pharmaceuticals

2007-11-14T08:45:00.000-08:00

Dolly (sheep)

Dolly and her first-born lamb, Bonnie

Dolly (July 5, 1996 – February 14, 2003), an ewe, was the first mammal to be cloned from an adult somatic cell. The cell used was a mammary cell, which is why she was named Dolly, after the curvaceous country western singer Dolly Parton.^[1] She was cloned at the Roslin Institute in Edinburgh, Scotland, and lived there until her death at age six.^[2] Her birth was announced in February 1997.

Death

Dolly's remains as exhibited in the Royal Museum of Scotland.

On February 15, 2003, it was announced that Dolly had been euthanised because of a progressive lung disease and crippling arthritis. A Finn Dorset such as Dolly would have had a life expectancy of about 12 years, but Dolly only lived to 6 years of age. Some believe the reason for this is because Dolly was actually born genetically 6 years old, the same age as her donor at the time that her genetic data was taken from her. Surprisingly, Dolly did not die because of being a clone, a necropsy confirmed she had Ovine Pulmonary Adenocarcinoma (Jaagsiekte), a fairly common disease of sheep caused by the retrovirus JSRV. Roslin scientists stated that they did not think there was a connection with Dolly being a clone, and that other sheep on the farm had similar ailments. Such lung diseases are especially a danger for sheep kept indoors, as Dolly had to be for security reasons.

Legacy

After the cloning was successfully demonstrated by Eric Akins and Dolly's creators, many other large mammals have been cloned, including horses and bulls.^[3] Cloning is now considered a promising tool for preserving endangered species.^[4] Most animal conservation professionals point out that cloning does not alleviate the problems of loss of genetic diversity (see inbreeding) and habitat, and so must be considered an experimental technology for the time being, and all in all would only rarely be worth the cost, which on a per-individual basis far exceeds conventional techniques such as captive breeding or embryo transfer. The attempt to clone argali sheep did not produce viable embryos.^[5] The attempt to clone a banteng bull was more successful, as were the attempts to clone mouflon, both resulting in viable offspring. The banteng example is a case illustrating the circumstances under which the uncertainties of cloning attempts are outweighed by the benefits. The cloned dog Snuppy was unfortunately associated with the Korean stem cell scandal involving Hwang Woo-Suk.

References

1. Dolly was world's hello to cloning's possibilities. usatoday (July 4, 2006). Retrieved on 2007-10-18.

2. "First cloned sheep Dolly dies at 6", CNN.com, 14 February 2003.

3. Lozano, Juan A. (June 27, 2005). A&M Cloning project raises questions still. Bryan-College Station Eagle. Retrieved on 2007-04-30.

4. "Texas A&M scientists clone world’s first deer" (HTML), Innovations Report, 2003-12-23. Retrieved on 2007-01-01.

5. Cloning Article (HTML). Retrieved on 2007-11-12.

External links

Detailed process of cloning and its success rate

Dolly the Sheep, 1996-2000 from the Science Museum, London

Roslin Institute: Update on Dolly and nuclear transfer

Photos of Dolly and other cloned animals at Roslin

Paracetamol

2007-11-07T12:27:00.000-08:00

Paracetamol



Paracetamol
Systematic (IUPAC) name
N-(4-hydroxyphenyl)ethanamide
Identifiers
CAS number	103-90-2
ATC code	N02 BE01
PubChem	1983
DrugBank	APRD00252
Chemical data
Formula	C₈H₉N O₂
Mol. mass	151.17 g/mol
Physical data
Density	1.263 g/cm³
Melt. point	169 °C (336 °F)
Solubility in water	1.4 g/100 ml or 14 mg/mL (20 °C)
Pharmacokinetic data
Bioavailability	almost 100%
Metabolism	90 to 95% Hepatic
Half life	1–4 hours
Excretion	Renal
Therapeutic considerations
Licence data	US
Pregnancy cat.	A(AU) B(US) safe
Legal status	Unscheduled(AU) GSL(UK) OTC(US)
Routes	Oral, rectal, intravenous

Paracetamol or acetaminophen (USAN), is the active metabolite of phenacetin, a so-called coal tar analgesic. It is an effective substitute for aspirin, due to its analgesic and antipyretic properties. However, unlike aspirin, it is not a very effective anti-inflammatory agent. It is well tolerated, lacks many of the side effects of aspirin, and is available over-the-counter, so it is commonly used for the relief of fever, headaches, and other minor aches and pains. Paracetamol is also useful in the management of more severe pain, where it allows lower dosages of additional non-steroidal anti-inflammatory drugs (NSAIDs) or opioid analgesics to be used, thereby minimizing overall side effects. It is a major ingredient in numerous cold and flu medications, including Tylenol and Panadol, among others. It is considered safe for human use at recommended doses, however, acute overdose can cause fatal hepatic damage, and the number of accidental self-poisonings and suicides has grown in recent years.

The words acetaminophen and paracetamol both come from the chemical names for the compound: para-acetylaminophenol and para-acetylaminophenol. In some contexts, it is shortened to APAP, for N-acetyl-para-aminophenol.

History

In ancient and medieval times, known antipyretic agents were compounds contained in white willow bark (a family of chemicals known as salicins, which led to the development of aspirin), and compounds NIGRA contained in cinchona bark.^[1] Cinchona bark was also used to create the anti-malaria drug quinine. Quinine itself also has antipyretic effects. Efforts to refine and isolate salicin and salicylic acid took place throughout the middle- and late-19th century, and was accomplished by Bayer chemist Felix Hoffmann (this was also done by French chemist Charles Frédéric Gerhardt 40 years earlier, but he abandoned the work after deciding it was too impractical).^[2]

When the cinchona tree became scarce in the 1880s, people began to look for alternatives. Two alternative antipyretic agents were developed in the 1880s: acetanilide in 1886 and phenacetin in 1887. Harmon Northrop Morse first synthesized paracetamol via the reduction of p-nitrophenol with tin in glacial acetic acid in 1878, however, paracetamol was not used medically for another 15 years. In 1893, paracetamol was discovered in the urine of individuals who had taken phenacetin, and was concentrated into a white, crystalline compound with a bitter taste. In 1899, paracetamol was found to be a metabolite of acetanilide. This discovery was largely ignored at the time.

In 1946, the Institute for the Study of Analgesic and Sedative Drugs awarded a grant to the New York City Department of Health to study the problems associated with analgesic agents. Bernard Brodie and Julius Axelrod were assigned to investigate why non-aspirin agents were associated with the development of methemoglobinemia, a condition that decreases the oxygen-carrying capacity of blood and is potentially lethal. In 1948, Brodie and Axelrod linked the use of acetanilide with methemoglobinemia and determined that the analgesic effect of acetanilide was due to its active metabolite paracetamol. They advocated the use of paracetamol, since it did not have the toxic effects of acetanilide.^[3]

The product was first sold in 1955 by McNeil Laboratories as a pain and fever reliever for children, under the brand name Tylenol Children's Elixir.^[4]

In 1956, 500 mg tablets of paracetamol went on sale in the United Kingdom under the trade name Panadol, produced by Frederick Stearns & Co, a subsidiary of Sterling Drug Inc. Panadol was originally available only by prescription, for the relief of pain and fever, and was advertised as being "gentle to the stomach," since other analgesic agents of the time contained aspirin, a known stomach irritant. In June 1958 a children's formulation, Panadol Elixir, was released.

In 1963, paracetamol was added to the British Pharmacopoeia, and has gained popularity since then as an analgesic agent with few side-effects and little interaction with other pharmaceutical agents.

The U.S. patent on paracetamol has long expired and generic versions of the drug are widely available under the Drug Price Competition and Patent Term Restoration Act of 1984, although certain Tylenol preparations are protected until 2007. U.S. patent 6,126,967 filed September 3, 1998 was granted for "Extended release acetaminophen particles."

Chemistry

Structure and reactivity

Paracetamol consists of a benzene ring core, substituted by one hydroxyl group and the nitrogen atom of an amide group in the para (1,4) pattern. The amide group is acetamide (ethanamide). It is an extensively conjugated system, as the lone pair on the hydroxyl oxygen, the benzene pi cloud, the nitrogen lone pair, the p orbital on the carbonyl carbon and the lone pair on the carbonyl oxygen are all conjugated. The presence of two activating groups also make the benzene ring highly reactive towards electrophilic aromatic substitution. As the substituents are ortho,para directing and para with respect to each other, all positions on the ring are more or less equally activated. The conjugation also greatly reduces the basicity of the oxygens and the nitrogen, while making the hydroxyl acidic through delocalisation of charge developed on the phenoxide anion.

[edit] Synthesis

From the starting material phenol, paracetamol can be made in the following manner:

Phenol is nitrated using sulfuric acid and sodium nitrate (as phenol is highly activated, its nitration requires very mild conditions compared to the oleum-fuming nitric acid mixture required to nitrate benzene).
The para isomer is separated from the ortho isomer by fractional distillation (there will be little of meta as OH is o-p directing).
The 4-nitrophenol is reduced to 4-aminophenol using a reducing agent such as sodium borohydride in basic medium.
4-aminophenol is reacted with acetic anhydride to give paracetamol.

Notice that the synthesis of paracetamol lacks one very significant difficulty inherent in almost all drug syntheses: lack of stereocenters means there is no need to design a stereo-selective synthesis. More efficient, industrial syntheses are also available.

Available forms

Tablets are the most common form of paracetamol.

500 mg Panadol suppositories

Panadol, which is marketed in Europe, Africa, Asia, Central America, and Australasia, is the most widely available brand, sold in over 80 countries. In North America, paracetamol is sold in generic form (usually labelled as acetaminophen) or under a number of trade names: for instance Tylenol (McNeil-PPC, Inc), Anacin-3, Tempra, and Datril.

In some formulations paracetamol is combined with the opioid codeine, sometimes referred to as co-codamol (BAN). In the United States and Canada, this is marketed under the name of Tylenol #1/2/3/4 which contain approximately 1/8 grain, approximately 1/4 grain, approximately 1/2 grain, and approximately 1 grain of codeine respectively. A US grain is 64.78971 milligrams - this is usually rounded in manufacture down to a multiple of 5 mg (so that a #3 contains 30 mg, and a #4 contains 60 mg, while a #1 may be 8 or 10 mg depending on manufacturer. In the U.S. this combination is only available by prescription, while the lowest strength is over-the-counter in Canada, and in other countries, other strengths may be over the counter. There are generics as well. In the UK and in many other countries, this combination is marketed under the names of Tylex CD and Panadeine. Other names include Captin, Disprol, Dymadon, Fensum, Hedex, Mexalen, Nofedol, Paralen, Pediapirin, Perfalgan, and Solpadeine. Paracetamol is also combined with other opioids such as dihydrocodeine, referred to as co-dydramol (BAN), oxycodone or hydrocodone, marketed in the U.S. as Percocet and Vicodin, respectively. Another very commonly used analgesic combination includes paracetamol in combination with propoxyphene napsylate, sold under the brand name Darvocet. A combination of paracetamol, codeine, and the calmative doxylamine succinate is marketed as Syndol or Mersyndol.

Paracetamol is commonly used in multi-ingredient preparations for migraine headache, typically including butalbital and paracetamol with or without caffeine, and sometimes containing codeine.

It is commonly administered in tablet, liquid suspension, suppository, intravenous or intramuscular form. The common adult dose is 500 mg to 1000 mg. The recommended maximum daily dose, for adults, is 4 grams. In recommended doses paracetamol is safe for children and infants as well as for adults.

Mechanism of action

The mechanism by which paracetamol reduces fever and pain is still a source of considerable debate. The reason for this confusion has largely been due to the fact that paracetamol reduces the production of prostaglandins, pro-inflammatory chemicals the production of which is also inhibited by aspirin, but unlike aspirin, paracetamol does not have much anti-inflammatory action. Likewise, while aspirin inhibits the production of the pro-clotting chemicals thromboxanes, paracetamol does not. Aspirin is known to inhibit the cyclooxygenase (COX) family of enzymes, and because of paracetamol's partial similarity of aspirin's action, much research has focused on whether paracetamol also inhibits COX. It is now clear, however, that paracetamol acts via (at least) two pathways.^[5][6][7][8]

The COX family of enzymes are responsible for the metabolism of arachidonic acid to prostaglandin H₂, an unstable molecule, which is in turn converted to numerous other pro-inflammatory compounds. Classical anti-inflammatories, such as the NSAIDs, block this step. The activity of the COX enzyme relies on it being in the oxidized form, specifically tyrosine 385 must be oxidized to a radical.^[9][10] It has been shown that paracetamol reduces the oxidized form of the COX enzyme, preventing it from forming pro-inflammatory chemicals.^[6][11]

Further research has shown that paracetamol also modulates the endogenous cannabinoid system.^[12] Paracetamol is metabolized to AM404, a compound with several actions; most importantly, it inhibits the reuptake of endogenous cannabinoids and activates the nociceptor TRPV1. Either of these two actions by themselves has been shown to reduce pain, and both are a possible mechanism for paracetamol, though it has been demonstrated that after blocking cannabinoid receptors and hence making any action of cannabinoid reuptake irrelevant, paracetamol no longer has any analgesic effect, suggesting its pain-relieving action is indeed mediated by the endogenous cannabinoid system.^[13]

A theory that held some sway, but has now largely been discarded, is that paracetamol inhibits the COX-3 isoform of the cyclooxygenase family of enzymes.^[5][14] This enzyme, when expressed in dogs, shares a strong similarity to the other COX enzymes, produces pro-inflammatory chemicals and is selectively inhibited by paracetamol. However, in humans or mice, the COX-3 enzyme is without inflammatory action, and is not modulated by paracetamol.^[5]

Metabolism

Paracetamol is metabolised primarily in the liver, where its major metabolites include inactive sulfate and glucuronide conjugates, which are excreted by the kidneys. Only a small, yet significant amount is metabolised via the hepatic cytochrome P450 enzyme system (specifically, its CYP2E1 and CYP1A2 isoenzymes), which is responsible for the toxic effects of paracetamol due to a minor alkylating metabolite (N-acetyl-p-benzo-quinone imine, abbreviated as NAPQI).^[15] There is a great deal of polymorphism in the P450 gene, and genetic polymorphisms in CYP2D6 have been studied extensively. The population can be divided into "extensive", "ultrarapid" and "poor metabolizers" depending on their levels of CYP2D6 expression. CYP2D6 may also contribute to the formation of NAPQI, albeit to a lesser extent than other P450 isozymes, and its activity may contribute to paracetamol toxicity, particularly in extensive and ultrarapid metabolizers and when paracetamol is taken at very large doses.^[16]

The metabolism of paracetamol is an excellent example of toxication, because the metabolite NAPQI is primarily responsible for toxicity rather than paracetamol itself.

Paracetamol overdose results in more calls to poison control centers in the US than any other pharmacological substance, accounting for more than 100,000 calls, as well as 56,000 emergency room visits, 2,600 hospitalizations, and 458 deaths due to acute liver failure per year.^[17] A recent study of cases of acute liver failure between November 2000 and October 2004 by the Centers for Disease Control and Prevention (US) found that paracetamol was the cause of 41% of all cases in adults, and 25% of cases in children.^[18]

At usual doses, the toxic metabolite NAPQI is quickly detoxified by combining irreversibly with the sulfhydryl groups of glutathione or administration of a sulfhydryl compound such as N-acetylcysteine, to produce a non-toxic conjugate that is eventually excreted by the kidneys.^[15] Additionally, methionine has been recommended in some cases,^[19] although recent studies show that N-acetylcysteine is a more effective antidote to paracetamol overdose.^[20]

Comparison with NSAIDs

Paracetamol, unlike other common analgesics such as aspirin and ibuprofen, has relatively little anti-inflammatory properties, and so it is not a member of the class of drugs known as non-steroidal anti-inflammatory drugs (NSAIDs).

Efficacy

Regarding comparative efficacy, studies show conflicting results when comparing to NSAIDs. A randomized controlled trial of chronic pain from osteoarthritis in adults found similar benefit from acetaminophen and ibuprofen. ^[21] However, a randomized controlled trial of acute musculoskeletal pain in children found that the standard OTC dose of ibuprofen (400 mg) gives greater relief of pain than the standard dose of paracetamol (1000 mg).^[22]

Adverse effects

In recommended doses, paracetamol does not irritate the lining of the stomach, affect blood coagulation as much as NSAIDs, or affect function of the kidneys. However, some studies have shown that high dose-usage (greater than 2000 mg per day) does increase the risk of upper gastrointestinal complications.^[23]

Paracetamol is safe in pregnancy, and does not affect the closure of the fetal ductus arteriosus as NSAIDs can. Unlike aspirin, it is safe in children as paracetamol is not associated with a risk of Reye's syndrome in children with viral illnesses.

Like NSAIDs and unlike opioid analgesics, paracetamol has not been found to cause euphoria or alter mood in any way. Paracetamol and NSAIDs have the benefit of bearing a low risk of addiction, dependence, tolerance and withdrawal, but, unlike opioid medications, may damage the liver; however, this is generally taken into account when compared to the danger of addiction.

Paracetamol, particularly in combination with weak opioids, is more likely than NSAIDs to cause rebound headache (medication overuse headache), although less of a risk than ergotamine or triptans used for migraines.^[24]

Toxicity

Paracetamol is contained in many preparations (both over-the-counter and prescription-only medications). In some animals, for example cats, small doses are toxic. Because of the wide availability of paracetamol there is a large potential for overdose and toxicity.^[25] Without timely treatment, overdose can lead to liver failure and death within days; paracetamol toxicity is, by far, the most common cause of acute liver failure in both the United States and the United Kingdom.^[26][27] It is sometimes used in suicide attempts by those unaware of the prolonged timecourse and high morbidity (likelihood of significant illness) associated with paracetamol-induced toxicity in survivors.

In the UK, sales of over-the-counter paracetamol are restricted to packs of 32 tablets in pharmacies, and 16 tablets in non-pharmacy outlets. Up to 100 tablets may be sold in a single transaction. In Ireland, the limits are 24 and 12 tablets respectively. In Australia, paracetamol tablets are available at supermarkets in small pack sizes, while children's formulations, pack sizes greater than 48 tablets and suppositories are restricted to pharmacies.

Mechanism

Paracetamol is mostly converted to inactive compounds via Phase II metabolism by conjugation with sulfate and glucuronide, with a small portion being oxidized via the cytochrome P450 enzyme system. Cytochromes P450 2E1 (CYP2E1) and 3A4 (CYP3A4) convert paracetamol to a highly reactive intermediary metabolite, N-acetyl-p-benzo-quinone imine (NAPQI).^[28][29][30]

Under normal conditions, NAPQI is detoxified by conjugation with glutathione. In cases of paracetamol toxicity, the sulfate and glucuronide pathways become saturated, and more paracetamol is shunted to the cytochrome P450 system to produce NAPQI. As a result, hepatocellular supplies of glutathione become exhausted and NAPQI is free to react with cellular membrane molecules, resulting in widespread hepatocyte damage and death, clinically leading to acute hepatic necrosis. In animal studies, hepatic glutathione must be depleted to less than 70% of normal levels before hepatotoxicity occurs.^[28]

Toxic dose

The toxic dose of paracetamol is highly variable. In adults, single doses above 10 grams or 150 mg/kg have a reasonable likelihood of causing toxicity.^[31] Toxicity can also occur when multiple smaller doses within 24 hours exceeds these levels, or even with chronic ingestion of doses as low as 4 g/day, and death with as little as 6 g/day.

In children acute doses above 200 mg/kg could potentially cause toxicity. This higher threshold is largely due to children having larger kidneys and livers relative to body size than adults and hence being more tolerant of paracetamol overdose than adults.^[32] Acute paracetamol overdose in children rarely causes illness or death with chronic supratherapeutic doses being the major cause of toxicity in children.

In a normal dose of 1 gram of acetaminophen four times a day, one third of patients may have an increase in their liver function tests to three times the normal value.^[33] However, it is doubtful that this leads to liver failure.^[34]

Since paracetamol is often included in combination with other drugs, it is important to include all sources of paracetamol when checking a person's dose for toxicity. In addition to being sold by itself, paracetamol may be included in the formulations of various analgesics and cold/flu remedies as a way to increase the pain-relieving properties of the medication and sometimes in combination with opioids such as hydrocodone to deter people from using it recreationally or becoming addicted to the opioid substance, as at higher doses than intended the paracetamol will cause irreversible damage to the liver. In fact, the human toll of acetaminophen, in terms of both fatal overdoses and chronic liver toxicity to habitual abusers of pain medication, likely far exceeds the damage caused by the opioids themselves.^{[35][page # needed]} To prevent overdoses, one should read medication labels carefully for the presence of paracetamol and check with a pharmacist before using over-the-counter medications.

Risk factors

Chronic excessive alcohol consumption can induce CYP2E1, thus increasing the potential toxicity of paracetamol.^[36] For this reason, other analgesics such as aspirin or ibuprofen are sometimes recommended for hangovers.

Fasting is a risk factor, possibly because of depletion of hepatic glutathione reserves.

It is well documented that concomitant use of the CYP2E1 inducer isoniazid increases the risk of hepatotoxicity, though whether 2E1 induction is related to the hepatotoxicity in this case is unclear.^[37][38] Concomitant use of other drugs which induce CYP enzymes such as antiepileptics (including carbamazepine, phenytoin and barbiturates) have also been reported as risk factors.

Natural history

Individuals who have overdosed on paracetamol generally have no specific symptoms for the first 24 hours. Although nausea, vomiting, and diaphoresis may occur initially, these symptoms generally resolve after several hours. After resolution of these symptoms, individuals tend to feel better, and may believe that the worst is over. If a toxic dose was absorbed, after this brief feeling of relative wellness, the individual develops overt hepatic failure. In massive overdoses, coma and metabolic acidosis may occur prior to hepatic failure.

Damage generally occurs in hepatocytes as they metabolize the paracetamol. Rarely, acute renal failure also may occur. This is usually caused by either hepatorenal syndrome or Multiple organ dysfunction syndrome. Acute renal failure may also be the primary clinical manifestation of toxicity. In these cases, it has been suggested that the toxic metabolite is produced more in the kidneys than in the liver.^[39]

The prognosis of paracetamol toxicity varies depending on the dose and the appropriate treatment. In some cases, massive hepatic necrosis leads to fulminant hepatic failure with complications of bleeding, hypoglycemia, renal failure, hepatic encephalopathy, cerebral edema, sepsis, multiple organ failure, and death within days. In many cases, the hepatic necrosis may run its course, hepatic function may return, and the patient may survive with liver function returning to normal in a few weeks.

Diagnosis

Evidence of liver toxicity may develop in one to four days, although in severe cases it may be evident in 12 hours. Right upper quadrant tenderness may be present. Laboratory studies may show evidence of massive hepatic necrosis with elevated AST, ALT, bilirubin, and prolonged coagulation times (particularly, elevated prothrombin time). After paracetamol overdose, when AST and ALT exceed 1000 IU/L, paracetamol-induced hepatotoxicity can be diagnosed. However, the AST and ALT levels can exceed 10,000 IU/L. Generally the AST is somewhat higher than the ALT in paracetamol-induced hepatotoxicity.

A drug nomogram was developed in 1975 which estimated the risk of toxicity based on the serum concentration of paracetamol at a given number of hours after ingestion.^[40] To determine the risk of potential hepatotoxicity, the paracetamol level is traced along the standard nomogram. A paracetamol level drawn in the first four hours after ingestion may underestimate the amount in the system because paracetamol may still be in the process of being absorbed from the gastrointestinal tract. Delay of the initial draw for the paracetamol level to account for this is not recommended since the history in these cases is often poor and a toxic level at any time is a reason to give the antidote.

Treatment

Initial measures

The initial treatment for uncomplicated paracetamol overdose, similar to most other overdoses, is gastrointestinal decontamination. In addition, the antidote, acetylcysteine plays an important role. Paracetamol absorption from the gastrointestinal tract is complete within two hours under normal circumstances, so decontamination is most helpful if performed within this timeframe. Absorption may be somewhat slowed when it is ingested with food. There is considerable room for physician judgement regarding gastrointestinal decontamination; activated carbon administration is the most commonly used procedure, however, gastric lavage may also be considered if the amount ingested is potentially life threatening and the procedure can be performed within 60 minutes of ingestion.^[41] Syrup of ipecac has no role in paracetamol overdose because the vomiting it induces delays the effective administration of activated carbon and oral acetylcysteine.

Activated carbon adsorbs paracetamol, reducing its gastrointestinal absorption. Administering activated carbon also poses less risk of aspiration than gastric lavage. Previously there was reluctance to give activated carbon in paracetamol overdose, because of concern that it may also absorb acetylcysteine. Studies have shown that no more than 39% of an oral acetylcysteine is absorbed when they are administered together.^[42] Other studies have shown that activated carbon seems to be beneficial to the clinical outcome. It appears the most benefit from activated carbon is gained if it is given with two hours of ingestion.^[43] However, administering activated carbon later than this can be considered in patients who may have delayed gastric emptying due to co-ingested drugs or following ingestion of sustained or delayed release paracetamol preparations. Activated carbon should also be administered if co-ingested drugs warrant decontamination. There are conflicting recommendations^[42][44] regarding whether to change the dosing of oral acetylcysteine after the administration of activated carbon, and even whether the dosing of acetylcysteine needs to be altered at all.

Acetylcysteine

Acetylcysteine (also called N-Acetylcysteine or NAC) works to reduce paracetamol toxicity by supplying sulfhydryl groups (mainly in the form of glutathione, of which it is a precursor) to react with the toxic NAPQI metabolite so that it does not damage cells and can be safely excreted. (NAC can be bought as a dietary supplement in the United States.)

If the patient presents less than eight hours after paracetamol overdose, then acetylcysteine significantly reduces the risk of serious hepatotoxicity. If NAC is started more than 8 hours after ingestion, there is a sharp decline in its effectiveness because the cascade of toxic events in the liver has already begun and the risk of acute hepatic necrosis and death increases dramatically. Although acetylcysteine is most effective if given early, it still has beneficial effects if given as late as 48 hours after ingestion.^[45] In clinical practice, if the patient presents more than eight hours after the paracetamol overdose, then activated carbon is probably not useful, and acetylcysteine is started immediately. In earlier presentations the doctor can give carbon as soon as the patient arrives, start giving acetylcysteine, and wait for the paracetamol level from the laboratory.

In United States practice, intravenous (IV) and oral administration are considered to be equally effective. However, IV is the only recommended route in Australasian and British practice.

Oral acetylcysteine is given as a 140 mg/kg loading dose followed by 70 mg/kg every four hours for 17 more doses. Oral acetylcysteine may be poorly tolerated due to its unpleasant taste, odor, and its tendency to cause nausea and vomiting. It can be diluted to a 5% solution, from its marketed 10% or 20% solutions, to improve palatability. Where oral acetylcysteine is required, the inhalation formulation of acetylcysteine (Mucomyst) is often given orally. The respiratory formulation can also be diluted and filter sterilized by a hospital pharmacist for IV use, however this is an uncommon practice. If repeat doses of carbon are indicated because of another ingested drug, then subsequent doses of carbon and acetylcysteine should be staggered every two hours.

Intravenous acetylcysteine (Parvolex/Acetadote) is used as a continuous intravenous infusion over 20 hours (total dose 300 mg/kg). Recommended administration involves infusion of a 150 mg/kg loading dose over 15 minutes, followed by 50 mg/kg infusion over four hours; the last 100 mg/kg are infused over the remaining 16 hours of the protocol. Intravenous acetylcysteine has the advantage of shortening hospital stay, increasing both doctor and patient convenience, and it allows administration of activated carbon to reduce absorption of both the paracetamol and any co-ingested drugs without concerns about interference with oral acetylcysteine.^[46]

Baseline laboratory studies include bilirubin, AST, ALT, and prothrombin time (with INR). Studies are repeated at least daily. Once it has been determined that a potentially toxic overdose has occurred, acetylcysteine is continued for the entire regimen, even after the paracetamol level becomes undetectable in the blood. If hepatic failure develops, acetylcysteine should be continued beyond the standard doses until hepatic function improves or until the patient has a liver transplant.

[edit] Prognosis

The mortality rate from paracetamol overdose increases two days after the ingestion, reaches a maximum on day four, and then gradually decreases. Patients with a poor prognosis are usually identified for likely liver transplantation. Acidemia is the most important single indicator of probable mortality and the need for transplantation. A mortality rate of 95% without transplant was reported in patients who had a documented pH less than 7.30. Other indicators of poor prognosis include renal insufficiency, grade 3 or worse hepatic encephalopathy, a markedly elevated prothrombin time, or a rise in prothrombin time from day three to day four. One study has shown that a factor V level less than 10% of normal indicated a poor prognosis (91% mortality) while a ratio of factor VIII to factor V of less than 30 indicated a good prognosis (100% survival).^[47]

Prevention

Besides simply preventing an overdose, one way to prevent liver damage may be the use of Paradote. Paradote is a combination tablet containing 100 mg methionine and 500 mg paracetamol (i.e. 20% methionine). Methionine is included in order to ensure sufficient levels of glutathione in the liver are maintained to minimize the liver damage caused if a paracetamol overdose is taken.

Effects on animals

Paracetamol is extremely toxic to cats, and should not be given to them under any circumstances. Cats lack the necessary glucuronyl transferase enzymes to safely break paracetamol down and tiny fractions of a normal tablet for humans may prove fatal.^[48] Initial symptoms include vomiting, salivation and discolouration of the tongue and gums. After around two days liver damage is evident, typically giving rise to jaundice. Unlike an overdose in humans it is rarely liver damage which is the cause of death, instead methaemoglobin formation and the production of Heinz bodies in red blood cells inhibit oxygen transport by the blood, causing asphyxiation. Effective treatment is occasionally possible for small doses, but must be extremely rapid.

In dogs, paracetamol is a useful anti-inflammatory with a good safety record, causing a lower incidence of gastric ulceration than NSAIDs. It should only be administered on veterinary advice. A paracetamol-codeine product (trade name Pardale-V)^[49] licensed for use in dogs is available on veterinary prescription in the UK.^[50]

Any cases of suspected ingestion in cats or overdose in dogs should be taken to a veterinarian immediately for detoxification.^[51] The effects of toxicity can include liver damage, haemolytic anaemia, oxidative damage to the red blood cells and bleeding tendencies. There are no home remedies, and the amount of irreversible liver failure is dependent on how quickly veterinary intervention begins. Treatment of paracetamol overdose by a veterinarian may involve the use of supportive fluid therapy, acetylcysteine (trade name Mucomyst), methionine or S-adenosyl-L-methionine (SAMe) to slow liver damage and cimetidine (trade name Tagamet) to protect against gastric ulceration. Once liver damage has occurred it cannot be reversed.^[52]

Paracetamol is also lethal to snakes, and has been used in attempts to control the brown tree snake (Boiga irregularis) in Guam.^[53]

Serotonin

2007-10-23T11:24:00.000-07:00

Serotonin syndrome

Serotonin syndrome Classification & external resources

Serotonin
ICD-9	333.99
DiseasesDB	30044
eMedicine	ped/2786
MeSH	C21.613.276.720

Serotonin syndrome is a rare, but potentially life-threatening adverse drug reaction that results from intentional self-poisoning, therapeutic drug use, or inadvertent interactions between drugs. It is an iatrogenic (i.e. caused by medical treatment) toxidrome. It is most commonly referred to as serotonin syndrome, however, serotonin toxicity or serotonin toxidrome (from toxic + syndrome) are more accurate as it reflects the fact that it is a form of poisoning.^[1]^[2] Rarely it may also be called serotonin storm.

Serotonin syndrome is not a spontaneous drug reaction, it is a consequence of excess serotonergic activity at central nervous system (CNS) and peripheral serotonin receptors. This excess serotonin activity produces a specific spectrum of clinical findings which may range from barely perceptible to fatal.^[3]

1 Mechanism

Mechanism

Serotonin syndrome is caused by increased serotonin in the central nervous system. It is the result of overstimulation of 5-HT1A receptors in central grey nuclei and the medulla and, perhaps, of overstimulation of 5-HT2 receptors.^[3]^[4] These changes are more pronounced following supra-therapeutic doses and overdoses, and they merge in a continuum with the toxic effects.^[5]^[6]^[7]

Drugs which may contribute

A large number of drugs and drug combinations have been associated with the serotonin syndrome.

Class	Drugs
herbs	St John's Wort, Yohimbe
antidepressants	Monoamine oxidase inhibitors (MAOs), TCAs, SSRIs, SNRIs, mirtazapine, venlafaxine
opioids	tramadol, pethidine, dextromethorphan
CNS stimulants	phentermine, diethylpropion, hallucinogenic amphetamines, sibutramine, methylphenidate
5-HT₁ agonists	triptans
illicit drugs	methylenedioxymethamphetamine (MDMA or ecstasy), lysergic acid diethylamide (LSD), cocaine, PMA
others	tryptophan, buspirone, kanna, lithium, linezolid, dextromethorphan (DXM), 5-Hydroxytryptophan, chlorpheniramine, bupropion ^[8], risperidone ^[9]
Reference: Rossi, 2005;^[10] National Prescribing Service, 2005^[11]

The combination of MAOIs and other serotonin agonists or precursors poses a particularly severe risk of a life-threatening serotonin syndrome episode. Many MAOIs inhibit monoamine oxidase irreversibly, so that the enzyme cannot function until it has been replaced by the body, which can take at least two weeks. A dangerous serotonin syndrome reaction can occur unless serotonin agonists and even serotonin precursors such as foods containing tryptophan are strictly avoided until the monoamine oxidase has been replaced.

There have been no peer-reviewed case studies linking a combination of SSRIs and marijuana to serotonin syndrome, though numerous anecdotal reports exist on the internet.

Spectrum concept

A recently postulated ‘spectrum concept’ of serotonin toxicity emphasises the role that progressively increasing serotonin levels play in mediating the clinical picture as side effects merge into toxicity. The dose effect relationship is the term used to describe the effects of progressive elevation of serotonin, either by raising the dose of one drug, or combining it with another serotonergic drug (which may produce large elevations in serotonin levels).^[12]

Risk and severity

The relative risk and severity of serotonergic side effects and serotonin toxicity, with individual drugs and combinations, is complex. The serotonergic toxicity of SSRIs increases with dose, but even in over-dose it is insufficient to cause fatalities from serotonin syndrome in healthy adults. The syndrome occurs in approximately 14 to 16 percent of persons who overdose on SSRIs.^[6] It is usually only when drugs with different mechanisms of action are mixed together that elevations of central nervous system serotonin reach potentially fatal levels. The most frequent (and perhaps the only) combination of therapeutic drugs likely to elevate serotonin to that degree is the combination of monoamine oxidase inhibitors with serotonin reuptake inhibitors (various drugs, other than SSRIs, have clinically significant potency as serotonin reuptake inhibitors, e.g. tramadol, amphetamine, and mdma ^[13].

The relative risk of serotonin toxicity provides some clues and insights about the nature and extent of drugs’ serotonergic effects. For example, it suggests mirtazapine, which has no serotonergic toxicity, has no significant serotonergic effects at all, and is not in fact a dual action drug.^[14]

Symptoms

Symptom onset is usually rapid, often occurring within minutes after self-poisoning or a change in medication. Serotonin syndrome encompasses a wide range of clinical findings. Mild symptoms may only consist of tachycardia, and shivering, diaphoresis, mydriasis, intermittent tremor or myoclonus, as well as overactive or overresponsive reflexes. In addition moderate intoxication includes abnormalities such as hyperactive bowel sounds, hypertension and hyperthermia; a temperature as high as 40°C (104°F) is common in moderate intoxication. The overactive reflexes and clonus in moderate cases may be greater in the lower limbs than in the upper limbs. Mental status changes include hypervigilance and agitation.^[3]

Severe symptoms include severe hypertension and tachycardia that may lead to shock. Severe case often have agitated delirium as well as muscular rigidity and high muscular tension. Temperature may rise to above 41.1°C (105.98°F) in life-threatening cases. Other abnormalities include metabolic acidosis, rhabdomyolysis, seizures, renal failure, and disseminated intravascular coagulation.^[3]

The symptoms are often described as a clinical triad of abnormalities:

Cognitive effects: mental confusion, hypomania, hallucinations, agitation, headache, coma.
Autonomic effects: shivering, sweating, fever, hypertension, tachycardia, nausea, diarrhea.
Somatic effects: myoclonus/clonus (muscle twitching), hyperreflexia, tremor.

Diagnosis

There is no lab test for serotonin syndrome, so diagnosis is by symptom observation and the patient’s history. Serotonin toxicity is a toxidrome (i.e. has a characteristic picture). It is unique and hard to confuse with other medical conditions but in some situations it may go unrecognized because it may be mistaken for a viral illness, anxiety, neurological disorder, or worsening psychiatric condition.^[15] Much confusion has been produced by muddling it with side effects from serotonergic drugs. These rarely, if ever, become dangerous or fatal. Clinicians must also differentiate between serotonin syndrome and neuroleptic malignant syndrome, which has similar symptoms. Patients taking serotonergic drugs and who have sudden onset of symptoms should immediately seek medical care.

Management

There is no antidote to the condition itself, and management involves the removal of the precipitating drugs, the initiation of supportive care, the control of agitation, the administration of serotonin antagonists (cyproheptadine or methysergide), the control of autonomic instability, and the control of hyperthermia.^[16]^[3]

The intensity of therapy depends on the severity of symptoms. If the symptoms are mild, treatment may only consist of discontinuation of the offending medication or medications, offering supportive measures, giving benzodiazepines, and waiting for the symptoms to resolve. If the offending medication is discontinued, the condition will often resolve on its own within 24 hours.^[17]^[18] Moderate cases should have all thermal and cardiorespiratory abnormalities corrected and can benefit from serotonin antagonists (i.e. cyproheptadine). Critically ill patients should receive the above therapies as well as sedation, neuromuscular paralysis, and intubation.^[3]

Neuroleptic malignant syndrome and serotonergic syndrome

The clinical features of neuroleptic malignant syndrome (NMS) and serotonergic syndrome are very similar. This can make differentiating them very difficult.^[19]

Features, classically present in NMS, that are useful for differentiating the two syndromes are:^[20]

Fever
Muscle rigidity
Labratory values (increased WBC and CK)

Notable cases

The death of Libby Zion was due to serotonin syndrome caused by a combination of meperidine and phenelzine.^[3] This case had a profound impact on graduate medical education and residency work hour limitations.^[21]

Methylene

2007-10-23T11:23:00.002-07:00

Methylene blue

Methylene blue


IUPAC name	3,7-bis(Dimethylamino)- phenazathionium chloride Tetramethylthionine chloride
Identifiers
CAS number	61-73-4
SMILES	CN(C)c3ccc2nc1ccc(N(C) C)cc1[s+]c2c3.[Cl-]
Properties
Molecular formula	C₁₆H₁₈N₃ClS
Molar mass	319.85 g/mol
Melting point	100 °C
Boiling point	Decomposes
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) Infobox disclaimer and references

Methylene blue is aa heterocyclic aromatic chemical compound with molecular formula: C₁₆H₁₈Cl N₃S. It has many uses in a range of different fields, such as biology or chemistry. At room temperature it appears as a solid, odorless, dark green powder, that yields a blue solution when dissolved in water. Methylene blue should not be confused with methyl blue, another histology stain, new methylene blue, nor with the methyl violets often used as pH indicators.

[hide]

1 Uses

Uses

Chemistry

Methylene blue is widely used as a redox indicator in analytical chemistry. Solutions of this substance are blue when in an oxidizing environment, but will turn colorless if exposed to a reducing agent. The redox properties can be seen in a classical demonstration of chemical kinetics in general chemistry, the "blue bottle" experiment. Typically, a solution is made of dextrose, methylene blue, and sodium hydroxide. Upon shaking the bottle, oxygen oxidizes methylene blue, and the solution turns blue. The dextrose will gradually reduce the methylene blue to its colorless, reduced form. Hence, when the dissolved oxygen is entirely consumed, the solution will turn colorless. Methylene blue is also used to make the reaction between Fehling's solution and reducing sugars more visible.

Biology

In biology methylene blue is used as a dye for a number of different staining procedures, such as Gram's stain, Wright's stain, and Jenner's stain. Since it is a temporary staining technique, methylene blue can also be used to examine RNA or DNA under the microscope or in a gel: as an example, a solution of methylene blue can be used to stain RNA on hybridization membranes in northern blotting to verify the amount of nucleic acid present. While methylene blue is not as sensitive as ethidium bromide, it is less toxic and it does not intercalate in nucleic acid chains, thus avoiding interference with nucleic acid retention on hybridization membranes or with the hybridization process itself.

It can also be used as an indicator to determine if a cell such as yeast is alive or not. The blue indicator turns colourless in the presence of active enzymes, thus indicating living cells. However if it stays blue it doesn't mean that the cell is dead - the enzymes could be inactive/denatured. It must be noted that methylene blue can inhibit the respiration of the yeast as it picks up hydrogen ions made during the process. The yeast cell cannot then use those ions to release energy.

Medicine

Owing to its reducing agent properties, methylene blue is employed as a medication for the treatment of methemoglobinemia, which can arise from ingestion of certain pharmaceuticals or broad beans. Basically, methylene blue acts to reduce the heme group from methemoglobin to hemoglobin. Methylene blue also blocks accumulation of cyclic guanosine monophosphate (cGMP) by inhibiting the enzyme guanylate cyclase: this action results in reduced responsiveness of vessels to cGMP-dependent vasodilators like nitric oxide and carbon monoxide.

Methylene blue is used in endoscopic polypectomy as an adjunct to saline or epinephrine, and is used for injection into the submucosa around the polyp to be removed. This allows the submucosal tissue plane to be identified after the polyp is removed, which is useful in determining if more tissue needs to be removed, or if there has been a high risk for perforation. Methylene blue is also used as a dye in chromoendoscopy, and is sprayed onto the mucosa of the gastrointestinal tract in order to identify dysplasia, or pre-cancerous lesions.

Methylene blue was used at the end of the century as a successful treatment for malaria. It disappeared as an anti-malarial during the wars in Asia, as U.S. soldiers disliked its two inevitable, fully reversible side effects: green urine and blue sclera. Interest in its use has recently been revived,^[1] especially because it is very cheap. Several clinical trials are in progress, trying to find a suitable drug combination. Initial attempts to combine methylene blue with chloroquine were disappointing;^[2] however, more recent attempts have appeared more promising.

In surgeries such as sentinel lymph node dissections, methylene blue can be used to visually trace the lymphatic drainage of pertinent tissues. Similarly, methylene blue is added to bone cement in orthopedic operations to provide easy discrimination between native bone and cement. Additionally, methylene blue accelerates the hardening of bone cement, increasing the speed at which bone cement can be effectively applied.

Since its reduction potential is similar to that of oxygen and can be reduced by components of the electron transport chain, large doses of methylene blue are sometimes used as an antidote to potassium cyanide poisoning, a method first successfully tested in 1933 by Dr. Matilda M. Brooks in San Francisco.^[3] Methylene blue was also used at mid-century in the treatment of carbon monoxide poisoning.^[3]

Methylene blue is probably a monoamine oxidase inhibitor, and if infused intravenously at doses exceeding 5 mg/kg, may precipitate serious serotonin toxicity, serotonin syndrome, if combined with any selective serotonin reuptake inhibitors (SSRIs) or other serotonin reuptake inhibitor (e.g., duloxetine, sibutramine, venlafaxine, clomipramine, imipramine).^[4]

Another, less well-known use of methylene blue is its utility for treating ifosfamide neurotoxicity. Methylene blue was first reported for treatment and prophylaxis of ifosfamide neuropsychiatric toxicity in 1994. A toxic metabolite of ifosfamide, chloracetaldehyde (CAA), disrupts the mitochondrial respiratory chain, leading to an accumulation of nicotinamide adenine dinucleotide hydrogen (NADH). Methylene blue acts as an alternative electron acceptor, and reverses the NADH inhibition of hepatic gluconeogenesis while also inhibiting the transformation of chloroethylamine into chloroacetaldehyde, and inhibits multiple amine oxidase activities, preventing the formation of CAA.^[5] The dosing of methylene blue for treatment of ifosfamide neurotoxicity varies, depending upon its use simultaneously as an adjuvant in ifosfamide infusion, versus its use to reverse psychiatric symptoms that manifest after completion of an ifosfamide infusion. Reports suggest that methylene blue at 50-60mg up to six doses a day have resulted in improvement of symptoms within 10 minutes to several days.^[6] Alternatively, it has been suggested that intravenous methylene blue 50mg every six hours for prophylaxis during ifosfamide treatment in patients with history of ifosfamide neuropsychiatric toxicity.^[7] Prophylactic administration of 50mg of methylene blue the day before initiation of ifosfamide, and 50mg three times daily during ifosfamide chemotherapy has been recommended to lower the occurrence of ifosfamide neurotoxicity.^[8]

Aquaculture

Methylene blue is used in aquaculture and by tropical fish hobbyists as a treatment for fungal infections. It can also be effective in treating fish infected with ich, the parasitic protozoa Ichthyophthirius multifiliis.

Methylene blue is highly stable in the human body, and if ingested, it resists the acidic environment of the stomach as well as the many hydrolytic enzymes present. It is not significantly metabolized by the liver, and is instead quickly filtered out by the kidneys. A common prank among chemists and biochemists of the early and middle 20th century was to add small amounts of methylene blue (generally a few drops of a stain solution sufficed) to coffee, cola, or another dark beverage.^[^{citation needed}^] The stain's color was masked by the beverage, and its taste is fairly faint. Within a few hours, the methylene blue was removed by the prank victim's kidneys, which caused his or her urine to change color^[9] The urine may become green if little methylene blue was added; larger amounts create a deep blue color. The prank is fairly harmless if small amounts of methylene blue are used.

Adverse Reactions

Cardiovascular	Central Nervous System	Dematologic	Gastrointestinal	Genitourinary	Hematologic
•Hypertension •Precordial pain	•Dizziness •Mental confusion •Headache •Fever	•Staining of skin •Injection site necrosis (SC)	•Fecal discoloration •Nausea •Vomiting •Abdominal pain	•Discoloration of urine •Bladder irritation	•Anemia

cancer

2007-10-23T11:23:00.001-07:00

Skin cancer

Skin cancer Classification & external resources
ICD-10	C 43.-C 44.
ICD-9	172, 173
ICD-O:	8010-8720
MeSH	D012878

Skin cancer is a malignant growth on the skin which can have many causes. Skin cancer generally develops in the epidermis (the outermost layer of skin), so a tumor is usually clearly visible. This makes most skin cancers detectable in the early stages. There are three common types of skin cancer, each of which is named after the type of skin cell from which it arises. Cancers caused by UV exposure may be prevented by avoiding exposure to sunlight or other UV sources, wearing sun-protective clothes, and using a broad-spectrum sun screen.^[^{citation needed}^]

Skin cancers are the fastest growing type of cancer in the United States. Skin cancer represents the most commonly diagnosed malignancy, surpassing lung, breast, colorectal and prostate cancer. More than 1 million Americans will be diagnosed with skin cancer in 2007.^[1]

Risk Factors

Skin cancer is most closely associated with chronic inflammation of the skin. This includes:

Sunburn or excessive sun damage, especially early in life. UVA & UVB have both been implicated in causing DNA damage resulting in cancer. Sun exposure between 10AM and 4PM is thought to be most harmful. Natural (sun) & artificial UV exposure (tanning salons) are associated with skin cancer.
Chronic non-healing wounds, especially burns. These are called Marjolin's ulcers based on their appearance and can develop into squamous cell carcinomaand.
Genetic predisposition, including "Congenital Melanocytic Nevi Syndrome". CMNS is characterized by the presence of "nevi" or moles of varying size that either appear at or within 6 months of birth. Nevi larger than 20 mm (3/4") in size are at higher risk for becoming cancerous.

Skin can be protected by avoiding sunlight entirely, or wearing protective clothing while outdoors. Skin cancer is usually caused by exposing skin to UV rays excessively.

Types

The most common types of skin cancer are basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) which may be locally disfiguring but are unlikely to metastasize (spread to other parts of the body). The most dangerous type of skin cancer is malignant melanoma. This form of skin cancer can be fatal if not treated early but comprises only a small proportion of all skin cancers.

More rare types of skin cancer include:

Prevalence

Skin cancer is an increasingly common condition. This is in part attributed to increased exposure to ultraviolet radiation, which in turn is thought to be caused by the increased popularity of sun tanning (sun bathing).^[^{citation needed}^] Lighter-skinned individuals are more vulnerable. ^[^{citation needed}^] In the United States, about one out of every three new cancers arises from the skin. ^[^{citation needed}^]

Signs and symptoms

There are a variety of different skin cancer symptoms. These include crabs or changes in the skin that do not heal, ulcers in the skin, discoloration, and changes in existing moles.

Basal cell carcinoma usually looks like a raised, smooth, pearly bump on the sun-exposed skin of the head, neck or shoulders. Sometimes small blood vessels can be seen within the tumor. Crusting and bleeding in the center of the tumor frequently develops. It is often mistaken for a sore that does not heal.

Squamous cell carcinoma is commonly a red, scaling, thickened patch on sun-exposed skin. Ulceration and bleeding may occur. When SCC is not treated, it may develop into a large mass.

Most melanomas are brown to black looking lesions. Signs that might indicate a malignant melanoma include change in size, shape, color or elevation of a mole. The appearance of a new mole during adulthood, or new pain, itching, ulceration or bleeding of an existing mole should be checked.

Treatment

Most skin cancers can be treated by removal of the lesion, making sure that the edges (margins) are free of the tumor cells. These excisions provide the best cure for both early and high-risk disease.

For low-risk disease, radiation therapy and cryotherapy (freezing the cancer off) can provide adequate control of the disease; both, however, have lower overall cure rates than surgery.

Moh's Microsurgery is a technique used to remove the cancer with the least amount of surrounding tissue and the edges are checked immediately to see if tumor is found. This provides the opportunity to remove the least amount of tissue and provide the best cosmetically favorable results. This is especially important for areas where excess skin is limited, such as the face. Cure rates are equivalent to wide excision. Special training is required to perform this technique.

In the case of disease that has spread (metastasized) further surgical or chemotherapy may be required.^[2]

Reduction of risk

Although it is impossible to completely eliminate the possibility of skin cancer, the risk of developing such a cancer can be reduced significantly with the following steps:

reducing exposure to ultraviolet (UV) radiation, especially in early years
avoiding sunburns
avoiding sun exposure during the day (usually from 10 AM to 3 PM), when the sun is highest in the sky
wearing protective clothing (long sleeves and hats) when outdoors
using a broad-spectrum sunscreen that blocks both UVA and UVB radiation
use SPF sun block of at least 75
reapply sun block every 2 hours and after swimming

Although it is generally accepted that UV exposure is the greatest risk factor in melanoma development, some skeptics say that there is no proven data that links moderate sun exposure with the appearance of melanoma.

References

^ Common Cancer Types - National Cancer Institute. Retrieved on 2007-07-21.
^ Doherty, Gerard M.; Mulholland, Michael W. (2005). Greenfield's Surgery: Scientific Principles And Practice. Baltimore: Williams & Wilkins. ISBN 0-7817-5626-X.

American Cancer Society: Cancer Facts and Figures-1999. Atlanta, Ga: American Cancer Society, 1999.

Serotonin-noradrenaline-dopamine reuptake inhibitor

Serotonin-norepinephrine-dopamine-reuptake-inhibitors (SNDRI) are a class of psychoactive antidepressants. They act upon neurotransmitters in the brain, namely, serotonin, norepinephrine and dopamine. These three biogenic monoamines are associated with depression and increasing the availability in the brain is used to treat the disease.

SNDRIs are so-called triple reuptake inhibitors, which elevate extracellular plasma concentrations of all three monoamine neurotransmitters, serotonin, norepinephrine and dopamine in the synaptic cleft. These compounds show high potency but low selectivity between the different monoamine transporter proteins. No SNDRIs are yet on the market, although the first of these agents tesofensine is currently in clinical trials,^[1]^[2] and other compounds such as brasofensine ^[3] and GlaxoSmithKline's NS2359 ^[4] are under development.

It should be noted that some SNRI drugs such as Venlafaxine (Effexor) and Sibutramine (Meridia/Reductil) are known to weakly inhibit the reuptake of dopamine at high doses, and so while these drugs are selective for the serotonin and noradrenaline transporters at normal doses, they can start to act as SNDRIs when taken at doses above the normal therapeutic range.

Tetrahydrocannabinol

2007-10-23T11:22:00.001-07:00

Tetrahydrocannabinol



Δ⁹-tetrahydrocannabinol
Systematic (IUPAC) name
(−)-(6aR,10aR)-6,6,9-trimethyl- 3-pentyl-6a,7,8,10a-tetrahydro- 6H-benzo[c]chromen-1-ol
Identifiers
CAS number	1972-08-3
ATC code	?
PubChem	16078
Chemical data
Formula	C₂₁H₃₀O₂
Mol. mass	314.45
Physical data
Boiling point	200 °C (392 °F) vacuum
Solubility in water	2.8 mg/L (23 °C) mg/mL (20 °C)

Tetrahydrocannabinol, also known as THC, Δ⁹-THC, Δ⁹-tetrahydrocannabinol (delta-9-tetrahydrocannabinol), Δ¹-tetrahydrocannabinol (using an older numbering scheme), or dronabinol, is the main psychoactive substance found in the Cannabis plant. It was isolated by Raphael Mechoulam, Yechiel Gaoni, and Habib Edery from the Weizmann Institute in Rehovot, Israel in 1964. In pure form it is a glassy solid when cold and becomes viscous and sticky if warmed. An aromatic terpenoid, THC has a very low solubility in water, but good solubility in most organic solvents such as butane or hexane. As in the case of nicotine and caffeine, THC's most likely function in Cannabis is to protect the plant from herbivores or pathogens ^[1]. THC also possesses high UV-B (280-315 nm) absorption properties, protecting the plant from harmful radiation.

1 Pharmacology

1.1 Toxicity

Pharmacology

Its pharmacological actions are the result of its binding to the cannabinoid receptor CB₁, located in the brain. The presence of these specialized receptors in the brain implied to researchers that endogenous cannabinoids were manufactured by the body, so the search began for a substance normally manufactured in the brain that binds to these receptors, the so-called natural ligand or agonist, leading to the eventual discovery of anandamide, 2 arachidonyl glyceride (2-AG) and other related compounds. This story resembles the discovery of the endogenous opiates (endorphins, enkephalins, and dynorphin), after the realization that morphine and other opiates bound to specific receptors in the brain. Additionally, it has been shown that cannabinoids, through a presently-unknown mechanism, activate endogenous opioid pathways via the μ₁ opioid receptor, precipitating a dopamine release in the nucleus accumbens. The effects of the drug can be suppressed by the CB1 cannabinoid receptor antagonist rimonabant (SR141716A) or, interestingly, the opioid receptor antagonists (opioid blockers) naloxone and naloxonazine.^[2]

The mechanism of endocannabinoid synaptic transmission is understood by the following events: an excitatory transmission of the neurotransmitter glutamate causes an influx of calcium ions into the post-synaptic neuron. Through a mechanism not yet fully understood, the presence of calcium post-synaptically induces the production of endocannabinoids in the post synaptic neuron. These endocannabinoids (such as anandamide) are released into the synaptic cleft. Once in the synaptic cleft, binding occurs at cannabinoid receptors present in pre-synaptic neurons where they can then modulate neurotransmission presynaptically. This form of neurotransmission is termed retrograde transmission as the signal is carried in the opposite direction of orthodox propagation; it provides an interesting insight into neurotransmission, which previously was thought to be exclusively one way.

THC has analgesic effects that, even at low doses, causes a "high", thus leading to the fact that medical cannabis can be used to treat pain. The mechanism for analgesic effects caused directly by THC or other cannabinoid agonists is not fully elucidated. Other effects include: relaxation; euphoria; altered space-time perception; alteration of visual, auditory, and olfactory senses; disorientation; fatigue; and appetite stimulation related to CB1 receptor activity in the central nervous system. The mechanism for appetite stimulation in subjects is somewhat understood and explained through a gastro-hypothalamic axis. CB1 activity in the hunger centres in the hypothalamus that increase the palatability of food, a hunger hormone--ghrelin increases hunger signals as food enters the stomach. After chyme is passed into the duodenum, signaling hormones such as CCK and leptin are released causing reduction in gastric emptying and satiety signals to the hypothalamus, respectively. Cannabinoid activity is reduced through the satiety signals induced by leptin release. It also has anti-emetic properties, and also may reduce aggression in certain subjects.

THC has an active metabolite, 11-Hydroxy-THC which may also play a role in the analgesic and recreational effects of the herb.

Toxicity

According to the Merck Index, 12th edition, THC has a LD₅₀ value of 1270 mg/kg (male rats) and 730 mg/kg (female rats) administered orally dissolved in sesame oil.^[3]

If this were scaled up to an adult human, the LD₅₀ would be between approximately 50 and 86 g for a 68 kg (150 lb) female or male person respectively. This would be equivalent to 1-1.8 kg of cannabis with a 5% THC content (roughly average) taken orally. The LD₅₀ value for rats by inhalation of THC is 42 mg/kg of body weight. It is important to note, however, that toxicity studies in animal models do not necessarily correlate to human toxicity. THC receptor distribution in the rat central nervous system is different from that of humans, meaning that there is the significant possibility that toxicity in humans varies from the published animal LD₅₀ studies. There has never been a documented fatality from marijuana or THC overdose. Absorption is limited by serum lipids which can become saturated with THC, thus the inherent solubility may mitigate toxicity.

Studies of the distribution of the cannabinoid receptors in the brain explain why THC's toxicity is so low (i.e., the LD₅₀ of the compound is so large): parts of the brain that control vital functions such as respiration do not have many receptors, so they are relatively unaffected even by doses larger than could ever be ingested under any normal conditions. There are no known reports of death caused by THC.

Research

A number of studies indicate that THC may provide medical benefits for cancer and AIDS patients by increasing appetite and decreasing nausea. It has been shown to assist some glaucoma patients by reducing pressure within the eye, and is used in the form of cannabis by a number of multiple sclerosis patients to relieve the spasms and pain associated with their condition. New scientific evidence is showing that THC can prevent Alzheimer's Disease by counteracting the activation of microglia and thus inducing the inflammation of microglia binding to amyloid protein.

Some studies also claim a variety of negative effects associated with constant, long-term use, including short-term memory loss. Other studies have refuted this by evidence of MRIs of long term users showing little or no difference to MRIs of the non-using control group. Although using positron emission tomography (PET), at least one study claims to have observed altered memory-related brain function in marijuana users ^[4]. The long-term effects of THC on humans have been disputed because its status as an illegal drug makes research difficult.

Preliminary research on synthetic THC has been conducted on patients with Tourette syndrome, with results suggesting that it may help in reducing nervous tics and urges by a significant degree. Animal studies suggested that Marinol and nicotine could be used as an effective adjunct to neuroleptic drugs in treating TS. Research on twelve patients showed that Marinol reduced tics with no significant adverse effects. A six-week controlled study on 24 patients showed the patients taking Marinol had a significant reduction in tic severity without serious adverse effects. Seven patients dropped out or had to be excluded from the study, one due to adverse side-effects. More significant reduction in tic severity was reported with longer treatment. No detrimental effects on cognitive functioning and a trend towards improvement in cognitive functioning were reported during and after treatment. Marinol's usefulness as a treatment for TS cannot be determined until/unless longer controlled studies on larger samples are undertaken.^[5]^[6]^[7]^[8]

Recent research has shown that many adverse side effects, generally known as the "stoner" stereotype, fail to hold up to the scientific method. Recent studies with synthetic cannabinoids show that activation of CB1 receptors can facilitate neurogeneration, as well as neuroprotection, and can even help prevent natural neural degradation from neurodegenerative diseases such as MS, Parkinson's, and Alzheimer's. This, along with research into the CB2 receptor (throughout the immune system), has given the case for medical marijuana more support.

In in-vitro experiments THC at extremely high concentrations, which could not be reached with commonly consumed doses, caused inhibition of plaque formation, the cause of Alzheimer's disease, better than currently approved drugs.^[9]

THC may also be an effective anti-cancer treatment, with studies showing tumor reduction in mice, conducted in 1975.^[10]

In early May 2007, British Doctors released a study that linked THC to psychotic episodes (paranoid delusions and hallucinations) in healthy test subjects. Another study conducted at Yale University showed similar results in healthy subjects, but also included a schizophrenic group. The effect on the schizophrenics was so profound that it merited cancellation of the study due to fear that it would be unethical to continue. ^[11]

On July 28th 2007, British medical journal The Lancet published a study that indicated that cannabis users had, on average, a 41% greater risk of developing psychosis than non users. The risk was most pronounced in cases with an existing risk of psychotic disorder, and was said to grow up to 200% for the most frequent users. ^[12] ^[13] ^[14]

A two year study in which rats and mice were force-fed tetrahydrocannabinol dissolved in corn oil showed reduced body mass, enhanced survival rates, and decreased tumor incidences in several sites, mainly organs under hormonal control. It also caused testicular atrophy and uterine and ovarian hypoplasia, as well as hyperactivity and convulsions immediately after administration.^[15]

Synthetic THC

Synthetic THC, also known under the substance name dronabinol, is available as a prescription drug (under the trade name Marinol) in several countries including the U.S., The Netherlands, and Germany. In the United States, Marinol is a Schedule III drug, available by prescription, considered to be non-narcotic and to have a low risk of physical or mental dependence. Efforts to get cannabis rescheduled as analogous to Marinol have not succeeded thus far, though a 2002 petition has been accepted by the DEA. As a result of the rescheduling of Marinol from Schedule II to Schedule III, refills are now permitted for this substance. Marinol has been approved by the FDA in the treatment of anorexia in AIDS patients, as well as for refractory nausea and vomiting of patients undergoing chemotherapy.

An analog of dronabinol, nabilone, is available commercially in Canada under the trade name Cesamet, manufactured by Valeant. Cesamet has also received FDA approval for future availability in the United States and is a Schedule II drug.

In April 2005, Canadian authorities approved the marketing of Sativex, a mouth spray for multiple sclerosis to alleviate pain. Sativex contains tetrahydrocannabinol together with cannabidiol. It is marketed in Canada by GW Pharmaceuticals, being the first cannabis-based prescription drug in the world.

pharmaceuticals

Paracetamol

Serotonin

Serotonin syndrome

Contents

Mechanism

Drugs which may contribute

Spectrum concept

Risk and severity

Symptoms

Diagnosis

Management

Neuroleptic malignant syndrome and serotonergic syndrome

Notable cases

Methylene

Methylene blue

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Uses

Chemistry

Biology

Medicine

Aquaculture

Adverse Reactions

cancer

Skin cancer

Contents

Risk Factors

Types

Prevalence

Signs and symptoms

Treatment

Reduction of risk

See also

References

Serotonin-noradrenaline-dopamine reuptake inhibitor

Tetrahydrocannabinol

Tetrahydrocannabinol

Contents

Pharmacology

Toxicity

Research

Synthetic THC