not blanch with pressure. It may be the heralding lesion of skin ulceration.
- Stage 2 - There is partial skin loss involving the epidermis, dermis, or both. The ulcer is superficial and presents as an abrasion, blister, or wound with a shallow center.
- Stage 3 - This is an entire thickness skin loss. It may involve damage to or necrosis of subcutaneous tissue that may extend down to underlying fascia. The ulcer presents as a deep crater with or without undermining of adjacent intact tissues.
- Stage 4 - Here there is entire thickness skin loss with extensive destruction, tissue necrosis, or damage to muscle, bone, or supporting structures. Tendons, and joints may also be exposed or involved. There may be undermining and holes or sinus tracts associated with ulcers at this stage.

Wagner's classification

- Grade 0 - Skin with prior healed ulcer scars, areas of pressure which are sometimes called pre-ulcerative lesion or the presence of bony deformity which puts pressure on an unguarded point.
- Grade I - A The wound is superficial in nature, with partial or full-thickness skin involvement but does not include tendon, capsule or bone.
- Grade I-B - As above, the wound is superficial in nature, with partial or full thickness skin involvement but not including tendon, capsule nor bone; however the wound is infected. The definition of this wound implies superficial infection without involvement of underlying structures. If the wound shows signs of significant purulence or fluctuance, further exploration to expose a higher grade classification of infection is in order.
- Grade I-C - As above but with vascular compromise.
- Grade I-D - As above but with ischemia. Because ischemia is a type of vascular compromise, the distinction between these two grades is often difficult to make.
- Grade 2-A - Penetration through the subcutaneous tissue exposing tendon or ligament, but not bone.
- Grade 2-B - Penetration through the deep tissues including tendon or ligament and even joint capsule but not bone.
- Grade 2-C - As above 2B, but including ischemia
- Grade 2-D - As above 2c, but including infection
- Grade 3-A - A wound which probes to bone but shows no signs of local infection nor systemic infection.
- Grade 3-B - A wound which probes to bone and is infected
- Grade 3-C - A wound which probes to bone is infected and is ischemic.
- Grade 3-D - A wound which probes to bone characterized by active infection, ischemic tissues and exposed bone.
- Grade 4 - Gangrene of the forefoot
- Grade 5 - Gangrene of the entire foot

Other locations

# Inferior members: most ulcers of the foot and leg are caused by underlying vascular insufficiency. The skin breaks down or fails to heal because of repeated insult or trauma. Pressure of the nail can cause subungual ulceration. These are most frequently seen in diabetics who have a very low potential to heal from injury. # Sacrum and ischium # Mouth ulcer # Intestinal ulcers: This includes ulcers of the esophagus, stomach, large and small intestine # Genitalia: May be penile, vulvar or labial. Most often are due to sexually-transmitted diseases # Eyes: corneal ulcers are the most common type. Conjunctival ulcers also occur.

Pathology of ulceration

The most common causes are:
- Bacterial infection
- Viral infection
- Fungal infection
- Cancer
- Venous stasis
- Diabetes
- Amyloidosis
- Loss of mobility
- Hypertension Some specific types of ulcers are:
- Peptic ulcer (of the stomach or duodenum)
- Mouth ulcer
- Pressure ulcer (decubitus)
- Crural ulcer (due to venous insufficiency or other causes) Category:Anatomical pathology Category:Dermatology Category:Symptoms ja:潰瘍 simple:ulcer

Duodenum

In anatomy of the digestive system, the duodenum is a hollow jointed tube connecting the stomach to the jejunum. It is the first part of the small intestine. It starts with the duodenal bulb and ends at the ligament of Treitz. Two very important ducts open into the duodenum, namely the bile duct and the pancreatic duct. The duodenum is largely responsible for the breakdown of food in the small intestine. Brunner’s glands are only found in the duodenum and they secrete mucus. These mucus filled glands are composed of simple cuboid-shaped epithelial cells. The duodenum wall is composed of a very thin layer of smooth muscle cells that forms the muscularis mucosa. The duodenum is divided into four sections for the purposes of description. The first three sections form a "C" shape. The first comes from the pylorus, goes right and makes a sharp right angle turn downwards to become the second part of the duodenum. The second part of the duodenum is where the hepatopancreatic duct (or less often, separately, the pancreatic duct and common bile duct) empty into the gastrointestinal tract. The duodenum makes another sharp turn to the left into the third part of the duodenum before joining with the jejunum. The duodenum is almost all retroperitoneal. The pH in the duodenum is approximately 9 (slightly basic). The name duodenum is from the Latin duodenum digitorum, twelve fingers' breadths or inches. Category:Digestive system

Helicobacter pylori

Helicobacter pylori is a bacterium that infects the mucus lining of the human stomach. Many peptic ulcers and some types of gastritis are caused by H. pylori infection, although most humans who are infected will never develop symptoms. This bacterium lives in the human stomach exclusively and is the only known organism that can thrive in that highly acidic environment. It is helix-shaped (hence the name helicobacter) and can literally screw itself into the stomach lining to colonize.

History

In 1875, German scientists found spiral bacteria in the lining of the human stomach; the bacteria could not be grown in culture and the results were eventually forgotten. (Blaser 2005) In 1892, the Italian researcher Giulio Bizzozero described spiral bacteria living in the acidic environment of the stomach of dogs. Professor Walery Jaworski of the Jagiellonian University in Kraków investigated sediments of gastric washings obtained from humans in 1899. Among some rod-like bacteria, he also found bacteria with a characteristic spiral shape, which he called Vibrio rugula. He was the first to suggest a possible role of this organism in the pathogeny of gastric diseases. This work was included in the "Handbook of Gastric Diseases" but it did not have much impact as it was written in Polish. Jaworski was not able to culture the organism. (Konturek 2003). The bacterium was rediscovered in 1982 by two Australian scientists Robin Warren and Barry Marshall; they isolated the organisms from mucosal specimens from human stomachs and were the first to successfully culture them. In their original paper, Warren and Marshall contended that most stomach ulcers and gastritis were caused by colonization with this bacterium, not by stress or spicy food as had been assumed before. Some maintain that the medical community was slow to recognize the role of this bacterium in stomach ulcers and gastritis, believing that no bacterium could survive for long in the acidic environment of the stomach. The community began to come around after further studies were done, including one in which Marshall drank a Petri dish of H. pylori, developed gastritis, and the bacteria were recovered from his stomach lining, thereby satisfying three out of the four Koch's postulates. Marshall's gastritis later resolved without treatment. Marshall and Warren went on to show that antibiotics are effective in the treatment of gastritis. In 1994, the National Institutes of Health published an opinion stating that most recurrent gastric ulcers were caused by H. pylori, and recommended that antibiotics be included in the treatment regimen. In 2005, Warren and Marshall were awarded the Nobel Prize in Medicine for their work on H. pylori. Before the appreciation of the bacterium's role, stomach ulcers were typically treated with medicines that neutralize stomach acid or decrease its production. While this worked well, the ulcers very often reappeared. A traditional medication against gastritis was bismuth subsalicylate. It was often effective, but fell out of use, since its mechanism of action was a mystery. Nowadays it is quite clear that it is due to the bismuth salt acting as an antibiotic. Today, many stomach ulcers are treated with antibiotics effective against H. pylori. The bacterium was initially called Campylobacter pyloridis, then C. pylori (after a correction to the Latin grammar) and in 1989, after DNA sequencing and other data showed that the bacterium did not belong in the Campylobacter genus, it was placed in its own genus Helicobacter. The name pylori comes from the Latin word pylorus, which means gatekeeper, and refers to the pyloric valve (the circular opening leading from the stomach into the duodenum). While H. pylori remain the most important known bacteria to inhabit the human stomach, several other species of the Helicobacter genus have now been identified in other mammals and some birds, and some of these can infect humans. Helicobacter species have also been found to infect the livers of certain mammals and to cause liver disease.

Structure of the bacterium

H. pylori is a spiral-shaped gram-negative bacterium, about 3 micrometres long with a diameter of about 0.5 micrometre. It has 4-6 flagella. It is microaerophilic, i.e. it requires oxygen but at lower levels than those contained in the atmosphere. It uses hydrogen methanogenesis as an energy source. Under conditions of environmental stress, Helicobacter will convert from a spiral to a coccoid form. This coccoid form of the organism has not been cultured, but has been found in the water supply in the US and is apparently involved in the epidemiology of the bacterium. The coccoid form has also been found to be able to adhere to gastric epithelial cells in vitro. in vitro With its flagella and its spiral shape, the bacterium drills into the mucus layer of the stomach, and then can either be found suspended in the gastric mucosa or attached to epithelial cells. It excretes the enzyme urease, which converts urea into ammonia and bicarbonate. The release of ammonia is beneficial to the bacterium since it partially neutralizes the very acidic environment of the stomach (whose very purpose is to kill bacteria). Ammonia is, however, toxic to the epithelial cells, and with other products of H. pylori, including protease, catalase, and phospholipases, causes damage to those cells. A recent finding is that some strains of the bacteria have a particular mechanism for "injecting" the inflammatory agent peptidoglycan from their own cell wall into epithelial stomach cells. (See below for "cagA pathogenicity island" in the section "Genome studies of different strains".) It remains unknown how this mechanism is advantageous to the bacterium. (Viala et al. 2004)

Infection and diagnosis

Infection may be symptomatic or asymptomatic (without visible ill effects). It is estimated that up to 70% of infection is asymptomatic. The bacteria have been isolated from feces, saliva and dental plaque of infected patients, which suggests gastro-oral or fecal-oral as possible transmission routes. It is estimated that about 2/3 of the world population are infected by the bacterium. Actual infection rates vary from nation to nation - the West (Western Europe, North America, Australasia) having rates around 25% and the Third World much higher. In the latter, it is common, probably due to poor sanitary conditions, to find infections in children. In the United States, infection is primarily in the older generations (about 50% for those over the age of 60 compared with 20% under 40 years) and the poorest. This is largely attributed to higher hygiene standards and widespread use of antibiotics. However, antibiotic resistance is appearing in H. pylori. There are already metronidazole resistant strains present in the UK population. In the absence of antibiotic based treatments, H. pylori infection apparently persists for life; the human immune system is not able to eradicate it. One can test for H. pylori infection with blood antibody or stool antigen tests, or with the carbon urea breath test (in which the patient drinks ¹⁴C- or ¹³C-labelled urea, which the bacterium metabolizes producing labelled carbon dioxide that can be detected in the breath), or endoscopy to provide a biopsy sample for testing for the presence of urease ('rapid urease test'), histology or microbial culture.

Treatment

In patients who are asymptomatic, treatment is not usually recommended. In gastric ulcer patients where H. pylori is detected, normal procedure is eradication to allow the ulcer to heal. The standard first-line therapy is a one week triple-therapy of amoxicillin, clarithromycin and omeprazole – though sometimes a different proton pump inhibitor is substituted, or metronidazole is used in place of amoxicillin in those allergic to penicillin. Such a therapy has revolutionised the treatment of gastric ulcers and has made a cure to the disease possible, where previously symptom-control using antacids, H₂-antagonists or proton pump inhibitors alone was the only option. Unfortunately, an increasing number of infected individuals are found to harbour bacteria resistant to first-line antibiotics. This results in initial treatment failure and requires additional rounds of antibiotic therapy. For resistant cases, a quadruple therapy may be used. Bismuth compounds are also effective in combination with the above drugs. However, there are authors that suggests that an H. pylori infection may be protective against certain diseases of the esophagus and cardia, including GERD (GORD), Barrett's esophagus, and esophageal adenocarcinoma (a particularly deadly form of cancer). Therefore, a more cautious approach to its eradication may be necessary. There is some preliminary evidence that regular consumption of broccoli might eradicate H. pylori (Galan 2004). As explained below, some authors suggest that an H. pylori infection may be protective against certain diseases of the esophagus and cardia. Therefore, a more cautious approach than complete eradication may be necessary in some cases.

Gastric cancer connection

Gastric cancer (rare) and gastric MALT lymphoma (lymphoma of the mucosa-associated lymphoid tissue) have been associated with H. pylori, and the bacterium has been categorized as a group I carcinogen by the International Agency for Research on Cancer (IARC). While the association is reasonably strong, it is not entirely clear that there is a causal relationship involved. Two related mechanisms by which H. pylori could promote cancer are under investigation. One mechanism involves the enhanced production of free radicals near H. pylori and an increased rate of host cell mutation. The other proposed mechanism has been called a "perigenetic pathway" (Tsuji et al 2003) and involves enhancement of the transformed host cell phenotype by means of alterations in cell proteins such as adhesion proteins. It has been proposed that H. pylori induces inflammation and locally high levels of TNF-alpha and/or interleukin 6. According to the proposed perigenetic mechanism, inflammation-associated signaling molecules such as TNF-alpha can alter gastric epithelial cell adhesion and lead to the dispersion and migration of mutated epithelial cells without the need for additional mutations in tumor suppressor genes such as genes that code for cell adhesion proteins.

Acid reflux and esophageal cancer

The infection rate with H. pylori has been decreasing in developing countries, presumably because of improved hygiene and increased antibiotics use. Accordingly, the incidence of gastric cancer in the U.S. has fallen by 80 percent from 1900 to 2000. However, gastroesophageal reflux disease (GORD or GERD depending on the use of British or American English, respectively) and cancer of the esophagus (BE: oesophagus) have increased dramatically during the same period. In 1996, Martin Blaser put forward the theory that H. pylori might also have a beneficial effect: by regulating the acidity of the stomach contents, it lowers the impact of regurgitation of stomach acids into the esophagus. While some favorable evidence has been accumulated, as of 2005 the theory is not universally accepted.

Genome studies of different strains

Several strains are known, and the genomes of two have been completely sequenced. The [http://genolist.pasteur.fr/PyloriGene/ Pylori Gene] website allows easy access to genome information for the H. pylori 26695 and H. pylori J99 strains. The genome consists of 1.7 million base pairs, with some 1550 genes. The two sequenced strains show large genetic differences; with up to 6% of the nucleotides differing. Study of the H. pylori genome is centered on attempts to understand pathogenesis, the ability of this organism to cause disease. There are 62 genes in the "pathogenesis" category of the genome database. Both sequenced strains have an approximately 40 kb long Cag pathogenicity island (a common gene sequence believed responsible for pathogenesis) that contains over 40 genes. This pathogenicity island is usually absent from H. pylori strains isolated from humans who are carriers of H. pylori but remain asymptomatic. The cagA gene codes for one of the major H. pylori virulence proteins. Bacterial strains that have the cagA gene are associated with an ability to cause severe ulcers. The cagA gene codes for a relatively long (1186 amino acid) protein. The CagA protein is transported into human cells where it may disrupt the normal functioning of the cytoskeleton. The Cag pathogenicity island has about 30 genes that code for a complex type IV secretion system. After attachment of H.pylori to stomach epithelial cells, the CagA protein is injected into the epithelial cells by the type IV secretion system. The CagA protein is phosphorylated on tyrosine residues by a host cell membrane-associated tyrosine kinase. Pathogenic strains of H. pylori have been shown to activate the epidermal growth factor receptor (EGFR), a membrane protein with a tyrosine kinase domain. Activation of the EGFR by H. pylori is associated with altered signal transduction and gene expression in host epithelial cells that may contribute to pathogenesis. It has also been suggested that a c-terminal region of the CagA protein (amino acids 873-1002) can regulate host cell gene transcription independent of protein tyrosine phosphorylation. It is thought, due to cagA's low GC content relative to the rest of the helicobacter genome, that the gene was acquired by horizontal transfer from another cagA+ bacterial species. Each human population has a characteristic distribution of H. pylori strains that typically infect members of that population. This allows researchers to use H. pylori to study human migration patterns. It could be established that H. pylori in Amazon Indians has East Asian rather than European origins, suggesting that it arrived with the original immigrants at least 11,000 years ago.

References

- Marshall BJ. Unidentified curved bacillus on gastric epithelium in active chronic gastritis. Lancet 1983;1((8336):1273-1275. PMID 6134060.
- Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach patients with gastritis and peptic ulceration. Lancet 1984;1(8390):1311-1315. PMID 6145023.
- Helicobacter pylori in peptic ulcer disease. NIH Consensus Statement Online 1994 Jan 7-9.12(1):1-23. Cited 2004 Dec 21. [http://consensus.nih.gov/cons/094/094_statement.htm Fulltext].
- Helicobacter pylori and peptic ulcer. Centers for Disease Control and Prevention. Cited 2004 Dec 21. [http://www.cdc.gov/ulcer/ Fulltext].
- Blaser MJ. An Endangered Species in the Stomach. Scientific American 2005;292(2):38-45. [http://www.sciam.com/article.cfm?articleID=00024948-2764-11E8-A28583414B7F0000&ref=sciam&chanID=sa006 partial text]. PMID 15715390.
- Logan RPH, Walker MM. Clinical review: ABC of the upper gastrointestinal tract. Epidemiology and diagnosis of Helicobacter pylori infection. BMJ 2001;323:920-922. [http://bmj.bmjjournals.com/cgi/content/full/323/7318/920 Full text]. PMID 11668141.
- Tsuji S, Kawai N, Tsujii M, Kawano S, Hori M. Review article: inflammation-related promotion of gastrointestinal carcinogenesis - a perigenetic pathway. Aliment Pharmacol Ther 2003;18(Suppl 1):82-9. PMID 12925144.
- Viala J, Chaput C, Boneca IG, Cardona A, Girardin SE, Moran AP, Athman R, Memet S, Huerre MR, Coyle AJ, DiStefano PS, Sansonetti PJ, Labigne A, Bertin J, Philpott DJ, Ferrero RL. Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nature Immunol 2004;5:1166-74. [http://dx.doi.org/10.1038/ni1131 Fulltext]. PMID 15489856.
- Galan MV, Kishan AA, Silverman AL. Oral broccoli sprouts for the treatment of Helicobacter pylori infection: a preliminary report. Dig Dis Sci. 2004 Aug;49(7-8):1088-90. PMID 15387326
- Konturek JW. Discovery by Jaworski of Helicobacter pylori and its pathogenetic role in peptic ulcer, gastritis and gastric cancer. J Physiol Pharmacol. 2003 Dec;54 Suppl 3:23-41. [http://www.jpp.krakow.pl/journal/archive/1203_s3/articles/03_article.html Fulltext] PMID 15075463

External links

- [http://www.helico.com/ The Helicobacter Foundation] provides information on Helicobacter pylori and its effects - founded by Dr. Barry J. Marshall, one of the discoverers of H. Pylori
- http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=14755326
- [http://www.helicobacter.org/ European Helicobacter Study Group] sponsors annual international workshop, yearbook, and clinical guidelines
- [http://www.blackwell-synergy.com/links/toc/hel/10/s1?cookieSet=1 The Year in Helicobacter pylori 2005] Helicobacter journal Sept 2005 - Free content
- [http://www.helicobacter.org/content/publications/helicobacter_2004/2004.htm The Year in Helicobacter pylori 2004] Helicobacter journal August 2004 - Free Content on line
- Atwood KC. Bacteria, Ulcers, and Ostracism?: H. Pylori and the Making of a Myth. Skeptical Inquirer November 2004. [http://www.csicop.org/si/2004-11/bacteria.html Fulltext] Claims that medicine’s purported ostracism of the discovery of H. pylori has achieved a mythological quality, but isn't true: after appropriate initial scientific skepticism, the hypothesis was accepted right "on schedule".
- [http://genolist.pasteur.fr/PyloriGene/ Pylori Gene], giving the genome sequences of various strains
- [http://www.pathologyatlas.ro/Helicobacter%20pylori.html Microscopic image of Helicobacter pylori]
- [http://nobelprize.org/medicine/laureates/2005/index.html The Nobel Prize in Physiology or Medicine 2005]
- [http://www.dsmz.de/bactnom/nam3637.htm List of species in the genus Helicobacter] Category:Proteobacteria Category:Gastroenterology zh-min-nan:Helicobacter pylori ko:헬리코박터 파일로리 ja:ヘリコバクター・ピロリ

Aspirin

Aspirin or acetylsalicylic acid is a drug in the family of salicylates, often used as an analgesic (against minor pains and aches), antipyretic (against fever), and anti-inflammatory. It has also an anticoagulant (blood thinning) effect and is used in long-term low-doses to prevent heart attacks. The brand name Aspirin was coined by the Bayer company of Germany. In some countries the name is used as a generic term for the drug rather than the manufacturer's trademark. In countries in which Aspirin remains a trademark, the initialism ASA is used as a generic term (ASS in German language countries, for Acetylsalicylsäure; AAS in Spanish language countries, for ácido acetilsalicílico). Because there appears to be a connection between aspirin and Reye's syndrome, aspirin is no longer used to control flu-like symptoms in children. Low-dose long-term aspirin irreversibly blocks formation of thromboxane A2 in platelets, producing an inhibitory effect on platelet aggregation, and this blood thinning property makes it useful for reducing the incidence of heart attacks. Aspirin produced for this purpose often comes in 75 or 81 mg dispersible tablets. High doses of aspirin are also given immediately after an acute heart attack. These doses may also inhibit the synthesis of prothrombin and may therefore produce a second and different anticoagulant effect. tablet Several hundred fatal overdoses of aspirin occur annually, but the vast majority of its uses are beneficial. Its primary undesirable side effects, especially in stronger doses, are gastrointestinal distress (including ulcers and stomach bleeding) and tinnitus. Another side effect, due to its anticoagulant properties, is increased bleeding in menstruating women. Aspirin was the first discovered member of the class of drugs known as non-steroidal anti-inflammatory drugs (NSAIDs), not all of which are salicylates, though they all have similar effects and a similar action mechanism.

History of discovery

NSAID Hippocrates, a Greek physician for whom the Hippocratic Oath is named, wrote in the 5th century BC about a bitter powder extracted from willow bark that could ease aches and pains and reduce fevers. This remedy is also mentioned in texts from ancient Sumeria, Egypt and Assyria. Native Americans claim to have used it for headaches, fever, sore muscles, rheumatism, and chills. The Reverend Edward Stone, a vicar from Chipping Norton in Oxfordshire England, noted in 1763 that the bark of the willow was effective in reducing a fever. The active extract of the bark, called salicin, after the Latin name for the White willow (Salix alba), was isolated to its crystalline form in 1828 by Henri Leroux, a French pharmacist, and Raffaele Piria, an Italian chemist, who then succeeded in separating out the acid in its pure state. Salicin is highly acidic when in a saturated solution with water (pH = 2.4), and is called salicylic acid for that reason. This chemical was also isolated from meadowsweet flowers (genus Filipendula, formerly classified in Spiraea) by German researchers in 1839. While their extract was somewhat effective, it also caused digestive problems such as irritated stomach and diarrhea, and even death when consumed in high doses. In 1853, a French chemist named Charles Frederic Gerhardt neutralized salicylic acid by buffering it with sodium (sodium salicylate) and acetyl chloride, creating acetosalicylic anhydride. Gerhardt's product worked but he had no desire to market it and abandoned his discovery. In 1897, Felix Hoffmann, a researcher at Friedrich Bayer & Co. in Germany, derivatized one of the hydroxyl functional groups in salicylic acid with an acetyl group (forming the acetyl ester) which greatly reduced the negative effects. This was the first synthetic drug, not a copy of something that existed in nature, and the start of the pharmaceuticals industry. Hoffmann made some of the formula and gave it to his father, who was suffering from the pain of arthritis and could not stand the side effects of salicylic acid. With good results, he then convinced Bayer to market the new wonder drug. Aspirin was patented on March 6, 1899. It was marketed alongside another of Hoffmann's products, an acetylated synthetic of morphine called Heroin. Heroin was initially the more successful of the two painkillers, but as Heroin's shortcoming of addictiveness became more obvious, Aspirin stepped to the forefront. Aspirin was originally sold as a powder and was an instant success; in 1915, Bayer introduced Aspirin tablets. Several claims to invention of aspirin have arisen. Acetylsalicylic acid was already being manufactured by the Chemische Fabrik von Heyden Company in 1897, although without a brand name. Arthur Eichengrün claimed in 1949 that he planned and directed the synthesis of aspirin while Hoffmann's role was restricted to the initial lab synthesis using Eichengrün's process. In 1999, Walter Sneader of the Department of Pharmaceutical Sciences at the University of Strathclyde in Glasgow re-examined the case and agreed with Eichengrün's account. Bayer continues to recognize Felix Hoffmann as aspirin's official inventor. Despite its argued origin, Bayer's marketing was responsible for bringing it to the world. It was not until the 1970s that the mechanism of action of aspirin and similar drugs called NSAIDs was elucidated (see below).

Synthesis of aspirin

Aspirin (acetylsalicylic acid) can be synthesized from salicylic acid and acetic anhydride. It is a common experiment performed in organic chemistry labs, and generally tends to produce low yields due to the relative difficulty of its extraction from an aqueous state. Image:Aspirin-synthesis.gif

History of the name "Aspirin"

Image:Aspirin-synthesis.gif The name "aspirin" is composed of a- (from the acetyl group) -spir- (from the spiraea flower) and -in (a common ending for drugs at the time). Bayer registered it as a trademark on March 6, 1899. However, the German company lost the right to use the trademark in many countries as the Allies seized and resold its foreign assets after World War I. The right to use "Aspirin" in the United States (along with all other Bayer trademarks) was purchased from the U.S. government by Sterling Drug, Inc in 1918. Even before the patent for the drug expired in 1917, Bayer had been unable to stop competitors from copying the formula and using the name elsewhere, and so with a flooded market, the public was unable to recognize "Aspirin" as coming from only one manufacturer. Sterling was subsequently unable to prevent "Aspirin" from being ruled a genericized trademark in a U.S. federal court in 1921. Other countries (such as Canada) still consider "Aspirin" a protected trademark.

How it works

In a piece of research for which he was awarded both a Nobel prize in Physiology or Medicine in 1982 and a knighthood, John Robert Vane, who was then employed by the Royal College of Surgeons in London, showed in 1971 that aspirin suppresses the production of prostaglandins and thromboxanes. This happens because cyclooxygenase, an enzyme which participates in the production of prostaglandins and thromboxanes, is irreversibly inhibited when aspirin acetylates it. This makes aspirin different from other NSAIDS (such as diclofenac and ibuprofen) which are reversible inhibitors. Prostaglandins are local hormones (paracrine) produced in the body and have diverse effects in the body, including but not limited to transmission of pain information to the brain, modulation of the hypothalamic thermostat and inflammation. Thromboxanes are responsible for the aggregation of platelets that form blood clots. Heart attacks are primarily caused by blood clots, and their reduction with the introduction of small amounts of aspirin has been seen to be an effective medical intervention. The side effect of this is that the ability of the blood in general to clot is reduced, and excessive bleeding may result from the use of aspirin. More recent work has shown that there are at least two different types of cyclooxygenase: COX-1 and COX-2. Aspirin inhibits both of them. Newer NSAID drugs called COX-2 selective inhibitors have been developed that only inhibit COX-2, with the hope that this would reduce the gastrointestinal side effects. However, several of the new COX-2 selective inhibitors have been recently withdrawn, after evidence emerged that COX-2 inhibitors increase the risk of heart attack. It is proposed that endothelial cells lining the arteries in the body express COX-2, and by selectively inhibiting COX-2, prostaglandins (specifically PGF2) are downregulated with respect to thromboxane levels, as COX-1 in platelets is unaffected. Thus, the protective anti-coagulative effect of PGF2 is decreased, increasing the risk of thrombus and associated heart attacks and other circulatory problems. Since platelets have no DNA, they are unable to synthesize new COX once aspirin has irreversibly inhibited the enzyme, rendering them "useless": an important difference with reversible inhibitors. Additionally, aspirin has 2 additional modes of actions, contributing to its strong analgesic, antipyretic and antiinflammitive properties :
- It uncouples oxidative phosphorylation in cartilaginous (and hepatic) mitochondria.
- It induces the formation of NO-radicals in the body that enable the white blood cells (leucocyts) to fight infections more effectively. This has been found recently by Dr. Derek W. Gilroy, winning Bayer's International Aspirin Award 2005. Also recently aspirin has been proven to prevent carcinoma of the colon, if given in low doses over years.

Indications

Aspirin, as many older drugs, has proven to be useful in many conditions, and despite its well known toxicity, it is widely used, since physicians are familiar with its properties. Indications include:
- Fever
- Pain (Specially useful in osteoid osteoma, arthritis and chronic pain conditions)
- Migraine
- Myocardial infarction prophylaxis (low dose)
- Drug of choice for rheumatic fever

Contraindications and Warnings

- Do NOT take this medicine if you are allergic to aspirin, ibuprofen or naproxen.
- Talk to your doctor if your symptoms do NOT improve after a few days of therapy.
- If you have kidney disease, ulcers, mild diabetes, gout, gastritis, talk to your doctor before using this medicine.
- Taking aspirin with alcohol increases the chance of stomach bleeding. Avoid alcohol with this medicine.
- Giving aspirin to children, including teenagers having a cold or flu can cause a serious condition known as Reye's syndrome.
- Patients with hemophilia, other bleeding tendencies, or a bleeding ulcer should not take salicylates.

Common side effects

- Gastrointestinal complaints (stomach upset, dyspepsia, heartburn, small blood loss). To help avoid these problems, it is recommended that aspirin be taken at or after meals. Undetected blood loss may lead to hypochromic anemia.
- Severe gastrointestinal complaints (gross bleeding and/or ulceration), requiring discontinuation and immediate treatment. Patients receiving high doses and/or long-term treatment should receive gastric protection with high dosed antacids, ranitidine or omeprazol.
- Frequently central effects (dizziness, tinnitus, hearing loss, vertigo, centrally mediated vision disturbances, and headaches). The higher the daily dose is, the more likely it is that central nervous system side effects will occur.
- Sweating, seen with high doses, independent from antipyretic action
- Long-term treatment with high doses (arthritis and rheumatic fever) : often increased liver enzymes without symptoms, rarely reversible liver damage. The potentially fatal Reye's syndrome may occur, if given to pediatric patients with fever and other signs of infections. The syndrome is due to fatty degeneration of liver cells. Up to 30% of those afflicted will eventually die. Prompt hospital treatment may be life-saving.
- Chronic nephritis with long-term use, usually if used in combination with certain other painkillers. This condition may lead to chronic renal failure.
- Prolonged and more severe bleeding after operations and post-traumatic for up to 10 days after the last aspirin dose. If one wishes to counteract the bleeding tendency, fresh thrombocyte concentrate will usually work.
- Skin reactions, angioedema, and bronchospasm have all been seen infrequently.

Overdose

Aspirin overdose has serious consequences and is potentially lethal. 52 deaths involving single-ingredient aspirin were reported in the United States in the year 2000. Effects of overdose include:
- Tinnitus
- Abdominal pain
- Hypokalemia
- Hypoglycemia
- Pyrexia
- Hyperventilation
- dysrhythmia
- Hypotension
- Hallucination
- Renal failure
- confusion
- Seizure
- Coma
- Death Overdose can be acute or chronic; that is, a person can overdose by taking one very large dose or smaller doses over a period of time. Acute overdose has a mortality rate of 2%. Chronic overdose is more commonly lethal with a mortality rate of 25%. The most common cause of death during an aspirin overdose is noncardiogenic pulmonary edema. An acute overdose patient must be taken to a hospital immediately. Contrary to the urban legend, you can die from eating a bottle of pills, even if you subsequently throw up. Treatment of an acute overdose requires ingestion of activated charcoal to neutralize the acetylsalicylic acid in the gastrointestinal tract, followed by a stomach pump with subsequent re-ingestion of activated charcoal. Patients are then monitored for at least 24 hours and typically given intravenous potassium chloride to counteract hypokalemia, sodium bicarbonate to neutralize salicylate in the blood and restore the blood's sensitive pH balance, and dextrose to restore blood sugar levels. Frequent blood work is performed to check metabolic, salicylate, and blood sugar levels; arterial blood gas assessments are performed to test for respiratory alkalosis and metabolic acidosis. If the overdose was intentional, the patient will undergo psychiatric evaluation as with any suicide attempt.

External links

- http://www.bayeraspirin.com
- http://almaz.com/nobel/medicine/aspirin.html
- http://chemed.chem.purdue.edu/genchem/topicreview/bp/1biochem/research7.html
- http://www.med.mcgill.ca/mjm/issues/v02n02/aspirin.html
- http://www.jhu.edu/~jhumag/0297web/health.html
- http://www.howstuffworks.com/aspirin

References

# Litovitz TL. 2000 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2001;19(5):337-395 Category:Non-steroidal anti-inflammatory drugs Category:Over-the-counter substances Category:Anticoagulants Category:Aromatic compounds Category:Esters Category:Carboxylic acids ko:아스피린 ms:Aspirin ja:アスピリン th:แอสไพริน

NSAID

Non-steroidal anti-inflammatory drugs, usually abbreviated to NSAIDs, are drugs with analgesic, antipyretic and anti-inflammatory effects - they reduce pain, fever and inflammation. The term "non-steroidal" is used to distinguish these drugs from steroids, which (amongst a broad range of other effects) have a similar eicosanoid-depressing, anti-inflammatory action. NSAIDs are sometimes also referred to as non-steroidal anti-inflammatory agents/analgesics (NSAIAs). The most prominent members of this group of drugs are aspirin and ibuprofen. Paracetamol (acetaminophen) has negligible anti-inflammatory activity, and is strictly speaking not an NSAID. Beginning in 1829, with the isolation of salicylic acid from the folk remedy willow bark, NSAIDs have become an important part of the pharmaceutical treatment of pain (at low doses) and inflammation (at higher doses). Part of the popularity of NSAIDs is that, unlike opioids, they do not produce sedation, respiratory depression, or addiction. NSAIDs, however, are not without their own problems (see below). Certain NSAIDs, including ibuprofen and aspirin, have become accepted as relatively safe and are available over-the-counter without prescription.

Mode of action

Most NSAIDs act as non-selective inhibitors of the enzyme cyclooxygenase, inhibiting both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes. Cyclooxygenase catalyses the formation of prostaglandins and thromboxane from arachidonic acid (itself derived from the cellular phospholipid bilayer by phospholipase A₂). Prostaglandins act (among other things) as messenger molecules in the process of inflammation. This mechanism of action was elucidated by John Vane, who later received a Nobel Prize for his work.

Examples of NSAIDs

NSAIDs can be broadly classified based on their chemical structure. NSAIDs within a group will tend to have similar characteristics and tolerability. There is little difference in clinical efficacy between the NSAIDs when used at equivalent doses. Rather, differences between compounds tended to be with regards to dosing regimens (related to half-life), route of administration, and tolerability profile. Some more common examples are given below. Paracetamol (acetaminophen), owing to its inhibitory action on cyclooxygenase, is sometimes grouped together with the NSAIDs. Paracetamol, however, does not have any significant anti-inflammatory properties and is not a true NSAID. Though it has not been clearly elucidated, it is suspected that this lack of anti-inflammatory action may be due to the paracetamol inhibiting cyclooxygenase predominantly in the central nervous system. There is also some speculation that paracetamol acts through the inhibition of the recently discovered COX-3 isoform (see below).

coxibs

- celecoxib
- rofecoxib (withdrawn from market)
- valdecoxib
- parecoxib
- etoricoxib

sulphonanilides

- nimesulide

Uses of NSAIDs

NSAIDs are usually indicated for the treatment of acute or chronic conditions where pain and inflammation are present. Research continues into their potential for prevention of colorectal cancer, and treatment of other conditions, such as cancer and cardiovascular disease. NSAIDs are generally indicated for the symptomatic relief of the following conditions. (Rossi, 2004)
- rheumatoid arthritis
- osteoarthritis
- inflammatory arthropathies (e.g. ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome)
- acute gout
- dysmenorrhoea
- metastatic bone pain
- headache and migraine
- postoperative pain
- mild-to-moderate pain due to inflammation and tissue injury
- pyrexia
- renal colic Aspirin, the only NSAID able to irreversibly inhibit COX-1, is also indicated for inhibition of platelet aggregation; an indication useful in the management of arterial thrombosis and prevention of adverse cardiovascular events. In 2001, NSAIDs accounted for 70,000,000 prescriptions and 30 billion over-the-counter doses sold annually in the United States. (Green, 2001). With the aging of the Baby Boomer generation and the associated rise in the incidence of osteoarthritis and other such conditions for which NSAIDs are indicated, the use of NSAIDs may increase further still.

Adverse effects

The widespread use of NSAIDs has meant that the adverse effects of these relatively safe drugs have become increasingly prevalent. The two main adverse drug reactions (ADRs), associated with NSAIDs relate to gastrointestinal (GI) effects and renal effects of the agents. These effects are dose-dependent, and in many cases severe enough to pose the risk of ulcer perforation, upper gastrointestinal bleeding, and death, limiting the use of NSAID therapy. An estimated 10-20% of NSAID patients experience dyspepsia, and NSAID-associated upper gastrointestinal adverse events are estimated to result in 103,000 hospitalizations and 16,500 deaths per year in the United States, and represent 43% of drug-related emergency visits. Many of these events are avoidable; a review of physician visits and prescriptions estimated that unnecessary prescriptions for NSAIDs were written in 42% of visits. (Green, 2001)

Gastrointestinal ADRs

The main ADRs associated with use of NSAIDs relate to direct and indirect irritation of the gastrointestinal tract (GIT). NSAIDs cause a dual insult on the GIT - the acidic molecules directly irritate the gastric mucosa; and inhibition of COX-1 reduces the levels of protective prostaglandins. Common gastrointestinal ADRs include: (Rossi, 2004)
- nausea
- dyspepsia
- ulceration/bleeding
- diarrhoea Risk of ulceration increases with duration of therapy, and with higher doses. In attempting to minimise GI ADRs, it is prudent to use the lowest effective dose for the shortest period of time, a practice which studies show is not often followed. There are also some differences in the propensity of individual agents to cause gastrointestinal ADRs. Indomethacin, ketoprofen and piroxicam appear to have the highest prevalence of gastric ADRs, while ibuprofen (lower doses) and diclofenac appear to have lower rates. (Rossi, 2004) Certain NSAIDs, such as aspirin, have been marketed in enteric-coated formulations which are claimed to reduce the incidence of gastrointestinal ADRs. Similarly, there is a belief that rectal formulations may reduce gastrointestinal ADRs. However, in consideration of the mechanism of such ADRs and indeed in clinical practice, these formulations have not been shown to have a reduced risk of GI ulceration. (Rossi, 2004) Commonly, gastrointestinal adverse effects can be reduced through suppressing acid production, by concomitant use of a proton pump inhibitor, e.g. omeprazole; or the prostaglandin analogue misoprostol. Misoprostol is itself associated with a high incidence of gastrointestinal ADRs (diarrhoea). While these techniques may be effective, they prove to be expensive for maintenance therapy.

Renal ADRs

NSAIDs are also associated with a relatively high incidence of renal ADRs. The mechanism of these renal ADRs is probably due to changes in renal haemodynamics (bloodflow), ordinarily mediated by prostaglandins, which are affected by NSAIDs. Horses are particularly prone to these adverse affects compared to other domestic animal species. Common ADRs associated with altered renal function include: (Rossi, 2004)
- salt and fluid retention
- hypertension These agents may also cause renal impairment, especially in combination with other nephrotoxic agents. Renal failure is especially a risk if the patient is also concomitantly taking an ACE inhibitor and a diuretic - the so-called "triple whammy" effect. (Thomas, 2000) In rarer instances NSAIDs may also cause more severe renal conditions. (Rossi, 2004)
- interstitial nephritis
- nephrotic syndrome
- acute renal failure

Photosensitivity

Photosensitivity is a commonly overlooked adverse effect of many of the NSAIDs. (Moore, 2002) It is somewhat ironic that these antiinflammatory agents may themselves produce inflammation in combination with exposure to sunlight. The 2-arylpropionic acids have proven to be the most likely to produce photosensitivity reactions, but other NSAIDs have also been implicated including piroxicam, diclofenac and benzydamine. Benoxaprofen, since withdrawn due to its hepatotoxicity, was the most photoactive NSAID observed. The mechanism of photosensitivity, responsible for the high photoactivity of the 2-arylpropionic acids, is the ready decarboxylation of the carboxylic acid moiety. The specific absorbance characteristics of the different chromophoric 2-aryl substituents, affects the decarboxylation mechanism. Whilst ibuprofen is somewhat of an exception, having weak absorption, it has been reported to be a weak photosensitising agent.

Other ADRs

Common ADRs, other than listed above, include: raised liver enzymes, headache, dizziness (Rossi, 2004). Uncommon ADRs include: heart failure, hyperkalaemia, confusion, bronchospasm, rash (Rossi, 2004).

Newer NSAID'S: Selective COX inhibitors

COX-2 inhibitors

The discovery of COX-2 in 1991 by Daniel L. Simmons at Brigham Young University raised the hope of developing an effective NSAID without the gastric problems characteristic of these agents. It was thought that selective inhibition of COX-2 would result in anti-inflammatory action without disrupting gastroprotective prostaglandins. COX-1 is a constitutively expressed enzyme with a "house-keeping" role in regulating many normal physiological processes. One of these is in the stomach lining, where prostaglandins serve a protective role, preventing the stomach mucosa from being eroded by its own acid. When non-selective COX-1/COX-2 inhibitors (such as aspirin, ibuprofen, and naproxen)) lower stomach prostaglandin levels, these protective effects are lost and ulcers of the stomach or duodenum and potentially internal bleeding can result. COX-2 is an enzyme facultatively expressed in inflammation, and it is inhibition of COX-2 that produces the desirable effects of NSAID's. The relatively selective COX-2 inhibiting oxicam, meloxicam, was the first step towards developing a true COX-2 selective inhibitor. Coxibs, the newest class of NSAIDs, can be considered as true COX-2 selective inhibitors, and include celecoxib, rofecoxib, valdecoxib, parecoxib and etoricoxib.

Controversies with COX-2 inhibitors

While it was hoped that this COX-2 selectivity would reduce gastrointestinal adverse drug reactions (ADRs), there is little conclusive evidence that this is true. The original study touted by Searle (now part of Pfizer), showing a reduced rate of ADRs for celecoxib, was later revealed to be based on preliminary data - the final data showed no significant difference in ADRs when compared with diclofenac. Rofecoxib however, which has since been withdrawn, had been shown to produce significantly fewer gastrointestinal ADRs compared to naproxen. (Bombardier et al 2000). This study, the VIGOR trial, raised the issue of the cardiovascular safety of the coxibs - a statistically insignificant increase in the incidence of myocardial infarctions was observed in patients on rofecoxib. Further data, from the APPROVe trial, showed a relative risk of cardiovascular events of 1.97 versus placebo - a result which resulted in the worldwide withdrawal of rofecoxib in October 2004.

COX-3 inhibitors

Simmons also co-discovered COX-3 in 2002 and analyzed this new isozyme's relation to paracetamol, arguably the most widely used analgesic drug in the world. (Chandrasekharan et al 2002). The authors postulated that inhibition of COX-3 could represent a primary central mechanism by which these drugs decrease pain and possibly fever. The clinical ramifications and knowledge of COX isozymes are rapidly expanding and may offer significant hope for future treatments of pain, inflammation, and fever.

References

- Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ, VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;343(21):1520-8. PMID 11087881.
- Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS, Simmons DL. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci U S A 2002;99:13926-31. PMID 12242329.
- Green GA. Understanding NSAIDS: from aspirin to COX-2. Clin Cornerstone 2002;3:50-59. PMID 11464731.
- Moore DE. Drug-induced cutaneous photosensitivity. Drug Safety 2002;25:345-72. PMID 12020173.
- Rossi S (Ed.) (2004). Australian Medicines Handbook 2004. Adelaide: Australian Medicines Handbook. ISBN 0-9578521-4-2.
- Thomas MC. Diuretics, ACE inhibitors and NSAIDs - the triple whammy. Med J Aust 2000;172:184-185. PMID 10772593.
- ja:非ステロイド性抗炎症薬 th:เอ็นเซด

Abdominal pain

Abdominal pain can be one of the symptoms associated with transient disorders or serious disease. Making a definitive diagnosis of the cause of a person's abdominal pain can be quite difficult, because so many diseases can result in this symptom.

Introduction

Abdominal pain is traditionally described by its chronicity (acute or chronic), its progression over time, its nature (sharp, dull, colicky), its distribution (by various methods, such as abdominal quadrant (left upper quadrant, left lower quadrant, right upper quadrant, right lower quadrant) or other methods that divide the abdomen into nine sections), and by characterization of the factors that make it worse, or alleviate it.

Approaches

Due to the many organ systems in the abdomen, abdominal pain is a concern of general practitioners/family physicians, surgeons, internists, emergency medicine doctors, pediatricians, gastroenterologists, urologists and gynecologists. Occasionally, patients with rare causes can see a number of specialists before being diagnosed adequately (e.g. chronic functional abdominal pain).

Types and mechanisms

#The pain associated with inflammation of the parietal peritoneum is steady and aching, and worsened by changes in the tension of peritoneum caused by pressure or positional change, and is often accompanied by tension of the abdominal muscles contracting to relieve such tension. #The pain associated with obstruction of the hollow viscera is often intermittent or "colicky" #The pain associated with abdominal vascular disturbances (thrombosis or embolism) can be sudden or gradual in onset, and can be severe or mild. Pain associated with the rupture of an abdominal aortic aneurysm may radiate to the back, flank, or genitals. #Pain that is felt in the abdomen may be "referred" from elsewhere (e.g., a disease process in the chest, like a subdiaphragmatic abscess, may cause pain in the abdomen), and abdominal processes can cause radiated pain elsewhere (e.g. gall bladder pain—in cholecystitis or cholelithiasis—is often referred to the shoulder).

Selected causes

- parietal peritoneal inflammation
- due to infection: perforated appendix in appendicitis, pelvic inflammatory disease
- due to chemical irritation: perforated gastric or peptic ulcer; pancreatitis, Mittelschmerz, ruptured ectopic pregnancy
- miscellaneous (familial Mediterranean fever)
- inflammation of bowel wall Crohn's disease, ulcerative colitis, diverticulitis, gastroenteritis
- allergic: lactose intolerance, Celiac sprue
- autoimmune: sarcoidosis, vasculitis
- mechanical obstruction of hollow viscera such as the small intestine, the large intestine (e.g. by intusseception), the biliary tree (e.g. by gallstones), or the ureter (e.g. by urinary calculi)
- vascular disturbances (leading to ischemia): embolism, thrombosis, vascular rupture, torsional occlusion (volvulus), sickle cell anemia
- abdominal wall injury/disruption: mesenteric traction, muscle trauma, muscular infection, diverticulosis (rare)
- distention of visceral surfaces such as the hepatic or renal capsule
- referred pain from the thorax (pneumonia, coronary occlusion), the spine (radiculitis secondary to arthritis), genitals (testicular torsion)
- metabolic disturbance: lead poisoning, Black widow spider bite, uremia, diabetic ketoacidosis, porphyria, C1-esterase inhibitor deficiency, adrenal insufficiency
- neurogenic pain: tabes dorsalis, herpes zoster, Lyme disease (Lyme radiculitis or Bannwarth syndrome)
- functional pain, irritable bowel syndrome

Hematemesis

Hematemesis (American English) or haematemesis (International English) is the vomiting of fresh red blood. The source is generally the upper gastrointestinal tract. Patients can easily confuse it with hemoptysis (coughing up blood), although the former is more common.

Causes

Causes can be:
- Vomiting of ingested blood after hemorrhage in the oral cavity, nose or throat
- Mallory-Weiss syndrome (esophageal tear)
- Esophageal varices
- Peptic ulcer
- Gastritis
- Gastric varices

Management

Hematemesis is treated as a medical emergency. The most vital distinction is whether there is blood loss sufficient to cause shock. If this is not the case, the patient is generally administered a proton pump inhibitor (e.g. omeprazole), given blood transfusions (if the level of hemoglobin is extremely low, that is less than 8.0 mg/dL or 4.5-5.0 mmol/L), and kept nil per os until esophagogastroduodenoscopy (EGD, endoscopy) can be arranged. Adequate venous access (large-bore cannulas or a central venous catheter) is generally obtained in case the patient suffers a further bleed and becomes unstable. In a "hemodynamically significant" case of hematemesis resuscitation is an immediate priority to prevent cardiac arrest. Fluids and/or blood is adminstered, preferably by central venous catheter, and the patient is prepared for emergency endoscopy, which is typically done in theatres. Surgical opinion is usually sought in case the source of bleeding cannot be identified endoscopically, and laparotomy is necessary.

Oxidation

Redox reactions include all chemical processes in which atoms have their oxidation number (oxidation state) changed. This can be a simple redox process, such as the combustion of carbon to yield carbon dioxide, it could be the reduction of carbon by hydrogen to yield methane, or it could be the oxidation of sugar in the human body, through a series of very complex electron transfer processes. The term redox comes from the two concepts of reduction and oxidation. :Oxidation describes the loss of an electron by a molecule, atom, or ion; loss of hydrogen, or gain of oxygen. It also means an increase in oxidation number. :Reduction describes the uptake of an electron by a molecule, atom, or ion; loss of oxygen and gain of hydrogen. It also means a decrease in oxidation number. These two terms go together, because in a chemical reaction, one cannot occur without the other; electrons lost by one compound must be gained by another. Reduction can also be considered to be the reducing of an atom's positive charge, and oxidation its opposite (gaining positive charge). oxygen

Oxidizing and reducing agents

Substances that have the ability to oxidize (Commonwealth English oxidise) other substances are said to be oxidative and are known as oxidizing agents, oxidants or oxidizers. Put in another way, the oxidant removes electrons from the other substance, and is thus reduced itself. Oxidants are usually chemical substances with elements in high oxidation numbers (e.g. H₂O₂, MnO₄^-, CrO₃, Cr₂O₇^2-, OsO₄) or highly electronegative substances that can gain one or two extra electrons by oxidizing a substance (O₂, O₃, F₂, Cl₂, Br₂). Substances that have the ability to reduce other substances are said to be reductive and are known as reductive agents, reductants, or reducers. Put in another way, the reductant transfers electrons to the substance. Reductants in chemistry are very diverse. Metal reduction - electropositive elemental metals can be used (Li, Na, Mg, Fe, Zn, Al). These metals donate or give away electrons readily. Other kinds of reductants are hydride transfer reagents (NaBH₄, LiAlH₄), these reagents are widely used in organic chemistry, primarily in the reduction of carbonyl compounds to alcohols. Another useful method is reductions involving hydrogen gas (H₂) with a palladium, platinum, or nickel catalyst. These catalytic reductions are primarily used in the reduction of carbon-carbon double or triple bonds. The chemical way to look at redox processes is that the reductant transfers electrons to the oxidant. Thus, at the end of the reaction, the reductant will have been oxidized and the oxidant will have been reduced.

Former meaning (oxygen/hydrogen)

Formerly, oxidation simply meant the addition of oxygen or the removing of hydrogen (hence the name oxidation), and reduction was removal of oxygen or the addition of hydrogen. Currently, however, the terms are normally used in a more general sense, describing electron movement.

Examples of redox reactions

A good example is the reaction between hydrogen and fluorine: :H₂ + F₂ → 2HF We can write this overall reaction as two half-reactions: an oxidation reaction: :H₂ → 2H⁺ + 2e^- and a reduction reaction: :F₂ + 2e^- → 2F^- Elements always have an oxidation number of zero. In the first half reaction hydrogen is oxidized from an oxidation number of zero to an oxidation number of +1. In the second half reaction fluorine is reduced from an oxidation number of zero to an oxidation number of −1. When adding the reactions together the electrons cancel: :H₂ → 2H⁺ + ~~2e^-~~ :+ ~~2e^-~~ + F₂ → 2F^- : --------------------- :H₂ + F₂ → 2H⁺ + 2F^- And the ions combine to form hydrogen fluoride: 2H⁺ + 2F^- → 2HF

Other examples

- iron(II) oxidizes to iron(III): :Fe²⁺ → Fe³⁺ + e^-
- hydrogen peroxide reduces to hydroxide: :H₂O₂ + 2 e^- → 2 OH^- overall equation for the above: :2Fe²⁺ + H₂O₂ + 2H⁺ → 2Fe³⁺ + 2H₂O
- denitrification, nitrate reduces to nitrogen: :2NO₃^- + 10e^- + 12 H⁺ → N₂ + 6H₂O
- iron oxidizes to iron(III) oxide and oxygen is reduced forming iron(III) oxide (commonly known as rusting or tarnishing): :4Fe + 3O₂ → 2 Fe₂O₃.
- Combustion of hydrocarbons produces water, carbon dioxide, some partially oxidized forms such as carbon monoxide, and heat energy. Complete oxidation of materials containing carbon produces carbon dioxide.
- In organic chemistry, stepwise oxidation of a hydrocarbon produces water and, successively, an alcohol, an aldehyde or a ketone, carboxylic acid, and then a peroxide.

Redox reactions in biology

Much biological energy is stored and released by means of redox reactions. Photosynthesis involves the reduction of carbon dioxide into sugars and the oxidation of water into molecular oxygen. The reverse reaction, respiration, oxidizes sugars to produce carbon dioxide and water. As intermediate steps, the reduced carbon compounds are used to reduce nicotinamide adenine dinucleotide (NAD⁺), which then contributes to the creation of a proton gradient, which drives the synthesis of adenosine triphosphate (ATP) and is maintained by the reduction of oxygen. In animal cells, mitochondria perform similar functions. See Membrane potential article. The term redox state is often used to describe the balance of NAD⁺/NADH and NADP⁺/NADPH in a biological system such as a cell or organ. The redox state is reflected in the balance of several sets of metabolites (e.g., lactate and pyruvate, beta-hydroxybutyrate and acetoacetate) whose interconversion is dependent on these ratios. An abnormal redox state can develop in a variety of deleterious situations, such as hypoxia, shock, and sepsis.

External links

- [http://www.shodor.org/UNChem/advanced/redox/redoxcalc.html Redox Reactions Calculator]
- [http://www.chemguide.co.uk/inorganic/redox/definitions.html#top Redox reactions at Chemguide] Category:Electrochemistry ko:산화·환원 반응 ja:酸化還元反応

Heartburn

:This article is about the medical condition. For the film see Heartburn (film). Heartburn or pyrosis is a painful or burning sensation in the esophagus, just below the breastbone caused by regurgitation of gastric acid.[http://www.nlm.nih.gov/cgi/mesh/2005/MB_cgi?mode&term=heartburn] The pain often rises in the chest and may radiate to the neck or throat. Heartburn is also identified as one of the causes of asthma and chronic cough.

Pathophysiology

The sensation of heartburn is caused by exposure of the lower esophagus to the acidic contents of the stomach. Normally, the lower esophageal sphincter (LES) separating the stomach from the esophagus is supposed to contract to prevent this situation. If the sphincter relaxes for any reason (as normally occurs during swallowing), stomach contents, mixed with gastric acid, can return into the esophagus. This return is also known as reflux, and may progress to gastroesophageal reflux disease (GERD) if it occurs frequently. Peristalsis, the rhythmic wave of muscular contraction in the esophagus, normally moves food down and past the LES and is responsible for ultimately clearing refluxed stomach contents. In addition, gastric acid can be neutralized by buffers present in saliva.

Causes

Foods that may cause Heartburn:
- Alcohol
- Coffee, tea, cola, and other caffeinated and carbonated beverages
- Chocolate
- Citrus fruits and juices
- Tomatoes and tomato sauces (such as pizza and pasta sauce)
- Spicy foods and fatty foods (including full-fat dairy products)
- Peppermint and spearmint
- Dry fruits such as peanuts

Diagnosis

Physicians typically diagnose gastroesophageal reflux disease (GERD) based on symptoms alone. When the clinical presentation is unclear, other tests can be performed to confirm the diagnosis or exclude other disorders. Confirmatory tests include: Ambulatory pH Monitoring A probe can be placed via the nose into the esophagus to record the level of acidity in the lower esophagus. Because some degree of variation in acidity is normal, and small reflux events are relatively common, such monitors must be left in place for at least a 24-hour period to confirm the diagnosis of GERD. The test is particularly useful when the patient's symptoms can be correlated to episodes of increased esophageal acidity. Upper Gastrointestinal (GI) Series A series of x-rays of the upper digestive system are taken after drinking a barium solution. These can demonstrate reflux of barium into the esophagus, which suggests the possibility of gastroesophageal reflux disease. More accurately, fluoroscopy can be used to document reflux in real-time. Manometry In this test, a pressure sensor (manometer) is passed through the mouth into the esophagus and measures the pressure of the lower esophageal sphincter directly. Endoscopy The esophageal mucosa can be visualized directly by passing a thin, lighted tube with a tiny camera attached (an endoscope) through the mouth to examine the esophagus and stomach. In this way, evidence of esophageal inflammation can be detected, and biopsies taken if necessary. Biopsy A small sample of tissue from the esophagus is removed. It is then studied to check for inflammation, cancer, or other problems.

Treatment

Prevention

If heartburn occurs when lying down, raising the head with pillows or sitting up frequently provides relief – although care must be taken to avoid placing continuous strain on the neck. Avoidance of certain foods shortly before bedtime is frequently advised to avoid future attacks.

Medications

Antacids, H2-receptor antagonists and proton pump inhibitors are used (in that order) to treat heartburn.

Antacids

Daily treatment with Antacids is effective for 25-30% of people with GERD. Acid-blocking medications are the most effective for mild forms of the condition.

H2-receptor antagonists

With the advent of proton-pump inhibitors, H2-receptor antagonists are not widely used.

Proton-pump Inhibitors

Proton pump inhibitor is a class of medications which can be effective for people who do not respond to antacid or acid blockers. Proton-pump inhibitors directly block acid production in the stomach cells and provide more effective relief than less powerful medications.

Restricting Diet

Restricting diet is very important, since 90-95% of sufferers of heartburn or esophageal disorder can link their symptoms to specific foods. Therefore, it is important that heartburn sufferers manage their diets as a way to treat their heartburn. Sufferers should choose the kinds of foods and drinks which have little risk of causing acid reflux, while some kinds of foods or drinks should be avoided as they are major heartburn triggers.

External link

- [http://www.mediprimer.com/Gastroenterology/heartburn/ Heartburn and Gastroesophageal Reflux Disease Primer] Category:General practice Category:Gastroenterology

Intestinal ulcer

Signs and symptoms

Diagnosis

Pathophysiology

Epidemiology

Treatment

See also

External links

Ulcer

Description

Skin ulcers

Merck Manual classification

National Pressure Ulcer Advisory Panel (NPUAP)

Wagner's classification

Other locations

Pathology of ulceration

Duodenum

Helicobacter pylori

History

Structure of the bacterium

Infection and diagnosis

Treatment

Gastric cancer connection

Acid reflux and esophageal cancer

Genome studies of different strains

See also

References

External links

Aspirin

History of discovery

Synthesis of aspirin

History of the name "Aspirin"

How it works

Indications

Contraindications and Warnings

Common side effects

Overdose

External links

References

NSAID

Mode of action

Examples of NSAIDs

salicylates

arylalkanoic acids

2-arylpropionic acids (profens)

N-arylanthranilic acids (fenamic acids)

oxicams

coxibs

sulphonanilides

Uses of NSAIDs

Adverse effects

Gastrointestinal ADRs

Renal ADRs

Photosensitivity

Other ADRs

Newer NSAID'S: Selective COX inhibitors

COX-2 inhibitors

Controversies with COX-2 inhibitors

COX-3 inhibitors

References

Abdominal pain

Introduction

Approaches

Types and mechanisms

Selected causes

See also

Hematemesis

Causes

Management

See also

Oxidation

Oxidizing and reducing agents

Former meaning (oxygen/hydrogen)

Examples of redox reactions

Other examples

Redox reactions in biology

See also

External links

Heartburn

Pathophysiology