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Ceeoxx

Ceeoxx

Rofecoxib is a nonsteroidal anti-inflammatory drug (NSAID) that was used in the treatment of osteoarthritis, acute pain conditions, and dysmenorrhoea. Formerly marketed by Merck & Co. under the trade names Vioxx, Ceoxx and Ceeoxx, it was voluntarily withdrawn from the market in 2004 because of concerns about increased risk of heart attack and stroke. Rofecoxib was one of the most widely used drugs ever to be withdrawn from the market. Worldwide, over two million people were prescribed Vioxx at the time. In the year before withdrawal, Merck had a sales revenue of US$2.5 billion from Vioxx. Rofecoxib was available on prescription as tablets and as an oral suspension.

COX-2 selective inhibitor

Rofecoxib belongs to the group of NSAIDs known as COX-2 selective inhibitors or coxibs (CycloOXygenase-2 InhiBitors). Being COX-2 selective means that these drugs act specifically on one form of the cyclooxygenase (COX) enzyme, namely the COX-2, whereas previous NSAIDs inhibited both COX-1 and COX-2. This specificity allows rofecoxib and other COX-2 inhibitors to reduce inflammation and pain while minimizing undesired gastrointestinal adverse effects - peptic ulcers - that are common with non-selective NSAIDs such as aspirin, naproxen, and ibuprofen. Interestingly, at the time of its withdrawal, rofecoxib was the only coxib with clinical evidence of its superior gastrointestinal adverse effect profile over conventional NSAIDs. This was largely based on the VIGOR (Vioxx GI Outcomes Research) study, which compared the efficacy and adverse effect profiles of rofecoxib and naproxen. (Bombardier et al., 2000).

Adverse drug reactions

Aside from the reduced incidence of gastric ulceration, rofecoxib exhibits a similar adverse effect profile to other NSAIDs. Main article: Non-steroidal anti-inflammatory drug

Withdrawal from the market

VIGOR study

The VIGOR study, published in 2000, had indicated a significant 4-fold increased risk of acute myocardial infarction (heart attack) in rofecoxib patients when compared with naproxen patients (0.4% vs 0.1%, RR 0.25) over the 12 month span of the study. There was no significant difference in the mortality from cardiovascular events between the two groups. Nor was there any significant difference in the rate of myocardial infarction between the rofecoxib and naproxen treatment groups in patients without high cardiovascular risk. The difference in overall risk was accounted for by the patients meeting the criteria for low-dose aspirin prophylaxis of secondary cardiovascular events (previous myocardial infarction, angina, cerebrovascular accident, transient ischemic attack, or coronary bypass), but who were excluded from taking low-dose aspirin in the initial design study. Once this risk was noted, Merck notified investigators in other rofecoxib studies to modify allow high-risk patients to take low-dose aspirin. (Bombardier et al., 2000) Merck's scientists interpreted the finding as a protective effect of naproxen in reducing the risk of MI in high cardiovascular risk patients by 80 percent (which some commentators have noted would make naproxen three times as effective as aspirin). The results of the VIGOR study were submitted to the United States Food and Drug Administration (FDA) in February 2001, which led to the introduction, in April 2002, of warnings on Vioxx labelling concerning the increased risk of cardiovascular events (heart attack and stroke). In sum, the VIGOR study suggested that medium-term use of rofecoxib resulted in nearly four-times the risk of suffering a heart attack or stroke in patients already at high risk of adverse cardiovascuar events compared to patients receiving a placebo. There was no difference in risk for patients with normal cardiovascular risk.

APPROVe study

In 2001, Merck commenced the APPROVe (Adenomatous Polyp PRevention On Vioxx) study, a three year trial with the primary aim of evaluating the efficacy of rofecoxib for the prophylaxis of colorectal polyps. Celecoxib had already been approved for this indication, and it was hoped to add this to the indications for rofecoxib as well. An additional aim of the study was to further evaluate the cardiovascular safety of rofecoxib. The APPROVe study was terminated early when the preliminary data from the study showed an increased relative risk of adverse thrombotic cardiovascular events (including heart attack and stroke), beginning after 18 months of rofecoxib therapy. In patients taking rofecoxib, versus placebo, the relative risk of these events was 1.92 (rofecoxib 1.50 events vs placebo 0.78 events per 100 patient years). The results from the first 18 months of the APPROVe study did not show an increased relative risk of adverse cardiovascular events. (Bresalier et al., 2005) Previous Phase III clinical trials had also not shown this trend. (Swan, 2004) In sum, the APPROVe study suggested that long-term use of rofecoxib resulted in nearly twice the risk of suffering a heart attack or stroke compared to patients receiving a placebo.

Withdrawal

Merck publicly announced its voluntary withdrawal of the drug from the market worldwide on September 30, 2004. In addition to its own studies, on September 23, 2004 Merck apparently received information about new research by the FDA that supported previous findings of increased risk of heart attack among rofecoxib users (Grassley, 2004). FDA analysts estimated that Vioxx caused between 88,000 and 139,000 heart attacks, 30 to 40 percent of which were probably fatal, in the five years the drug was on the market. On November 5 the medical journal The Lancet published a meta-analysis of the available studies on the safety of rofecoxib (Jüni et al., 2004). The authors concluded that, owing to the known cardiovascular risk, rofecoxib should have been withdrawn several years earlier. The Lancet published an editorial which [http://thelancet.com/journal/vol364/iss9446/full/llan.364.9446.early_online_publication.31178.1 condemned both Merck and the FDA] for the continued availability of rofecoxib from 2000 until the recall. Merck responded by issuing a rebuttal of the Jüni et al. meta-analysis (Merck & Co., 2004). In 2005, advisory panels in both the U.S. and Canada encouraged the return of Vioxx to the market, stating that Vioxx's benefits outweighed the risks to patients. The advisory panel 17-15 ruling allowed the drug to return to the market despite being found to increase heart risk. It is believed, though not proven, that, rofecoxib, a weak acid, may ionize under physiological conditions (Reddy & Corey, 2005)[http://dx.doi.org/10.1016/j.tetlet.2004.12.055] (Rouhi, 2005)[http://pubs.acs.org/cen/news/83/i02/8302vioxx.html]. The ionized product may then react with molecular oxygen producing a potentially toxic maleic anhydride derivative.

Litigation

There have been over 7,000 cases filed against Merck over adverse cardiovascular events associated with rofecoxib. Merck & Co. lost the first wrongful death lawsuit on August 19, 2005, when a jury in Texas found the company liable for the death of Robert Ernst, a 59-year-old man who allegedlly died of a Vioxx-induced heart attack that led to fatal arrhythmia. Merck claimed the death was due to clogged arteries rather and Vioxx was not responsible. The jury awarded Carol, widow of Robert Ernst, USD$253.4 million in damages. However, this reward will likely be cut to no more than USD$26.1 million due to the cap on punitive damages under Texan law. [http://www.msnbc.msn.com/id/9006921/] Merck is waiting for the trial judge to accept the verdict and expects to file an appeal immediately afterwards. On November 3, 2005, Merck won the second case in Atlantic City, New Jersey in a personal injury case, Humeston V. Merck. The plaintiff suffered a mild heart attack and claimed that VIOXX was the cause. The plaintiff said he took the drug for two months. Merck said there is no medical or scientific evidence that VIOXX was the cause of Humeston's injury and that there is no medical or scientific evidece linking VIOXX to cardiac events at such short durations of use. The jury ruled that Merck had adequately warned doctors and patients of the drug's risk, the best possible verdict for Merck. [http://www.npr.org/templates/story/story.php?storyId=4988532] Merck currently has lost one lawsuit and won one lawsuit. A federal trial in a multi-district litigation (MDL) on VIOXX is set for Novemeber 29, 2005 in Houston, Texas. There are no other trials docketed for 2005.

Other COX-2 inhibitors

It is currently unknown whether the increased risk of adverse cardiovascular events is common to all COX-2 inhibitors. Recent studies have demonstrated the increased risk of cardiovascular events associated with the use of celecoxib, valdecoxib and parecoxib. (Solomon et al., 2005; Nussmeier et al., 2005) Newer and more specific COX-2 inhibitors, including etoricoxib (Arcoxia) and lumiracoxib (Prexige), are currently undergoing Phase III/IV clinical trials. It is likely that these trials will be extended in order to supply additional evidence of cardiovascular safety.

References

- Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, et al. (2000). Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 343 (21), 1520-8. PMID 11087881
- Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, et al. (2005). Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 352 (11), 1092-102. PMID 15713943
- Grassley CE (15 Oct 2004). [http://finance.senate.gov/press/Gpress/2004/prg101504.pdf Grassley questions Merck about communication with the FDA on Vioxx.] Press Release.
- Jüni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M (2004). [http://image.thelancet.com/extras/04art10237web.pdf Risk of cardiovascular events and rofecoxib: cumulative meta-analysis.] The Lancet (published online)
- Merck & Co., (5 Nov 2004). [http://www.merck.com/statement_2004_1105/lancet.pdf Response to Article by Juni et al. Published in The Lancet on Nov. 5.] Press Release.
- Nussmeier NA, Whelton AA, Brown MT, Langford RM, Hoeft A, Parlow JL, et al. (2005). Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 352 (11), 1081-91. PMID 15713945
- Reddy, L.R.; Corey, E.J. "Facile air oxidation of the conjugate base of rofecoxib (Vioxx™), a possible contributor to chronic human toxicity" Tet. Let., 2005, 46, 927. [http://dx.doi.org/doi:10.1016/j.tetlet.2004.12.055]
- Rouhi, A.M. "Investigating Vioxx Toxicity: Air oxidation of arthritis drug's anion forms a potentially toxic product" CN&E News, 2005, 83, 15. [http://pubs.acs.org/cen/news/83/i02/8302vioxx.html]
- Solomon SD, McMurray JJ, Pfeffer MA, Wittes J, Fowler R, Finn P, et al. (2005). Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 352 (11), 1071-80. PMID 15713944
- Swan L, Merck Sharp & Dohme (Australia) Pty Ltd. (1 October 2004). Urgent Medicine Recall VIOXX® (rofecoxib) - Merck Announces Voluntary Worldwide Withdrawal of VIOXX.

External links

- [http://www.vioxx.com/vioxx/documents/english/vioxx_press_release.pdf Merck's press release announcing the withdrawal] - September 30, 2004
- [http://www.fda.gov/cder/drug/infopage/vioxx/PHA_vioxx.htm FDA Public Health Advisory on Vioxx]
- David Michaels. [http://www.sciamdigital.com/browse.cfm?sequencenameCHAR=item2&methodnameCHAR=resource_getitembrowse&interfacenameCHAR=browse.cfm&ISSUEID_CHAR=B38CE21A-2B35-221B-67096ED4BD9F95F7&ARTICLEID_CHAR=B3AF7D6A-2B35-221B-601840861CEDAFE1&sc=I100322 Doubt is Their Product] Scientific American, June 2004, p.96-101
- [http://pubs.acs.org/cen/news/83/i02/8302vioxx.html Vioxx Toxicity] - January 17, 2005 Category:Non-steroidal anti-inflammatory drugs Category:Withdrawn drugs

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

Pain

:Pain is also the name of a musical group; for further information see Pain (band) Pain is an unpleasant sensation which may be associated with actual or potential tissue damage and which may have physical and emotional components. According to the International Association for the Study of Pain (IASP), one should distinguish between pain and nociception. The term "pain" is a subjective experience that typically accompanies nociception, but can also arise without any stimulus. It includes the emotional response. Nociception, on the other hand, is a neurophysiological term and denotes specific activity in nerve pathways. It is the transmission mechanism for physiological pain, and does not describe psychological pain. These pathways transmit the nominally "painful" signals, though they are not always perceived as painful. Although pain can be associated with tissue damage or inflammation, this is often not the case. Despite its unpleasantness, pain is a critical component of the body's defense system. It is part of a rapid warning relay instructing the motor neurons of the central nervous system to minimize detected physical harm.

Types of pain

Pain can be classified as acute or chronic.
- Acute pain is defined as short-term pain or pain with an easily identifiable cause. Acute pain is the body's warning of present damage to tissue or disease. It is often fast and sharp followed by aching pain. Acute pain is centralized in one area before becoming somewhat spread out. This type of pain responds well to medications.
- Chronic pain was originally defined as pain that has lasted 6 months or longer. It is now defined as pain that persists longer than the normal course of time associated with a particular type of injury. This constant or intermittent pain has often outlived its purpose, as it does not help the body to prevent injury. It is often more difficult to treat than acute pain. Expert care is generally necessary to treat any pain that has become chronic. An anterior cingulectomy, neurosurgury that disconnects the anterior cingulate gyrus, can be used in extreme cases to treat chronic pain. Post-surgery the patient will still feel the sensation of pain, but not the accompanying emotion. The experience of physiological pain can be grouped according to the source and related nociceptors (pain detecting neurons).
- Cutaneous pain is caused by injury to the skin or superficial tissues. Cutaneous nociceptors terminate just below the skin, and due to the high concentration of nerve endings, produce a well-defined, localised pain of short duration. Examples of injuries that produce cutaneous pain include paper cuts, minor (first degree) burns and lacerations.
- Somatic pain originates from ligaments, tendons, bones, blood vessels, and even nerves themselves. It is detected with somatic nociceptors. The scarcity of pain receptors in these areas produces a dull, poorly-localised pain of longer duration than cutaneous pain; examples include sprains and broken bones.
- Visceral pain originates from body's viscera, or organs. Visceral nociceptors are located within body organs and internal cavities. The even greater scarcity of nociceptors in these areas produces pain that is usually more aching and of a longer duration than somatic pain. Visceral pain is extremely difficult to localise, and several injuries to visceral tissue exhibit "referred" pain, where the sensation is localised to an area completely unrelated to the site of injury. Myocardial ischaemia (the loss of blood flow to a part of the heart muscle tissue) is possibly the best known example of referred pain; the sensation can occur in the upper chest as a restricted feeling, or as an ache in the left shoulder, arm or even hand. Referred pain can be explained by the findings that pain receptors in the viscera also excite spinal cord neurons that are excited by cutaneous tissue. Since the brain normally associates firing of these spinal cord neurons with stimulation of somatic tissues in skin or muscle, pain signals arising from the viscera are interpreted by the brain as originating from the skin. The theory that visceral and somatic pain receptors converge and form synapses on the same spinal cord pain-transmitting neurons is called "Ruch's Hypothesis".
- Phantom limb pain is the sensation of pain from a limb that has been lost or from which a person or no longer receives physical signals. It is an experience almost universally reported by amputees and quadriplegics.
- Neuropathic pain, or "neuralgia", can occur as a result of injury or disease to the nerve tissue itself. This can disrupt the ability of the sensory nerves to transmit correct information to the thalamus, and hence the brain interprets painful stimuli even though there is no obvious or known physiologic cause for the pain.

Physiology

Pain receptors

All pain receptors are free nerve endings. There are mechanical, thermal and chemical pain receptors. They are found in skin and on internal surfaces such as periosteum and joint surfaces. Deep internal surfaces are only weakly supplied with pain receptors and will propagate sensations of chronic, aching pain if tissue damage in these areas is experienced. Pain receptors do not adapt to stimulus. In some conditions, excitation of pain fibres becomes greater as the pain stimulus continues, leading to a condition called hyperalgesia. Nociceptors are the free nerve endings of neurons that have their cell bodies outside the spinal column in the dorsal root ganglion and are named based upon their appearance at their sensory ends. These sensory endings look like the branches of small bushes. Two main types of nociceptor, Aδ and C fibres, mediate fast and slow pain respectively. Thinly myelinated type Aδ fibres, which transmit signals at rates of between 6 to 30 metres per second mediate fast pain. This type of pain is felt within a tenth of a second of application of the pain stimulus. It can be described as sharp, acute, pricking pain and includes mechanical and thermal pain. Slow pain, mediated by slower, unmyelinated ("bare") type C pain fibres that send signals at rates of between 0.5 to 2 metres per second, is an aching, throbbing, burning pain. Chemical pain is an example of slow pain.

Transmission of pain signals in the central nervous system

The perception of pain occurs when the nociceptors are stimulated and transmit signals through sensory neurons in the spinal cord. These neurons release glutamate, a major exicitory neurotransmitter that relays signals from one neuron to another. The signals are sent to the thalamus, in which pain perception occurs. From the thalumus, the signal travels to the somatosensory cortex in the cerebrum, at which point the individual becomes fully aware of the pain. There are 2 pathways for transmission of pain in the CNS. These are the neospinothalamic tract (for fast pain) and the paleospinothalamic tract (for slow pain).
- Fast pain travels via type Aδ fibres to terminate on lamina I (lamina marginalis) of the dorsal horn. Second order neurons of the neospinothalamic tract then take off and give rise to long fibres which cross the midline through the anterior commisure and pass upwards in the contralateral anterolateral columns. These fibres then terminate on the Ventrobasal Complex (VBC) of the thalamus. From here, third order neurons communicate with the somatosensory cortex. Fast pain can be localised easily if Aδ fibres are stimulated together with tactile receptors.
- Slow pain is transmitted via slower type C fibres to laminae II and III of the dorsa horns, together known as the substantia gelatinosa. Second order neurons take off and terminate in lamina V, also in the dorsal horn. Third order neurons then join fibres from the fast pathway, crossing to the opposite side via the anterior commisure, and travelling upwards through the anterolateral pathway. These neurons terminate widely in the brain stem, with one tenth of fibres stopping in the thalamus, and the rest stopping in the medulla, pons and mesencephalon. Slow pain is poorly localized.

Analgesia

The gate control theory of pain, proposed by Patrick Wall and Ron Melzack, postulates that pain is "gated" by non-painful stimuli such as vibration. Thus, rubbing a bumped knee seems to relieve pain by preventing its transmission to the brain. Pain is also "gated" by signals that descend from the brain to the spinal cord to suppress (and in other cases enhance) incoming pain information. The analgesia system is mediated by 3 major components : the periaquaductal grey matter (in the midbrain), the nucleus raphe magnus (in the medulla), and the pain inhibitory neurons within the dorsal horns of the spinal cord, which act to inhibit pain-transmitting neurons also located in the spinal dorsal horn. The body has several different types of opioid receptors that are activated in response to the binding of the body's endogenous endorphins. These receptors, which exist in a variety of areas in the body, inhibit firing of neurons that would otherwise be stimulated to do so by nociceptors.

Survival benefit

Despite its unpleasantness, pain is an important part of the existence of humans and other animals; in fact, it is vital to survival. Pain encourages an organism to disengage from the noxious stimulus associated wtih the pain. Preliminary pain can serve to indicate that an injury is imminent, such as the ache from a soon-to-be-broken bone. Pain may also promote the healing process, since most organisms will protect an injured region in order to avoid further pain. People born with congenital insensitivity to pain usually have short life spans, and suffer numerous ailments such as broken bones, bed sores, and chronic infection. The study of pain has in recent years diverged into many different fields from pharmacology to psychology and neurobiology. It was even proposed that fruit flies may be used as an animal model for pharmacological pain research [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15763072&query_hl=21]. Pain is also of interest in the search for the neural correlates of consciousness, as pain has many subjective psychological aspects besides the physiological nociception. Interestingly, the brain itself is devoid of nociceptive tissue, and hence cannot experience pain. Thus, a headache is not due to stimulation of pain fibers in the brain itself. Rather, the membrane surrounding the brain and spinal cord, called the dura mater, is innervated with pain receptors, and stimulation of these dural nociceptors (pain receptors) is thought to be involved to some extent in producing headache pain. Some evolutionary biologists have speculated that this lack of nociceptive tissue in the brain might be due to the fact that any injury of sufficient magnitude to cause pain in the brain has a sufficiently high probability of being fatal that development of nociceptive tissue therein would have little to no survival benefit. Since pain is defined as a signal of present or impending tissue damage effected by a harmful stimulus, the ability to experience pain or irritation is observable in most multicellular organisms. Even some plants have the ability to retract from a noxious stimulus. Whether this sensation of pain is equivalent to the human experience is debatable. Chronic pain, in which the pain becomes pathological rather that beneficial, is an exception to the idea that pain is helpful to survival.

Children and pain

Children have been proven to be markedly more sensitive to pain, but this fact is commonly dismissed as a fear reaction or a lack of coping abilities. Research has been carried out on how children can cope with pain due to increased sensitivity and it has been established that strategies that remove pain can help prevent long-term increases in sensitivity as the nervous system is still developing.

Pain and alternative medicine

A recent [http://nccam.nih.gov/news/2004/052704.htm survey] by NCCAM found pain was the most common reason that people use complementary and alternative medicine (CAM). Among American adults who used CAM in 2002, 16.8% used CAM to treat back pain; 6.6% for neck pain; 4.9% for arthritis; 4.9% for joint pain; 3.1% for headache; and 2.4% used CAM to treat recurring pain. (Some survey respondents may have used CAM to treat more than one of these pain conditions.) One such alternative, traditional Chinese medicine, views pain as a qi "blockage" equivalent to electrical resistance, or as "stagnation of blood" – theorized as dehydration inhibiting metabolism. Traditional Chinese treatments such as acupuncture are more effective for nontraumatic pain than traumatic pain.

External links

- [http://www.iasp-pain.org/ International Association for the Study of Pain] - scientific multidisciplinany body
- [http://www.pain.remedica.com International Journal of Pain Medicine and Palliative Care]
- [http://www.lower-back-pain-answers.com Lower Back Pain Answers]
- [http://www.thenakedscientists.com/html/columnists/barrygibbcolumn3.htm Sea Snails (Conus) harbour powerful new painkillers] - the ACV1 snail polypeptide appears to be a potential analgesic
- [http://www.newscientist.com/news/news.jsp?id=ns99993673 Fish capable of experiencing pain] (rainbow trout may show pain responses, contrary to popular belief) - New Scientist 2003
- [http://www.thenakedscientists.com/html/columnists/petermcnaughtoncolumn1.htm Developments in the neuroscience of pain]
- [http://www.childsdoc.org/spring2002/chronicpain.asp Children and pain treatment] Category:Nociception simple:Pain

Dysmenorrhea

Dysmenorrhea (or dysmenorrhoea), cramps or painful menstruation, involves menstrual periods that are accompanied by either sharp, intermittent pain or dull, aching pain, usually in the pelvis or lower abdomen. Painful menstruation affects approximately 40% of menstruating women, and 10% are incapacitated for up to 3 days. Painful menstruation is the leading cause of lost time from school and work among women of childbearing age. This pain may precede menstruation by several days or may accompany it, and it usually subsides as menstruation tapers off. Although some pain during menstruation is normal, excessive pain is not. Dysmenorrhea refers to menstrual pain severe enough to limit normal activities or require medication. There are two general types of dysmenorrhea:
- Primary dysmenorrhea refers to menstrual pain that occurs in otherwise healthy women. This type of pain is not related to any specific problems with the uterus or other pelvic organs.
- Secondary dysmenorrhea is menstrual pain that is attributed to some underlying disease process or structural abnormality either within or outside the uterus (for example, pelvic inflammatory disease, fibroids, endometriosis, adhesions, adenomyosis, or uterine displacement). Endometriosis is the most common cause of dysmenorrhea associated with a disease process and is frequently misdiagnosed. Activity of the hormone prostaglandin is thought to be a factor in primary dysmenorrhea. Prostaglandin levels have been found to be much higher in women with severe menstrual pain than in women who experience mild or no menstrual pain. The presence of an IUD (intrauterine device) for contraception may be a potential cause of menstrual pain, although they usually lead to pelvic pain only around the time of insertion. Some women also find that use of tampons exacerbates menstrual cramps and pain. Psychological distress, often accompanied by physical pain and bloating, is commonly known as premenstrual syndrome (PMS). Symptoms include stress, anxiety, depression, irritability, mood swings, and crying jags. If these symptoms are severe enough to interfere with work or relationships, the condition is known as premenstrual dysphoric disorder (PMDD), and medications such as antidepressants may be helpful for treatment. The incidence of menstrual pain is greatest in women in their late teens and 20s, then declines with age. Some women experience increased menstrual pain in their late 30s and 40s as their endocrine systems prepare for menopause by decreasing hormone levels and thus fertility. It does not appear to be affected by childbearing. An estimated 10 percent to 15 percent of women experience monthly menstrual pain severe enough to prevent normal daily function at school, work, or home. The majority of women will suffer this degree of disability at least once during their reproductive years. Increased risk is associated with younger age, and past medical history of any of the conditions associated with secondary dysmenorrhea.

External link

- [http://www.nlm.nih.gov/medlineplus/ency/article/003150.htm NIH] Category:Gynecology

Merck & Co.

Merck & Co., Inc. or Merck Sharp and Dohme (as it is known outside the USA and Canada) is a US pharmaceutical company. It was originally the US subsidiary of the German company, Merck KGaA. In common with many other German assets in the United States, Merck & Co. was confiscated in 1917 during First World War and set up as an independent company. It is now one of the top 5 largest pharmaceutical companies in the world both by capital and revenue.

History

Merck & Co. traces its origins to Friedrich Jacob Merck (1668) and Emanuel Merck (1816) of Darmstadt, Hesse. Emanuel and his successors gradually built up a chemical-pharmaceutical factory that produced — in addition to raw materials for pharmaceutical preparations — a multitude of other chemicals. In 1891, George Merck established his roots in the United States and set up Merck & Co. in New York, USA. Merck & Co. was confiscated in 1917 during First World War and set up as an independent company in the United States. Today, the US company has about 70,000 employees in 120 countries and 31 factories worldwide. It is one of the top 5 pharmaceutical companies worldwide, much larger than its German ancestor, which currently employees around 28,600 people in 54 countries. In 2005, the CEO, Raymond Gilmartin, retired at the age of 64 following the Vioxx scandal. Former president of manufacturing Richard Clark was named CEO of the company. On November 28, 2005, Merck announced it will cut 7,000 jobs (11 percent of its work force) and close or sell five manufacturing plants in the first phase of a restructuring meant to save up to US$4 billion by the end of the decade. [http://news.yahoo.com/s/ap/20051128/ap_on_bi_ge/merck_cuts;_ylt=AvwoXkky6QPoBgjvbKQIpu0DW7oF;_ylu=X3oDMTBiMW04NW9mBHNlYwMlJVRPUCUl]

Corporate governance

Current members of the board of directors of Merck & Co. are: Lawrence Bossidy, William Bowen, Richard Clark, Johnnetta Cole, William Harrison, William Kelley, Rochelle Lazarus, Thomas Shenk, Anne Tatlock, Samuel Thier, Wendell Weeks, and Peter Wendell.

Mission

Merck & Co. or MSD describes itself as a “a global research-driven pharmaceutical company. Merck discovers, develops, manufactures and markets a broad range of innovative products to improve human and animal health, directly and through its joint ventures.” Its mission is “to provide society with superior products and services by developing innovations and solutions that improve the quality of life and satisfy customer needs, and to provide employees with meaningful work and advancement opportunities, and investors with a superior rate of return. Merck also states that it prides itself on its commitment to diversity and its social conscience. The Merck Company Foundation has distributed over $160 million to educational and non-profit organizations since it was founded in 1957. Merck has published the Merck Manual of Medical Information since 1899, which has been used by doctors and families alike. Merck is also famous for publishing their Merck Index, an authoritative collection of information about chemicals.

Products

- Vytorin (ezetimibe;simvastatin) a first-of-its kind cholesterol lowering drug that reduces cholesterol levels more than any existing product.
- Zocor (simvastatin) a powerful cholesterol lowering statin; one component of Vytorin.
- Propecia (finasteride) the most effective hair-loss medication available.
- Emend (aprepitant)
- Fosamax (alendronate) osteroporosis medication.
- Singulair (montelukast) a powerful anti-asthma medication.
- Crixivan (indavinir)
- Maxalt (rizatriptan)
- Zetia (ezetimibe)

Vioxx

In 1999, the United States Food and Drug Administration ("FDA") approved Vioxx (known generically as rofecoxib,) a Merck product that became widely used for treating arthritis. Vioxx was stronger than existing medications, while easier on the stomach than established anti-inflammatory drugs such as Naproxen. Vioxx became one of the most prescribed drugs in history. Thereafter, studies by Merck and by others found an increased risk of heart attack associated with Vioxx use when compared with Naproxen. There was no indication of this risk in the original placebo-controlled safety trials, and that it was possible that the effect was more related to Naproxen decreasing the risk of heart attacks than one of Vioxx increasing the risk. Nontheless, in 2002 Merck adjusted the labeling of Vioxx to reflect possible cardiovascular risks. On September 23, 2004, Merck received information about results from a clinical trial it was conducting that included findings of increased risk of heart attacks among Vioxx users who had been using the medication for over eighteen months[http://finance.senate.gov/press/Gpress/2004/prg101504.pdf] On September 28. Merck notified the FDA that it was withdrawing Vioxx from the market, and it publicly announced the withdrawal on September 30. The FDA has since recommended that Vioxx be put back on the market, but with a more prominent warning regarding cardiovascular risks on its label. On November 5 the medical journal The Lancet published the results of its analysis of the available studies. It concluded that “the unacceptable cardiovascular risks of Vioxx (rofecoxib) were evident as early as 2000...” [http://thelancet.com/journal/vol364/iss9446/full/llan.364.9446.early_online_publication.31178.1] The Lancet condemned Merck for having kept the drug on the market, despite its knowledge of the risks, and also criticized the FDA for its failure of regulatory oversight. On August 19, 2005, Merck was found liable in the death of a man who took Vioxx. The plaintiff was awarded $253.4 million in damages, which were subsequently reduced to $20 million, the maximum allowed by Texas statute. In a followup case in New Jersey, Merck was found not liable. A third case is pending in Lousiana. Merck's stock fell $2.35 to $28.06/share (7.73%) in the minutes after the verdict was announced and three months later 7,000 Merck employees were laid off. At the time of the verdict, there were over 4,000 other lawsuits pending against Merck regarding Vioxx, and several thousand against Pfizer, the maker of competing anti-inflammatory drug Bextra, which, in some cases, causes an adverse skin reaction which burns patients "from the inside out". Merck is currently trying to get a successor drug to Vioxx, called Arcoxia (known generically as etoricoxib) approved in the USA. The FDA has said it will approve Arcoxia if it proves to be safer than Vioxx. Two other drug companies, Pfizer and Novartis, are trying to get alternatives to Vioxx approved. Their drugs are called Dynastat (parecoxib) and Prexige (lumiracoxib), respectively.

Diversity

Merck & Co. was named one of the 100 Best Companies for Working Mothers in 2004 by Working Mothers magazine.

External links

- [http://www.merck.com/about/ About Merck & Co.]
- [http://biz.yahoo.com/ic/10/10986.html Yahoo! - Merck & Co., Inc. Company Profile]
- [http://pb.merck.de/servlet/PB/menu/1012970/ About Merck KGaA]
- [http://www.msd.com.hk/about_us/e_history_of_merck.html History of Merck]
- [http://biz.yahoo.com/ap/050819/vioxx_trial.html?.v=14 Information about first lawsuit against Merck from Yahoo! Finance]
- [http://news.bbc.co.uk/2/hi/business/4522032.stm Vioxx law suit ends as mistrial, from BBC.] Category:Companies traded on NASDAQ Category:Companies traded on the New York Stock Exchange Category:Companies based in New Jersey Category:Fortune 500 companies Category:Biotechnology companies Category:Multinational corporations Category:Pharmaceutical companies of the United States ja:メルク

Myocardial infarction

and then suddenly ruptures, totally occluding the artery and preventing blood flow downstream. (Please note: the details of artery disease and occlusion, as illustrated in the image above, are misleading; see the links.)]] Acute myocardial infarction (AMI or MI), commonly known as a heart attack, is a serious, sudden heart condition usually characterized by varying degrees of chest pain or discomfort, weakness, sweating, nausea, vomiting, and arrhythmias, sometimes causing loss of consciousness. It occurs when a part of the heart muscle is injured, and this part may die because of sudden total interruption of blood flow to the area. It is often a life-threatening medical emergency which demands both immediate attention and activation of the emergency medical services. Diagnosis is by the combination of medical history, ECG findings and blood tests for cardiac enzymes. The most important treatment in myocardial infarction is restoring the blood flow to the heart, by thrombolysis (enzymatically dissolving the clot in the artery) and/or angioplasty (using a balloon to push the artery open). Close monitoring on a coronary care unit is mandatory to observe for various complications. There is emphasis on secondary prevention, the elimination of risk factors that could lead to further heart attacks. The medical term myocardial infarction derives from myocardium (the heart muscle) and infarction (tissue death), in this case caused by an obstruction of blood flow. The phrase "heart attack" is occasionally used to refer to heart problems other than a myocardial infarction, such as unstable angina pectoris.

Symptoms

Acute myocardial infarction is usually characterized by varying degrees of chest pain or discomfort, weakness, sweating, nausea, vomiting, and arrhythmias, sometimes causing loss of consciousness. Chest pain is the most common symptom of acute myocardial infarction and it is often described as tightness, pressure, or squeezing. Pain may radiate to the jaw, neck, arms, back, and epigastrium, most often to the left arm or neck. Chest pain is more likely caused by myocardial infarction when it lasts for more than 30 minutes. The patient may complain of shortness of breath (dyspnoea) especially if the decrease in myocardial contractility due to the infarct is sufficient to cause left ventricular failure with pulmonary congestion or even pulmonary oedema. Approximately one quarter of all myocardial infarction are silent, without chest pain or other symptoms. This happens more often in elderly patients and patients with diabetes mellitus. They may complain though of atypical symptoms like fatigue, syncope, or weakness. Approximately half of all MI patients have experienced warning symptoms like angina pectoris prior to the infarct.

Diagnosis

Myocardial infarctions vary greatly in severity. Classical cases of myocardial infarction are often identified by ambulance staff, emergency room doctors and cardiac specialist nurse practitioners quickly. Yet many myocardial infarctions, tending to be smaller, are not recognized by victims, never receive medical attention and result in either sudden death or progressive heart weakness. For a more complete diagnosis, the medical history, combined with electrocardiogram results and blood tests for heart muscle cell damage, are vital. Myocardial perfusion tests (see stress tests) and echocardiograms can also be helpful. stress tests

Electrocardiogram

Electrocardiogram (ECG/EKG) findings suggestive of MI are elevations of the ST segment and changes in the T wave. After a myocardial infarction, changes can often be seen on the ECG called Q waves, representing scarred heart tissue. The ST segment elevation distinguishes between:
- STEMI ("ST-Elevation Myocardial Infarction")
- NSTEMI ("Non-ST-Elevation Myocardial Infarction") -- diagnosed when cardiac enzymes are elevated. The leads with abnormalities on the EKG can [http://medstat.med.utah.edu/kw/ecg/ecg_outline/Lesson9/ help] [http://www.madsci.com/manu/ekg_mi.htm identify] the [http://www.usfca.edu/fac-staff/ritter/ekg.htm location]:
- anterior wall (I21.0): V1-V4
- inferior wall (I21.1): II, III, F
- lateral wall (I21.2): I, F, V5, V6
- posterior wall (I21.2): V1, V2

Myocardial markers

Cardiac enzymes are proteins from cardiac tissue found in the blood. Until the 1980s, the enzymes SGOT and LDH were used to assess cardiac injury. Then it was found that disproportional elevation of the MB subtype of the enzyme creatine phosphokinase (CPK) was very specific for myocardial injury. Current guidelines are generally in favor of troponin isoenzymes I or T, which are thought to rise before permanent injury develops. A positive troponin in the setting of chest pain may accurately predict a high likelihood of a myocardial infarction in the near future. The diagnosis of myocardial infarction used to require that all three components (history, ECG, and enzymes) were positive for MI. Currently the cardiac enzymes have become so reliable that enzyme elevations alone are considered reliable measures of cardiac injury, with ECG serving to determine where in the heart the damage has occurred, and history serving to screen patients for further enzyme and ECG testing. In difficult cases or in situations where intervention to restore blood flow is appropriate, an angiogram can be done (see below for an image). Using a catheter inserted into an artery (usually the femoral artery), obstructed or narrowed vessels can be identified, and angioplasty applied as a therapeutic measure (see below). Angiography requires extensive skill, especially in emergency settings, and may not always be available out of hours. It is commonly performed by cardiologists. There is a very small risk of plaque and vessel rupture on ballon inflation; should this occur, then emergency open-chest cardiac surgery may be required. Patients commonly experience bruising at the catheter insertion point in the groin and occasionally a hematoma. Dissection (tearing) of the blood vessel is rare but usually managed with a local thrombotic injection.

Pathophysiology

Ischemia and infarction

thromboticThe underlying mechanism of a heart attack is the destruction of heart muscle cells due to a lack of oxygen. If these cells are not supplied with sufficient oxygen by the coronary arteries to meet their metabolic demands, they die by a process called infarction. The decrease in blood supply has the following consequences: # Heart muscle which has lost blood flow long enough, e.g. 10-15 minutes, ends up dying (necrosis) and does not grow back. Thus the heart ends up permanently weaker as a pump for the remainder of the individual's life; # Injured, but still living, heart muscle conducts the electrical impulses which initiate each heart beat much more slowly. The speed can end up so slow that the spreading impulse is preserved long enough for the uninjured muscle to complete contraction; now the slowed electrical signal, still traveling within the injured area, can re-enter and trigger the healthy muscle (termed re-entry) to beat again too soon for the heart to relax long enough and receive any blood return from the veins. If this re-entry process results in sustained heart rates in the >200 to over 400 beats per minute range called ventricular tachycardia (V-Tach) or ventricular fibrillation (V-Fib), then the rapid heart rate effectively stops heart pumping. Heart output and blood pressure falls to near zero and the individual quickly dies. This is the most common mechanism of the sudden death that can result from a myocardial infarction. The cardiac defibrillator device was specifically designed for stopping these too rapid heart rates. If used properly, it stimulates the entire heart muscle to contract all at once, in synchrony; hopefully stopping continuation of the re-entry process. If used within one minute of onset of V-Tach or V-Fib, the defibrillator has a high success rate in stopping these often fatal arrhythmias allowing a functional heart rhythm to return. Histopathological examination of the heart shows that there is a circumscribed area of ischemic necrosis (coagulative necrosis). In the first 12-48 hours, myocardial fibers are still well delineated, with intense eosinophilic (pink) cytoplasm, but lose their transversal striations and the nucleus. The interstitial space may be infiltrated with red blood cells. When the healing has commenced (e.g. after 5 -10 days) the area of coagulative ischemic necrosis shows myocardial fibers with preservation of their contour, but the cytoplasm is intensely eosinophilic and transversal striations and nuclei are completely lost. The interstitium of the infarcted area is initially infiltrated with neutrophils, then with lymphocytes and macrophages, in order to phagocytose the myocyte debris. The necrotic area is surrounded and progressively invaded by granulation tissue, which will replace the infarct with a fibrous (collagenous) scar.

Atherosclerosis

The most common cause of heart attack by far is atherosclerosis, a gradual buildup of cholesterol and fibrous tissue in plaques in the arterial wall, typically over decades. However plaques can become unstable, rupture, and additionally promote a thrombus (blood clot) that occludes the artery; this can occur in minutes. When a severe enough plaque rupture occurs in the coronary vasculature, it leads to myocardial infarction (necrosis of downstream myocardium). All risk factors for atherosclerosis are also (modifiable) risk factors for ischemic heart disease: older age, smoking, hypercholesterolemia (more accurately hyperlipoproteinemia, especially high low density lipoprotein (LDL) and low high density lipoprotein (HDL), diabetes (with or without insulin resistance) and obesity. obesity The blood flow problem is nearly always a result of exposure of atheroma tissue within the wall of the artery to the blood flow inside the artery, atheroma being the primary lesion of the atherosclerotic process. The many blood stream column irregularities, visible in the single frame angiogram image to the right, reflects artery lumen changes as a result of decades of advancing atherosclerosis. Heart attacks rates are higher in association with intense exertion, be it stress or physical exertion, especially if the exertion is unusually more intense than the individual usually performs. Quantitatively, the period of intense exercise and subsequent recovery is associated with about a 6-fold higher myocardial infarction rate (compared with other more relaxed times frames) for people who are physically very fit. For those in poor physical condition, the rate differential is over 35-fold higher. One observed mechanism for this phenomenon is the increased arterial pulse pressure stretching and relaxation of arteries with each heart beat which, as has been observed with IVUS, increases mechanical "shear stress" on atheromas and the likelihood of plaque rupture. Increased spasm/contraction of coronary arteries in association with cocaine abuse can also precipitate myocardial infarction.

First aid

Immediate care

As myocardial infarction is a common medical emergency, the signs are often part of first aid courses. General management in the acute setting is:
- calling for help as soon as possible
- giving aspirin (162-325 mg), which inhibits formation of further blood clots
- giving the patient nitroglycerin under the tongue if the patient is carrying tablets or liquid spray
- being prepared to administer cardiopulmonary resuscitation (CPR) in case of arrhythmia or cardiac arrest Since the publication of data showing that the availability of automated external defibrillators (AEDs) in public places may significantly increase chances of survival, many of these have been installed in public buildings, public transport facilities and in non-ambulance emergency vehicles (e.g. police cars and fire engines). AEDs analyze the rhythm and determine whether the arrhythmia is amenable to defibrillation ("shockable").

Emergency services

Emergency services may recommend the patient to take nitroglycerin tablets or patches, in case these are available, particularly if they had prior heart attacks or angina. In an ambulance, an intravenous line is established, and the patient is transported immediately if breathing and pulse are present. Oxygen first aid is provided and the patient is calmed. Close cardiac monitoring (with an electrocardiogram) is initiated if available. If the patient has lost breathing or circulation advanced cardiac life support (including defibrillation) may be necessary and (at the paramedic level) injection of medications may be given per protocol. CPR is performed if there is no satisfactory cardiac output. About 20% of patients die before they reach the hospital; the cause of death is often ventricular fibrillation.

Wilderness first aid

In wilderness first aid, a possible heart attack justifies medical evacuation by the fastest available means, including MEDEVAC, even in the earliest or precursor stages. The patient will rapidly be incapable of further exertion and have to be carried out.

Air travel

Doctors traveling by commercial aircraft may be able to assist an MI patient by using the on-board first aid kit, which contains basic cardiac drugs used in advanced cardiac life support, and oxygen. Flight attendants are generally aware of the location of these materials. Pilots are required to divert the flight to the nearest airport.

Treatment

A heart attack, especially because of cardiac arrhythmias, is often a life-threatening medical emergency which demands both immediate attention and activation of the emergency medical services. Immediate termination of arrhythmias and transport by ambulance to a hospital where advanced cardiac life support (ACLS) is available can greatly improve both chances for survivial and recovery. The more time that passes, even 1-2 minutes, before medical attention is available/sought, the more likely the occurrence of both (a) life threatening arrhythmias/death and (b) more severe and permanent the heart damage.

First line

In the hospital, oxygen, aspirin, nitroglycerin and analgesia (usually morphine, hence the popular mnemonic MONA) are administered as soon as possible, if this has not already happened during transport.

Reperfusion

The ultimate goal of the management in the acute phase of the disease is to salvage as much myocardium as possible and restore contractile function of heart chambers. This is achieved primarily with thrombolytic drugs, such as streptokinase, urokinase, alteplase (recombinant tissue plasminogen activator, rtPA) or reteplase. Heparin alone as an anticoagulant is substandard. Although clinical trials suggest better outcomes, angioplasty as a first-line measure is probably still underused. This is largely dependent on the availability of an experienced interventional cardiologist on-site, or the availability of rapid transport to a referral centre. Emergency coronary surgery, in the form of coronary artery bypass surgery is another option, although this option is in decline since the development of primary angioplasty. The same limitations apply here: cardiothoracic surgery services are not available in many hospitals. NSTEMI (non-ST elevation MI) is initially indistinguishable from unstable angina in most cases, and is therefore managed similarly with aspirin, heparin and usually with clopidogrel.

Monitoring and follow-up

Additional objectives are to prevent life-threatening arrhythmias or conduction disturbances. This requires monitoring in a coronary care unit and protocolised administration of antiarrhythmic agents. Long-term beta-blocker medication is routinely commenced. Patients are also initiated on aspirin and/or clopidogrel (Plavix® or Iscover®); other anticoagulant drugs have not shown additional benefit. ACE inhibitors are commenced in the course of follow-up to assist in ventricular remodeling. Recent studies have shown benefit of the initiation of a statin (e.g. simvastatin 40 mg daily), even in patients without known hypercholesterolemia. Patients are discouraged from working and sexual activity for about two months, while they undergo cardiac rehabilitation training. Local authorities may place limitations on driving motorised vehicles. During a follow-up outpatient visit, or increasingly before discharge from hospital, it will be determined if the patient suffers from angina pectoris. If this is the case, treadmill testing, thallium scintigraphy or coronary angiography are often performed to identify treatable causes, as this will decrease the risk of future myocardial infarction.

History

Before the discovery of the electrocardiogram, it was impossible to objectively diagnose myocardial infarction. The term angina pectoris had already been extant for 150 years (William Heberden coined the term in 1772), but little was known about the disease mechanism. As a disease entity, myocardial infarction was described in full by Dr James Herrick in an 1912 article in JAMA. He is credited as the originator of the "thrombogenic theory", i.e. the theory that myocardial infarction is due to thrombosis in the coronary artery. Subsequently, atherosclerosis and plaque rupture were discovered as underlying mechanisms. A major breakthrough in the identification of risk factors was the 1956 British doctors study, which showed an increased risk of myocardial infarction in heavy smokers.

References

- Herrick JB. Clinical features of sudden obstruction of the coronary arteries. JAMA 1912;59:2015-2019.

External links

- [http://www.pathologyatlas.ro/Acute%20Myocardial%20Infarction.html Atlas of Pathology]
- [http://chdrisk.uni-muenster.de/risk.php?iSprache=1&iVersion=1&iSiVersion=0 Risk Score Calculator] Category:Cardiovascular diseases Category:Ischemic heart disease Category:Medical emergencies ko:심근경색 ja:心筋梗塞 ko:심근경색증

Stroke

A stroke or cerebrovascular accident (CVA) occurs when the blood supply to a part of the brain is suddenly interrupted. In brain tissue, ischemia, a reduction of blood flow, leads to an ischemic cascade that can damage or kill brain cells. Death of brain tissue can lead to loss of the function controlled by that tissue. Thus stroke is the third leading cause of death and leading cause of adult disability in the US and industrialized European nations (Jauch, 2005), and is a medical emergency. To underscore the seriousness of stroke, in recent years the term brain attack has become increasingly popular, in relation to the established term "heart attack" used for myocardial infarctions.

Types of stroke

Ischemic stroke

Stroke is classified by its cause into two main types: ischemic and hemorrhagic. In ischemic stroke, which occurs in approximately 85-90% of strokes, a blood vessel becomes occluded and the blood supply to part of the brain is totally or partially blocked. Ischemic stroke is commonly divided into thrombotic and embolic (Stroke Center, 2005). Rarer types of stroke can occur (see below)

Embolic stroke

In embolic stroke, an embolus, or a travelling particle in a blood vessel, flows with the bloodstream into progressively smaller arteries until it becomes lodged, inhibiting passage of blood. An embolus is most frequently a blood clot, but it can also be a plaque broken off from an atherosclerotic blood vessel or a number of other things including fat, air, and even cancerous cells (Perry and Miller 1961). An embolism may also be formed when the heart pumps ineffectively, allowing the blood to pool and coagulate, as occurs in certain heart arythmias such as atrial fibrillation (NINDS 1999).

Thrombotic stroke

In thrombotic stroke, the clot does not travel; it builds up and finally occludes the artery where it forms. When there is a tear in an artery wall, platelets and clotting factors in the blood are drawn to the area and aggregate there, forming a clot. They send out chemicals that can trigger a clotting cascade. Arterial clots usually form around atherosclerotic plaques (NINDS 1999). Since occlusion takes longer, onset of thrombotic strokes is slower. Blood flow can also be restricted in a condition called arterial stenosis, in which plaques build up on the artery wall, causing the vessel to become narrow and stiff (NINDS 1999).

Hemorrhagic stroke

:See full article: Hemorrhagic stroke. Hemorrhagic stroke, or intracranial hemorrhage, occurs in about 10% of strokes, when a blood vessel in the brain bursts, spilling blood into the spaces surrounding the brain cells. Hemorrhagic strokes generally carry a greater risk of death and permanent disability than ischemic strokes.

Watershed stroke

A small proportion of strokes are watershed strokes caused by hypoperfusion (usually due to hypotension) or other vascular problems including vasculitis.

Rarer types of stroke

Venous obstruction can obstruct flow so that an infarction occurs. This commonly occurs in the rare disease sinus vein thrombosis.

Causes

Ischemic stroke

Ischemic stroke is usually caused by atherosclerosis (fatty lumps in the artery wall), embolism (obstruction of blood vessels by blood clots from elsewhere in the body), or microangiopathy (small artery disease, the occlusion of small cerebral vessels). Atrial fibrillation and other arrhythmias can lead to clot formation in the heart, which can become emboli and lodge in the brain. Some forms of thrombophilia (increased coagulation tendency) have a predilection for arterial thrombosis and stroke; these include polycythemia vera and the rare paroxysmal nocturnal hemoglobinuria. Risk factors (for atherosclerosis and small vessel disease) are advanced age, hypertension (high blood pressure), diabetes mellitus, high cholesterol, and cigarette smoking. High blood pressure is the most important modifiable risk factor of stroke.

Hemorrhagic stroke

Causes of hemorrhagic stroke include hypertension, cerebral AVM, cerebral aneurysms, cerebral arteriosclerosis, head injury, congophilic angiopathy, congenital artery defects and prematurity.

Watershed stroke

As opposed to hemorrhagic stroke or embolic (or other atherogenic) stroke, watershed strokes occur in parts of the brain that lie at the boundary between zones of arterial distribution from different arteries. When there is hypotension from any cause, these watershed areas are more susceptible to damage than other areas of the brain.

Signs and symptoms

The symptoms of stroke include the following:
- sudden numbness or weakness, especially on one side of the body hemiplegia;
- reflexes can initially be decreased on the affected side, but are often more exaggerated than on the unaffected side;
- the face is normally spared (as this is served by both hemispheres), but the corner of the mouth can be affected on the same side as the limb symptoms;
- sudden confusion or aphasia (trouble speaking) or understanding speech;
- sudden trouble seeing in one eye (or rarely both);
- pupils of unequal size;
- impaired swallowing reflex;
- sudden trouble walking, dizziness, or loss of balance or coordination. Some patients lose consciousness as part of the initial presentation. This occurs more often in hemorrhagic stroke than in thrombosis. A sudden-onset severe headache can denote subarachnoid hemorrhage, which is a stroke-like clinical entity. Some other forms of stroke can feature headaches. If the symptoms resolve within an hour, or maximum 24 hours, the diagnosis is transient ischemic attack (TIA), and not a stroke. This syndrome may be a warning sign, and a proportion of patients develop strokes in the future. The chances of suffering a stroke can be reduced by using aspirin, which inhibits platelets from aggregating and forming obstructive clots.

Diagnosis

Stroke is diagnosed through several techniques: a neurological examination, blood tests, CT scans (without contrast enhancements) or MRI scans, Doppler ultrasound, and arteriography. If a stroke is confirmed on imaging, various other studies may be performed to determine whether there is a peripheral source of emboli:
- an ultrasound/doppler study of the carotid arteries (to detect carotid stenosis)
- an electrocardiogram (ECG) and echocardiogram (to identify arrhythmias and resultant clots in the heart which may spread to the brain vessels through the bloodstream)
- a Holter monitor study to identify intermittent arrhythmias
- an angiogram of the cerebral vasculature (if a bleed is thought to have originated from an aneurysm or arteriovenous malformation)

Pathophysiology

When neurons and glia receive insufficient oxygen and nutrients due to inadequate blood supply, a biochemical cascade called the ischemic cascade is unleashed. The ischemic cascade, as well as sudden bleeding from ruptured blood vessels into or around the brain, can injure and kill cells. These damaged cells can linger in a compromised state for several hours. With timely treatment, these cells can be saved. Intriguingly, when the brain cells suffer the ischemia, they begin to fill up with free zinc ions which are released from some of their proteins, especially metallothionein, which can release 7 zinc ions per molecule. This released zinc is a major player in the ensuing death of the brain cells. Drugs that buffer the zinc and reduce the level of free zinc are already being tested to reduce brain cell death after stroke.

Prevention

Prevention is an important public health concern. Identification of patients with treatable risk factors for stroke is paramount. Treatment of risk factors in patients who have already had strokes (secondary prevention) is also very important as they are at high risk of subsequent events compared with those who have never had a stroke. Medication or drug therapy is the most common method of stroke prevention. Surgery such as Carotid endarterectomy can be used to remove significant narrowing of the neck (internal) carotid artery which supplies blood to the brain and this operation has been shown to be an effective way to prevent stroke in particular groups of patients. Some brain damage that results from stroke may be secondary to the initial death of brain cells caused by the lack of blood flow to the brain tissue. This brain damage is a result of a toxic reaction to the primary damage. Researchers are studying the mechanisms of this toxic reaction and ways to prevent this secondary injury to the brain. Scientists hope to develop neuroprotective agents to prevent this damage. Another area of research involves experiments with vasodilators, medications that expand or dilate blood vessels and thus increase the blood flow to the brain. Basic research has also focused on the genetics of stroke and stroke risk factors. One area of research involving genetics is gene therapy. A promising area of stroke animal research involves hibernation. The dramatic decrease of blood flow to the brain in hibernating animals is extensive enough that it would kill a non-hibernating animal. If scientists can discover how animals hibernate without experiencing brain damage, then maybe they can discover ways to stop the brain damage associated with decreased blood flow in stroke patients. Other studies are looking at the role of hypothermia, or decreased body temperature, on metabolism and neuroprotection. Scientists are working to develop new and better ways to help the brain repair itself and restore important functions to stroke patients. Some evidence suggests that transcranial magnetic stimulation (TMS), in which a small magnetic current is delivered to an area of the brain, may possibly increase brain plasticity and speed up recovery of function after stroke.

Treatment

Early assessment

It is important to identify a stroke as early as possible because patients who are treated earlier are more likely to survive and have better recoveries. If a patient is suspected of having a stroke, emergency services should be contacted immediately. The patient should be transported to the nearest hospital that can provide a rapid evaluation and treatment with the latest available therapies targeted to the type of stroke. The faster these therapies are started for hemorrhagic and ischemic stroke, the chances for recovery from each type improves greatly. Quick decisions about medication and the need for surgery have been shown to improve outcome. Only detailed physical examination and medical imaging provide information on the presence, type, and extent of stroke. Recent research has shown that brain cells die after stroke by a signaling cascade using a protein called IKK2, presenting the possibility that cell death may be prevented by blocking this signaling [http://www.eurekalert.org/pub_releases/2005-11/embl-ltd110805.php]. Studies show that patients treated in hospitals with a dedicated Stroke Team or Stroke Unit and a specialized care program for stroke patients have improved odds of recovery.

Ischemic stroke

As ischemic stroke is due to a thrombus (blood clot) occluding a cerebral artery, a patient is given antiplatelet medication (aspirin, clopidogrel, dipyridamole), or anticoagulant medication (warfarin), dependant on the cause, when this type of stroke has been found. As such treatment would be dangerous in hemorrhagic stroke, it is essential that this form of stroke is ruled out with medical imaging. In increasing numbers of specialist centers, thrombolysis ("clot busting") is used to dissolve the clot and unblock the artery. However, this treatment is new, expensive, potentially dangerous and often contraindicated. There is also a time constraint: studies indicate that after three hours of symptom onset the damage to the brain is irreversible, and that after this time thrombolysis provides no benefit. These requirements prevent routine thrombolysis of ischemic stroke in most hospitals, especially when no stroke expert is available. Whether thrombolysis is performed or not, the following investigations are required:
- Stroke symptoms are documented, often using scoring systems such as the National Institutes of Health Stroke Scale, the Cincinnati Stroke Scale, and the Los Angeles Prehospital Stroke Scale. The latter is used by emergency medical technicians (EMTs) to determine whether a patient needs transport to a stroke center.
- A CT scan is performed to rule out hemorrhagic stroke
- Blood tests, such as a full blood count, coagulation studies (PT/INR and APTT), and tests of electrolytes, renal function, liver function tests and glucose levels are carried out. Other immediate strategies to protect the brain during stroke include ensuring that blood sugar is as normal as possible (such as commencement of an insulin sliding scale in known diabetics), and that the stroke patient is receiving adequate oxygen and intravenous fluids. The patient may be positioned so that his or her head is flat on the stretcher, rather than sitting up, since studies have shown that this increases blood flow to the brain. Additional therapies for ischemic stroke include aspirin (50 to 325 mg daily), clopidogrel (75 mg daily), and combined aspirin and dipyridamole extended release (25/200 mg twice daily). It is common for the blood pressure to be elevated immediately following a stroke. Studies indicated that while high blood pressure causes stroke, it is actually beneficial in the emergency period to allow better blood flow to the brain. If studies show carotid stenosis, and the patient has residual function in the affected side, carotid endarterectomy (surgical removal of the stenosis) may decrease the risk of recurrence. If the stroke has been the result of cardiac arrhythmia (such as atrial fibrillation) with cardiogenic emboli, treatment of the arrhythmia and anticoagulation with warfarin or high-dose aspirin may decrease the risk of recurrence.

Hemorrhagic stroke

Patients with bleeding into (intracerebral hemorrhage) or around the brain (subarachnoid hemorrhage), require neurosurgical evaluation to detect and treat the cause of the bleeding. Anticoagulants and antithrombotics, key in treating ischemic stroke, can make bleeding worse and cannot be used in intracerebral hemorrhage. Patients are monitored and their blood pressure, blood sugar, and oxygenation are kept at optimum levels.

Care and rehabilitation

Stroke rehabilitation is the process by which patients with disabling strokes undergo treatment to help them return to normal life as much as possible by regaining and relearning the skills of everyday living. It is multidisciplinary in the fact that it involves a team with different skills working together to help the patient. These include nursing staff, physiotherapy, occupational therapy, speech and language therapy and usually a physician trained in rehabiliation medicine. Some teams may also include psychologists and social workers and pharmacists. Good nursing care is fundamental in maintaining skin care, feeding, hydration, and positioning as well as the monitoring of vital signs such as temperature, pulse, and blood pressure. Stroke rehabilitation begins almost immediately. For most stroke patients, physical therapy is the cornerstone of the rehabilitation process. Another type of therapy involving relearning daily activities is occupational therapy (OT). OT involves exercise and training to help the stroke patient relearn everyday activities sometimes called the Activities of daily living (ADLs) such as eating, drinking and swallowing, dressing, bathing, cooking, reading and writing, and toileting. Speech and language therapy is appropriate for patients with problems understanding speech or written words, or problems forming speech. Patients may have particular problems such as complete or partial inability to swallow, which can cause swallowed material to pass into the lungs and cause aspiration pneumonia. The condition may improve with time but in the interim a nasogastric tube may be inserted, enabling liquid food to be given directly into the stomach. If after a week the swallow is still not safe then a percutaneous endoscopic gastrostomy (PEG) tube is passed and this can remain indefinitely. Stroke rehabilitation can last anywhere from a few days to several months. Most return of function is seen in the first few days and weeks, and then improvement falls off. Complete recovery is unusual but not impossible. Most patients will improve to some extent.

Prognosis

Disability affects 75% of stroke survivors enough to decrease their employability (Coffey et al., 2000 p.601). Stroke can affect patients physically, mentally, emotionally, or a combination of the three. The results of stroke vary widely depending on size and location of the lesion (Stanford, 2005). Dysfunctions correspond to areas in the brain that have been damaged. Some of the physical disabilities that can result from stroke include paralysis, numbness, pressure sores,

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