Paracetamol toxicity  has become the foremost cause of acute liver failure in the United States by 2003, [ 43 ]  and as of 2005 [update] , paracetamol accounted for most drug overdoses in the United States, the United Kingdom, Australia, and New Zealand. [ 108 ]  As of 2004, paracetamol overdose resulted in more calls to  poison control centers  in the U.S. than overdose of any other pharmacological substance. [ 109 ]  According to the FDA, in the United States, "56,000 emergency room visits, 26,000 hospitalizations, and 458 deaths per year [were] related to acetaminophen-associated overdoses during the 1990s. Within these estimates, unintentional acetaminophen overdose accounted for nearly 25 % of the emergency department visits, 10 % of the hospitalizations, and 25 % of the deaths." [ 110 ] [ needs update ]


Overdoses are frequently related to high-dose  recreational use  of prescription  opioids , as these opioids are most often combined with paracetamol. [ 111 ]  The overdose risk may be heightened by frequent consumption of alcohol. [ 112 ]


Untreated paracetamol overdose results in a lengthy, painful illness. Signs and symptoms of paracetamol toxicity may initially be absent or  non-specific symptoms . The first symptoms of overdose usually begin several hours after ingestion, with  nausea ,  vomiting , sweating, and pain as acute liver failure starts. [ 113 ]  People who take overdoses of paracetamol do not fall asleep or lose consciousness, although most people who attempt suicide with paracetamol wrongly believe that they will be rendered unconscious by the drug. [ 114 ] [ 115 ]


Treatment is aimed at removing the paracetamol from the body and replenishing  glutathione . [ 115 ]   Activated charcoal  can be used to decrease absorption of paracetamol if the person comes to the hospital soon after the overdose. While the antidote,  acetylcysteine  (also called  N -acetylcysteine or NAC), acts as a precursor for glutathione, helping the body regenerate enough to prevent or at least decrease the possible damage to the liver; a  liver transplant  is often required if damage to the liver becomes severe. [ 41 ] [ 116 ]


NAC was usually given following a treatment  nomogram  (one for people with risk factors, and one for those without), but the use of the nomogram is no longer recommended as evidence to support the use of risk factors was poor and inconsistent, and many of the risk factors are imprecise and difficult to determine with sufficient certainty in clinical practice. [ 117 ] [ 118 ]  Toxicity of paracetamol is due to its  quinone metabolite   NAPQI  and NAC also helps in neutralizing it. [ 115 ]   Kidney failure  is also a possible side effect. [ 112 ]


Prokinetic agents  such as  metoclopramide  accelerate gastric emptying, shorten time (t max ) to paracetamol  peak blood plasma concentration  (C max ), and increase C max . Medications slowing gastric emptying such as  propantheline  and  morphine  lengthen t max  and decrease C max . [ 119 ] [ 120 ]  The interaction with morphine may result in patients failing to achieve the therapeutic concentration of paracetamol; the clinical significance of interactions with metoclopramide and propantheline is unclear. [ 120 ]


There have been suspicions that  cytochrome inducers  may enhance the toxic pathway of paracetamol metabolism to  NAPQI  (see  Paracetamol#Pharmacokinetics ). By and large, these suspicions have not been confirmed. [ 120 ]  Out of the inducers studied, the evidence of potentially increased liver toxicity in paracetamol overdose exists for  phenobarbital ,  primidone ,  isoniazid , and possibly  St John's wort . [ 121 ]  On the other hand, the anti-tuberculosis drug  isoniazid  cuts the formation of NAPQI by 70%. [ 120 ]


Ranitidine  increased paracetamol  area under the curve  (AUC) 1.6-fold. AUC increases are also observed with  nizatidine  and  cisapride . The effect is explained by these drugs inhibiting  glucuronidation  of paracetamol. [ 120 ]


Paracetamol raises plasma concentrations of  ethinylestradiol  by 22 % by inhibiting its sulfation. [ 120 ]  Paracetamol increases  INR  during  warfarin  therapy and should be limited to no more than 2 g per week. [ 122 ] [ 123 ] [ 124 ]


Paracetamol appears to exert its effects through two mechanisms: the inhibition of  cyclooxygenase  (COX) and actions of its metabolite  N-arachidonoylphenolamine  (AM404). [ 125 ]


Supporting the first mechanism, pharmacologically and in its side effects, paracetamol is close to classical nonsteroidal anti-inflammatory drugs (NSAIDs) that act by inhibiting  COX-1  and  COX-2  enzymes and especially similar to selective  COX-2 inhibitors . [ 126 ]  Paracetamol inhibits  prostaglandin  synthesis by reducing the active form of COX-1 and COX-2 enzymes. This occurs only when the concentration of  arachidonic acid  and  peroxides  is low. Under these conditions, COX-2 is the predominant form of cyclooxygenase, which explains the apparent COX-2 selectivity of paracetamol. Under the conditions of inflammation, the concentration of peroxides is high, which counteracts the reducing effect of paracetamol. Accordingly, the anti-inflammatory action of paracetamol is slight. [ 125 ] [ 126 ]  The anti-inflammatory action of paracetamol (via COX inhibition) has also been found to primarily target the  central nervous system  and not peripheral areas of the body, explaining the lack of side effects associated with conventional NSAIDs such as gastric bleeding.


The second mechanism centers on the paracetamol metabolite  AM404 . This metabolite has been detected in the brains of animals and  cerebrospinal fluid  of humans taking paracetamol. [ 125 ] [ 127 ]  It is formed in the brain from another paracetamol metabolite  4-aminophenol  by action of  fatty acid amide hydrolase . [ 125 ]  AM404 is a weak agonist of cannabinoid receptors  CB1  and  CB2 , an inhibitor of  endocannabinoid transporter , and a potent activator of  TRPV1  receptor. [ 125 ]  This and other research indicate that the  endocannabinoid system  and TRPV1 may play an important role in the analgesic effect of paracetamol. [ 125 ] [ 128 ]


In 2018, Suemaru  et al . found that, in mice, paracetamol exerts an anticonvulsant effect by activation of the  TRPV1  receptors [ 129 ]  and a decrease in neuronal excitability by  hyperpolarization  of neurons. [ 130 ]  The exact mechanism of the anticonvulsant effect of acetaminophen is not clear. According to Suemaru  et al ., acetaminophen and its active metabolite  AM404  show a dose-dependent anticonvulsant activity against pentylenetetrazol-induced seizures in mice. [ 129 ]


After being taken by mouth, paracetamol is rapidly absorbed from the  small intestine , while absorption from the stomach is negligible. Thus, the rate of absorption depends on stomach emptying. Food slows the stomach's emptying and absorption, but the total amount absorbed stays the same. [ 131 ]  In the same subjects, the peak plasma concentration of paracetamol was reached after 20 minutes when fasting versus 90 minutes when fed. High carbohydrate (but not high protein or high fat) food decreases paracetamol peak plasma concentration by four times. Even in the fasting state, the rate of absorption of paracetamol is variable and depends on the formulation, with maximum plasma concentration being reached after 20 minutes to 1.5 hours. [ 6 ]


Paracetamol's  bioavailability  is dose-dependent: it increases from 63 % for 500   mg dose to 89 % for 1000   mg dose. [ 6 ]  Its plasma terminal elimination half-life is 1.9–2.5 hours, [ 6 ]  and  volume of distribution  is roughly 50   L. [ 132 ]  Protein binding is negligible, except under the conditions of overdose, when it may reach 15–21 %. [ 6 ]  The concentration in serum after a typical dose of paracetamol usually peaks below 30   μg/mL (200   μmol/L). [ 133 ]  After 4 hours, the concentration is usually less than 10   μg/mL (66   μmol/L). [ 133 ]


Paracetamol is  metabolized  primarily in the liver, mainly by  glucuronidation  and  sulfation , and the products are then eliminated in the urine (see the Scheme on the right). Only 2–5 % of the drug is excreted unchanged in the urine. [ 6 ]  Glucuronidation by  UGT1A1  and  UGT1A6  accounts for 50–70 % of the drug metabolism. Additional 25–35 % of paracetamol is converted to sulfate by sulfation enzymes  SULT1A1 ,  SULT1A3 , and  SULT1E1 . [ 134 ]


A minor metabolic pathway (5–15 %) of oxidation by  cytochrome P450  enzymes, mainly by  CYP2E1 , forms a toxic metabolite known as  NAPQI  ( N -acetyl- p -benzoquinone imine). [ 134 ]  NAPQI is responsible for the liver toxicity of paracetamol. At usual doses of paracetamol, NAPQI is quickly detoxified by conjugation with  glutathione . The non-toxic conjugate APAP-GSH is taken up in the bile and further degraded to mercapturic and cysteine conjugates that are excreted in the urine. In overdose, glutathione is depleted by a large amount of formed NAPQI, and NAPQI binds to  mitochondria  proteins of the liver cells causing  oxidative stress  and toxicity. [ 134 ]


Yet another minor but important direction of metabolism is deacetylation of 1–2 % of paracetamol to form  p -aminophenol .  p -Aminophenol is then converted in the brain by  fatty acid amide hydrolase  into  AM404 , a compound that may be partially responsible for the analgesic action of paracetamol. [ 132 ]


The classical methods for the production of paracetamol involve the  acetylation  of  4-aminophenol  with  acetic anhydride  as the last step. They differ in how 4-aminophenol is prepared. In one method,  nitration  of  phenol  with  nitric acid  affords  4-nitrophenol , which is reduced to 4-aminophenol by  hydrogenation  over  Raney nickel . In another method,  nitrobenzene  is reduced  electrolytically  giving 4-aminophenol directly. Additionally, 4-nitrophenol can be selectively reduced by  Tin(II) Chloride  in  absolute ethanol  or  ethyl acetate  to produce a 91 % yield of 4-aminophenol. [ 135 ] [ 136 ] [ 137 ]


An alternative industrial synthesis developed at  Celanese  involves firstly direct acylation of phenol with acetic anhydride in the presence of  hydrogen fluoride  to a ketone, then the conversion of the ketone with  hydroxylamine  to a  ketoxime , and finally the acid-catalyzed  Beckmann rearrangement  of the cetoxime to the para-acetylaminophenol product. [ 135 ] [ 138 ]


4 -Aminophenol may be obtained by the amide  hydrolysis  of paracetamol. This reaction is also used to determine paracetamol in urine samples: After hydrolysis with hydrochloric acid,  4 -aminophenol reacts in ammonia solution with a phenol derivate, e.g. salicylic acid, to form an  indophenol  dye under oxidization by air. [ 139 ]


Acetanilide  was the first  aniline  derivative serendipitously found to possess analgesic as well as antipyretic properties, and was quickly introduced into medical practice under the name of  Antifebrin  by Cahn & Hepp in 1886. [ 140 ]  But its unacceptable toxic effects—the most alarming being  cyanosis  due to  methemoglobinemia , an increase of hemoglobin in its ferric [Fe 3+ ] state, called  methemoglobin , which cannot bind oxygen, and thus decreases overall carriage of oxygen to tissue—prompted the search for less toxic aniline derivatives. [ 141 ]  Some reports state that Cahn & Hepp or a French chemist called Charles Gerhardt first synthesized paracetamol in 1852. [ 45 ] [ 46 ]


Harmon Northrop Morse  synthesized paracetamol at  Johns Hopkins University  via the reduction of  p -nitrophenol  with  tin  in glacial  acetic acid  in 1877, [ 142 ] [ 143 ]  but it was not until 1887 that clinical pharmacologist  Joseph von Mering  tried paracetamol on humans. [ 141 ]  In 1893, von Mering published a paper reporting on the clinical results of paracetamol with  phenacetin , another aniline derivative. [ 144 ]  Von Mering claimed that, unlike phenacetin, paracetamol had a slight tendency to produce  methemoglobinemia . Paracetamol was then quickly discarded in favor of phenacetin. The sales of phenacetin established  Bayer  as a leading pharmaceutical company. [ 145 ]


Von Mering's claims remained essentially unchallenged for half a century until two teams of researchers from the United States analyzed the metabolism of acetanilide and phenacetin. [ 145 ]  In 1947,  David Lester  and Leon Greenberg found strong evidence that paracetamol was a major metabolite of acetanilide in human blood, and in a subsequent study they reported that large doses of paracetamol given to albino rats did not cause methemoglobinemia. [ 146 ]  In 1948,  Bernard Brodie ,  Julius Axelrod  and Frederick Flinn confirmed that paracetamol was the major metabolite of acetanilide in humans, and established that it was just as efficacious an analgesic as its precursor. [ 147 ] [ 148 ] [ 149 ]  They also suggested that methemoglobinemia is produced in humans mainly by another metabolite,  phenylhydroxylamine . A follow-up paper by Brodie and Axelrod in 1949 established that phenacetin was also metabolized to paracetamol. [ 150 ]  This led to a "rediscovery" of paracetamol. [ 141 ]


Paracetamol was first marketed in the United States in 1950 under the name Trigesic, a combination of paracetamol, aspirin, and caffeine. [ 143 ]  Reports in 1951 of three users stricken with the blood disease  agranulocytosis  led to its removal from the marketplace, and it took several years until it became clear that the disease was unconnected. [ 143 ]  The following year, 1952, paracetamol returned to the U.S. market as a prescription drug. [ 151 ]  In the United Kingdom, marketing of paracetamol began in 1956 by  Sterling-Winthrop Co.  as Panadol, available only by prescription, and promoted as preferable to aspirin since it was safe for children and people with ulcers. [ 152 ] [ 153 ]  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. [ 152 ] [ 143 ]


Concerns about paracetamol's safety delayed its widespread acceptance until the 1970s, but in the 1980s paracetamol sales exceeded those of aspirin in many countries, including the United Kingdom. This was accompanied by the commercial demise of phenacetin, blamed as the cause of  analgesic nephropathy  and hematological toxicity. [ 141 ]  Available in the U.S. without a prescription since 1955 [ 151 ]  (1960, according to another source [ 154 ] ), paracetamol has become a common household drug. [ 155 ]  In 1988, Sterling Winthrop was acquired by  Eastman Kodak  which sold the over the counter drug rights to  SmithKline Beecham  in 1994. [ 156 ]


In June 2009, an FDA advisory committee recommended that new restrictions be placed on paracetamol use in the United States to help protect people from the potential toxic effects. The maximum single adult dosage would be decreased from 1000   mg to 650   mg, while combinations of paracetamol and other products would be prohibited. Committee members were particularly concerned by the fact that the then-present maximum dosages of paracetamol had been shown to produce alterations in liver function. [ 157 ]


In January 2011, the FDA asked manufacturers of prescription combination products containing paracetamol to limit its amount to no more than 325   mg per tablet or capsule and began requiring manufacturers to update the labels of all prescription combination paracetamol products to warn of the potential risk of severe liver damage. [ 158 ] [ 159 ] [ 160 ] [ 161 ] [ 162 ]  Manufacturers had three years to limit the amount of paracetamol in their prescription drug products to 325   mg per dosage unit. [ 159 ] [ 161 ]


In November 2011, the  Medicines and Healthcare products Regulatory Agency  revised UK dosing of liquid paracetamol for children. [ 163 ]


In September 2013, "Use Only as Directed", an episode of the radio program  This American Life [ 164 ]  highlighted deaths from paracetamol overdose. This report was followed by two reports by  ProPublica  alleging that the "FDA has long been aware of studies showing the risks of acetaminophen. So has the maker of Tylenol, McNeil Consumer Healthcare, a division of Johnson & Johnson" [ 165 ]  and "McNeil, the maker of Tylenol, ... has repeatedly opposed safety warnings, dosage restrictions and other measures meant to safeguard users of the drug." [ 166 ]


Paracetamol  is the  Australian Approved Name [ 167 ]  and  British Approved Name [ 168 ]  as well as the  international nonproprietary name  used by the WHO and in many other countries;  acetaminophen  is the  United States Adopted Name [ 168 ]  and  Japanese Accepted Name  and also the name generally used in Canada, [ 168 ]  Venezuela, Colombia, and Iran. [ 168 ] [ 169 ]  Both  paracetamol  and  acetaminophen  are contractions of chemical names for the compound. The word "paracetamol" is a shortened form of para-acetylaminophenol, [ 170 ]  and was coined by Frederick Stearns & Co in 1956, [ 171 ]  while the word "acetaminophen" is a shortened form of N-acetyl-p-aminophenol (APAP), which was coined and first marketed by McNeil Laboratories in 1955. [ 172 ]  The initialism  APAP  is used by dispensing pharmacists in the United States. [ 173 ]


Paracetamol is available in oral, suppository, and  intravenous  forms. [ 174 ]  Intravenous paracetamol is sold under the brand name Ofirmev in the United States. [ 175 ]


In some formulations, paracetamol is combined with the  opiate   codeine , sometimes referred to as  co-codamol  ( BAN ) and Panadeine in Australia. In the U.S., this combination is available only by prescription. [ 176 ]  As of 1 February 2018, medications containing codeine also became prescription-only in Australia. [ 177 ]  Paracetamol is also combined with other opioids such as  dihydrocodeine , [ 178 ]  referred to as  co-dydramol  ( British Approved Name  (BAN)),  oxycodone [ 179 ]  or  hydrocodone . [ 180 ]  Another very commonly used analgesic combination includes paracetamol in combination with  propoxyphene napsylate . [ 181 ]  A combination of paracetamol, codeine, and the  doxylamine succinate  is also available. [ 182 ]


Paracetamol is sometimes combined with  phenylephrine hydrochloride . [ 183 ]  Sometimes a third active ingredient, such as  ascorbic acid , [ 183 ] [ 184 ]   caffeine , [ 185 ] [ 186 ]   chlorpheniramine maleate , [ 187 ]  or  guaifenesin [ 188 ] [ 189 ] [ 190 ]  is added to this combination.


Claims that paracetamol is an effective analgesic medication to treat symptoms of  COVID-19  were found to be unsubstantiated. [ 191 ] [ 192 ] [ 193 ] [ 194 ]


Paracetamol is extremely toxic to cats, which lack the necessary  UGT1A6  enzyme to detoxify it. Initial symptoms include vomiting, salivation, and discoloration of the tongue and gums. Unlike an overdose in humans, liver damage is rarely the cause of death; instead,  methemoglobin  formation and the production of  Heinz bodies  in red blood cells inhibit oxygen transport by the blood, causing  asphyxiation  ( methemoglobinemia  and  hemolytic anemia ). [ 195 ]  Treatment of the toxicosis with  acetylcysteine  is recommended. [ 196 ]


Paracetamol has been reported to be as effective as aspirin in the treatment of musculoskeletal pain in dogs. [ 197 ]  A paracetamol–codeine product (brand name Pardale-V) [ 198 ]  licensed for use in dogs is available for purchase under supervision of a vet, pharmacist or other qualified person. [ 198 ]  It should be administered to dogs only on veterinary advice and with extreme caution. [ 198 ]


The main effect of toxicity in dogs is liver damage, and GI ulceration has been reported. [ 196 ] [ 199 ] [ 200 ] [ 201 ]  Acetylcysteine treatment is efficacious in dogs when administered within two hours of paracetamol ingestion. [ 196 ] [ 197 ]


Paracetamol is lethal to snakes [ 202 ]  and has been suggested as a chemical control program for the invasive  brown tree snake  ( Boiga irregularis ) in  Guam . [ 203 ] [ 204 ]  Doses of 80   mg are inserted into dead mice that are scattered by helicopter [ 205 ]  as lethal bait to be consumed by the snakes.


Phenytoin  ( PHT ), sold under the brand name  Dilantin  among others, [ 1 ]  is an  anti-seizure medication . [ 3 ]  It is useful for the prevention of  tonic-clonic seizures  (also known as grand mal seizures) and  focal seizures , but not  absence seizures . [ 3 ]  The intravenous form,  fosphenytoin , is used for  status epilepticus  that does not improve with  benzodiazepines . [ 3 ]   It may also be used for certain  heart arrhythmias  or  neuropathic pain . [ 3 ]  It can be taken  intravenously  or by mouth. [ 3 ]  The intravenous form generally begins working within 30 minutes and is effective for roughly 24 hours. [ 4 ]  Blood levels can be measured to determine the proper dose. [ 3 ]


Common side effects include nausea, stomach pain, loss of appetite, poor coordination,  increased hair growth , and  enlargement of the gums . [ 3 ]  Potentially serious side effects include  sleepiness ,  self harm , liver problems,  bone marrow suppression ,  low blood pressure ,  toxic epidermal necrolysis [ 3 ] , and atrophy of the  cerebellum . [ 6 ] [ 7 ] [ 8 ]  There is evidence that use during pregnancy results in abnormalities in the baby. [ 3 ]   It appears to be safe to use when  breastfeeding . [ 3 ]   Alcohol  may interfere with the medication's effects. [ 3 ]


Phenytoin was first made in 1908 by the German chemist  Heinrich Biltz  and found useful for seizures in 1936. [ 9 ] [ 10 ]  It is on the  World Health Organization's List of Essential Medicines . [ 11 ]  Phenytoin is available as a  generic medication . [ 12 ]   In 2020, it was the 260th most commonly prescribed medication in the United States, with more than 1   million prescriptions. [ 13 ] [ 14 ]


Though phenytoin has been used to treat seizures in infants, as of 2023, its effectiveness in this age group has been evaluated in only one study. Due to the lack of a comparison group, the evidence is inconclusive. [ 17 ]


Common side effects include nausea, stomach pain, loss of appetite, poor coordination,  increased hair growth , and  enlargement of the gums . Potentially serious side effects include  sleepiness ,  self harm , liver problems,  bone marrow suppression ,  low blood pressure , and  toxic epidermal necrolysis . There is evidence that use during pregnancy results in abnormalities in the baby. Its use appears to be safe during  breastfeeding .  Alcohol  may interfere with the medication's effects. [ 3 ]


Severe  low blood pressure  and abnormal heart rhythms can be seen with rapid infusion of IV phenytoin. IV infusion should not exceed 50 mg/min in adults or 1–3 mg/kg/min (or 50 mg/min, whichever is slower) in children. Heart monitoring should occur during and after IV infusion. Due to these risks, oral phenytoin should be used if possible. [ 21 ]


At therapeutic doses, phenytoin may produce  nystagmus  on lateral gaze. At toxic doses, patients experience vertical nystagmus,  double vision ,  sedation , slurred speech, cerebellar  ataxia , and  tremor . [ 22 ]  If phenytoin is stopped abruptly, this may result in increased seizure frequency, including  status epilepticus . [ 21 ] [ 20 ]


Phenytoin may accumulate in the  cerebral cortex  over long periods of time which can cause  atrophy  of the  cerebellum . The degree of atrophy is related to the duration of phenytoin treatment and is not related to dosage of the medication. [ 23 ]


Phenytoin is known to be a causal factor in the development of  peripheral neuropathy . [ 24 ]


Folate is present in food in a polyglutamate form, which is then converted into monoglutamates by  intestinal conjugase  to be absorbed by the jejunum. Phenytoin acts by inhibiting this enzyme, thereby causing  folate deficiency , and thus  megaloblastic anemia . [ 25 ]
Other side effects may include:  agranulocytosis , [ 26 ]   aplastic anemia , [ 27 ]   decreased white blood cell count , [ 28 ]  and  a low platelet count . [ 29 ]


Phenytoin is a known  teratogen , since children exposed to phenytoin are at a higher risk of  birth defects  than children born to women without epilepsy and to women with untreated epilepsy. [ 30 ] [ 31 ]  The birth defects, which occur in approximately 6% of exposed children, include  neural tube defects ,  heart defects  and  craniofacial abnormalities , including broad nasal bridge, cleft lip and palate, and  smaller than normal head . [ 31 ] [ 32 ]  The effect on IQ cannot be determined as no study involves phenytoin as monotherapy, however poorer language abilities and  delayed motor development  may have been associated with maternal use of phenytoin during pregnancy. [ 30 ]  This syndrome resembles the well-described  fetal alcohol syndrome . [ 33 ]  and has been referred to as " fetal hydantoin syndrome ". Some recommend avoiding polytherapy and maintaining the minimal dose possible during pregnancy, but acknowledge that current data fails to demonstrate a dose effect on the risk of birth defects. [ 30 ] [ 31 ]  Data now being collected by the Epilepsy and Antiepileptic Drug Pregnancy Registry may one day answer this question definitively.


There is no good evidence to suggest that phenytoin is a human  carcinogen . [ 34 ] [ 35 ]  However, lymph node abnormalities have been observed, including malignancies. [ 36 ]


Phenytoin has been associated with drug-induced  gingival enlargement  (overgrowth of the gums), probably due to above-mentioned folate deficiency; indeed, evidence from a  randomized controlled trial  suggests that folic acid supplementation can prevent gingival enlargement in children who take phenytoin. [ 37 ]  Plasma concentrations needed to induce gingival lesions have not been clearly defined.  Effects consist of the following: bleeding upon probing, increased gingival  exudate , pronounced gingival inflammatory response to plaque levels, associated in some instances with bone loss but without tooth detachment.


Hypertrichosis ,  Stevens–Johnson syndrome ,  purple glove syndrome , rash,  exfoliative dermatitis ,  itching ,  excessive hairiness , and coarsening of facial features can be seen in those taking phenytoin.


Phenytoin therapy has been linked to the life-threatening skin reactions  Stevens–Johnson syndrome  (SJS) and  toxic epidermal necrolysis  (TEN). These conditions are significantly more common in patients with a particular  HLA-B   allele ,  HLA-B*1502 . [ 38 ]  This allele occurs almost exclusively in patients with ancestry across broad areas of Asia, including South Asian Indians.


Phenytoin is primarily metabolized to its inactive form by the enzyme  CYP2C9 . Variations within the CYP2C9 gene that result in decreased enzymatic activity have been associated with increased phenytoin concentrations, as well as reports of drug toxicities due to these increased concentrations. [ 39 ]  The  U.S. Food and Drug Administration  (FDA) notes on the phenytoin drug label that since strong evidence exists linking HLA-B*1502 with the risk of developing SJS or TEN in patients taking  carbamazepine , consideration should be given to avoiding phenytoin as an alternative to carbamazepine in patients carrying this allele. [ 40 ]


Phenytoin has been known to cause drug-induced  lupus . [ 41 ]


Phenytoin is also associated with induction of reversible  IgA deficiency . [ 42 ]


Phenytoin may increase risk of suicidal thoughts or behavior. People on phenytoin should be monitored for any changes in mood, the development or worsening depression, and/or any thoughts or behavior of suicide. [ 20 ]


Chronic phenytoin use has been associated with decreased bone density and increased bone fractures. Phenytoin induces metabolizing enzymes in the liver. This leads to increased metabolism of  vitamin D , thus decreased vitamin D levels.  Vitamin D deficiency , as well as  low calcium  and  phosphate  in the blood cause decreased bone mineral density. [ 20 ]


Phenytoin is an inducer of the  CYP3A4  and  CYP2C9  families of the  P450  enzyme responsible for the liver's degradation of various drugs. [ 43 ]


A 1981 study by the  National Institutes of Health  showed that  antacids  administered concomitantly with phenytoin "altered not only the extent of absorption but also appeared to alter the rate of absorption.  Antacids administered in a peptic ulcer regimen may decrease the AUC of a single dose of phenytoin. Patients should be cautioned against concomitant use of antacids and phenytoin." [ 44 ]


Warfarin  and  trimethoprim  increase serum phenytoin levels and prolong the serum half-life of phenytoin by inhibiting its metabolism. Consider using other options if possible. [ 45 ]


In general, phenytoin can interact with the following drugs: [ citation needed ]


Phenytoin is believed to protect against seizures by causing voltage-dependent block of  voltage gated sodium channels . [ 46 ]  This blocks sustained high frequency repetitive firing of  action potentials . This is accomplished by reducing the amplitude of sodium-dependent action potentials through enhancing steady-state inactivation. Sodium channels exist in three main conformations: the resting state, the open state, and the inactive state.


Phenytoin binds preferentially to the inactive form of the sodium channel. Because it takes time for the bound drug to dissassociate from the inactive channel, there is a time-dependent block of the channel. Since the fraction of inactive channels is increased by membrane  depolarization  as well as by repetitive firing, the binding to the inactive state by phenytoin sodium can produce voltage-dependent, use-dependent and time-dependent block of sodium-dependent action potentials. [ 47 ]


The primary site of action appears to be the  motor cortex  where spread of seizure activity is inhibited. [ 48 ]  Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of  post-tetanic potentiation  at synapses which prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of generalized tonic-clonic seizures. [ 21 ]


Phenytoin elimination kinetics show mixed-order, non-linear elimination behaviour at therapeutic concentrations. Where phenytoin is at low concentration it is cleared by  first order kinetics , and at high concentrations by  zero order kinetics . A small increase in dose may lead to a large increase in drug concentration as elimination becomes saturated. The time to reach steady state is often longer than 2 weeks. [ 49 ] [ 50 ] [ 51 ] [ 52 ]


Phenytoin (diphenylhydantoin) was first synthesized by German chemist  Heinrich Biltz  in 1908. [ 53 ]
Biltz sold his discovery to Parke-Davis, which did not find an immediate use for it. In 1938, other physicians, including  H. Houston Merritt  and  Tracy Putnam , discovered phenytoin's usefulness for controlling seizures, without the sedative effects associated with  phenobarbital . [ 54 ]


According to  Goodman and Gilman's Pharmacological Basis of Therapeutics :


In contrast to the earlier accidental discovery of the antiseizure properties of  potassium bromide  and phenobarbital, phenytoin was the product of a search among nonsedative structural relatives of phenobarbital for agents capable of suppressing electroshock convulsions in laboratory animals. [ 55 ]


It was approved by the FDA in 1953 for use in seizures. [ citation needed ]


Jack Dreyfus , founder of the  Dreyfus Fund , became a major proponent of phenytoin as a means to control nervousness and  depression  when he received a prescription for Dilantin in 1966. He has claimed to have supplied large amounts of the drug to  Richard Nixon  throughout the late 1960s and early 1970s, although this is disputed by former White House aides [ 56 ]  and Presidential historians. [ 57 ]
Dreyfus' experience with phenytoin is outlined in his book,  A Remarkable Medicine Has Been Overlooked . [ 58 ]  Despite more than $70 million in personal financing, his push to see phenytoin evaluated for alternative uses has had little lasting effect on the medical community.  This was partially because  Parke-Davis  was reluctant to invest in a drug nearing the end of its patent life, and partially due to mixed results from various studies. [ citation needed ]


In 2008, the drug was put on the FDA's Potential Signals of Serious Risks List to be further evaluated for approval. The list identifies medications with which the FDA has identified potential safety issues, but has not yet identified a causal relationship between the drug and the listed risk. To address this concern, the Warnings and Precautions section of the labeling for Dilantin injection was updated to include additional information about  Purple glove syndrome  in November 2011. [ 59 ]


Phenytoin is available as a generic medication. [ 12 ]


Since September 2012, the marketing licence in the UK has been held by Flynn Pharma Ltd, of Dublin,  Ireland , and the product, although identical, has been called Phenytoin Sodium  xx mg Flynn Hard Capsules. (The  xx mg in the name refers to the strength—for example "Phenytoin sodium 25 mg Flynn Hard Capsules"). [ 60 ]   The capsules are still made by  Pfizer 's Goedecke subsidiary's plant in  Freiburg , Germany, and they still have Epanutin printed on them. [ 61 ]  After Pfizer's sale of the UK marketing licence to Flynn Pharma, the price of a 28-pack of 25 mg phenytoin sodium capsules marked Epanutin rose from 66p (about $0.88) to  £15.74  (about $25.06). Capsules of other strengths also went up in price by the same factor—2,384%, [ 62 ]  costing the UK's  National Health Service  an extra  £43 million  (about $68.44 million) a year. [ 63 ]   The companies were referred to the  Competition and Markets Authority  (CMA) who found that they had exploited their dominant position in the market to charge "excessive and unfair" prices. [ 64 ]


The CMA imposed a record  £84.2 million  fine on the manufacturer Pfizer, and a  £5.2 million  fine on the distributor Flynn Pharma and ordered the companies to reduce their prices. [ 65 ]


Phenytoin is marketed under many brand names worldwide. [ 1 ]


In the US, Dilantin is marketed by  Viatris  after Upjohn was spun off from Pfizer. [ 66 ] [ 67 ] [ 68 ]


Tentative evidence suggests that topical phenytoin is useful in wound healing in people with chronic skin wounds. [ 69 ] [ 70 ]  A meta-analysis also supported the use of phenytoin in managing various ulcers. [ 71 ]  Phenytoin is incorporated into compounded medications to optimize wound treatment, often in combination with  misoprostol . [ 72 ] [ 73 ]


Some clinical trials have explored whether phenytoin can be used as  neuroprotector  in  multiple sclerosis . [ 74 ]


Piroxicam  is a  nonsteroidal anti-inflammatory drug  (NSAID) of the  oxicam  class used to relieve the symptoms of painful inflammatory conditions like  arthritis . [ 4 ] [ 5 ]  Piroxicam works by preventing the production of endogenous  prostaglandins  which are involved in the mediation of pain, stiffness, tenderness and swelling. [ 4 ]  The medicine is available as  capsules ,  tablets  and, in some countries, as a prescription-free  gel  0.5%. [ 6 ]  It is also available in a  betadex  formulation, which allows a more rapid absorption of piroxicam from the digestive tract. [ 4 ]  Piroxicam is one of the few NSAIDs that can be given  parenteral  routes. [ citation needed ]


It was patented in 1968 by  Pfizer  and approved for medical use in 1979. [ 7 ]  It became generic in 1992, [ 8 ]  and is marketed worldwide under many brand names. [ 1 ]


It is used in the treatment of certain inflammatory conditions like  rheumatoid  and  osteoarthritis , primary  dysmenorrhoea , and postoperative pain; it acts as an  analgesic , especially where there is an  inflammatory  component. [ 4 ]  The  European Medicines Agency  issued a review of its use in 2007 and recommended that its use be limited to the treatment of chronic inflammatory conditions, as it is only in these circumstances that its risk-benefit ratio proves to be favourable. [ 6 ] [ 9 ]


As with other NSAIDs the principal side effects include: digestive complaints like  nausea , discomfort,  diarrhoea  and bleeds or ulceration of the  stomach , as well as  headache , dizziness, nervousness,  depression , drowsiness,  insomnia , vertigo, hearing disturbances (such as  tinnitus ),  high blood pressure ,  oedema , light sensitivity, skin reactions (including, albeit rarely,  Stevens–Johnson syndrome  and  toxic epidermal necrolysis ) and rarely,  kidney failure ,  pancreatitis ,  liver  damage, visual disturbances, pulmonary  eosinophilia  and  fibrosing alveolitis . [ 6 ]  Compared to other NSAIDs it is more prone to causing gastrointestinal disturbances and serious skin reactions. [ 6 ]


In October 2020, the U.S.  Food and Drug Administration  (FDA) required the  drug label  to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid. [ 10 ] [ 11 ]  They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy. [ 10 ] [ 11 ]


Piroxicam is an NSAID and, as such, is a non-selective  COX   inhibitor  possessing both analgesic and  antipyretic  properties. [ 6 ]


Piroxicam exists as  alkenol   tautomer  in organic solvents and as  zwitterionic  form in water. [ 12 ]


The project that produced piroxicam began in 1962 at  Pfizer ; the first clinical trial results were reported in 1977, and the product launched in 1980 under the brand name "Feldene". [ 8 ] [ 13 ]    Major patents expired in 1992 [ 8 ]  and the drug is marketed worldwide under many brandnames. [ 1 ]


Psoralen  (also called  psoralene ) is the parent compound in a family of naturally occurring organic compounds known as the linear  furanocoumarins . It is structurally related to  coumarin  by the addition of a fused  furan  ring, and may be considered as a derivative of  umbelliferone . Psoralen occurs naturally in the seeds of  Psoralea corylifolia , as well as in the  common fig ,  celery ,  parsley ,  West Indian satinwood , and in all  citrus fruits . It is widely used in  PUVA  (psoralen +  UVA ) treatment for  psoriasis ,  eczema ,   vitiligo , and  cutaneous T-cell lymphoma ; these applications are typically through the use of medications such as  Methoxsalen .  Many furanocoumarins are extremely toxic to fish, and some are deposited in streams in  Indonesia  to catch fish. [ 1 ]


Psoralen is a  mutagen , and is used for this purpose in molecular biology research. Psoralen  intercalates  into DNA and on exposure to ultraviolet (UVA) radiation can form  monoadducts  and  covalent interstrand cross-links  (ICL) with thymines, preferentially at 5'-TpA sites in the genome, inducing  apoptosis . Psoralen plus UVA (PUVA) therapy can be used to treat hyperproliferative skin disorders like  psoriasis  and certain kinds of  skin cancer . [ 2 ]  Unfortunately, PUVA treatment itself leads to a higher risk of skin cancer. [ 3 ]


An important use of psoralen is in PUVA treatment for skin problems such as  psoriasis  and, to a lesser extent, eczema and  vitiligo . This takes advantage of the high  UV  absorbance of psoralen. The psoralen is applied first to sensitise the skin, then UVA light is applied to address the condition. Psoralens are also used in  photopheresis , where they are mixed with the extracted leukocytes before UV radiation is applied.


Despite the  photocarcinogenic  properties of psoralen, [ 4 ] [ 5 ]  it was used as a  tanning activator  in sunscreens until 1996. [ 6 ]  Psoralens are used in tanning accelerators, because psoralen increases the skin's sensitivity to light.  Some patients have had severe skin loss after sunbathing with psoralen-containing tanning activators. [ 7 ]  Patients with lighter skin colour suffer four times as much from the melanoma-generating properties of psoralens than those with darker skin. [ 6 ]  Psoralens short term side effects include nausea, vomiting, erythrema, pruritus, xerosis, skin pain due to phototoxic damage of dermal nerve and may cause cutaneous and genital skin malignancies. [ 8 ]


An additional use for optimized psoralens is for the inactivation of pathogens in blood products. The synthetic amino-psoralen, amotosalen HCl, has been developed for the inactivation of infectious pathogens (bacteria, viruses, protozoa) in platelet and plasma blood components prepared for transfusion support of patients. Prior to clinical use, amotosalen-treated platelets have been tested and found to be non-carcinogenic when using the established p53  knockout mouse  model. [ 9 ]   The technology is currently in routine use in certain European blood centers and has been recently approved in the US. [ 10 ] [ 11 ] [ 12 ] [ 13 ]


Psoralen  intercalates  into the DNA double helix where it is ideally positioned to form one or more  adducts  with adjacent pyrimidine bases, preferentially thymine, upon excitation by an ultraviolet photon.


Several physicochemical methods have been employed to derive binding constants for psoralen-DNA interactions. Classically, two chambers of psoralen and buffered DNA solution are partitioned by a  semi-permeable membrane ; the affinity of the psoralen for DNA is directly related to the concentration of the psoralen in the DNA chamber after equilibrium. Water solubility is important for two reasons:  pharmacokinetics  relating to drug solubility in blood and necessitating the use of organic solvents (e.g.  DMSO ). Psoralens can also be activated by irradiation with long wavelength UV light. While  UVA  range light is the clinical standard, research that  UVB  is more efficient at forming photoadducts suggests that its use may lead to higher efficacy and lower treatment times. [ 14 ]


The photochemically reactive sites in psoralens are the alkene-like carbon-carbon double bonds in the furan ring (the five-member ring) and the pyrone ring (the six-member ring). When appropriately intercalated adjacent to a pyrimidine base, a four-center photocycloaddition reaction can lead to the formation of either of two cyclobutyl-type monoadducts. Ordinarily, furan-side monoadducts form in a higher proportion. The furan monoadduct can absorb a second UVA photon leading to a second four-center photocycloaddition at the pyrone end of the molecule and hence the formation of a diadduct or cross-link. Pyrone monoadducts do not absorb in the UVA range and hence cannot form cross-links with further UVA irradiation. [ 15 ]


Another important feature of this class of compounds is their ability to generate  singlet oxygen , although this process is in direct competition with adduct formation and may be an alternate pathway for the dissipation of excited state energy.


Research on psoralen has historically focused on interactions with DNA and RNA (in particular, ICL formation). Psoralen, however, has also been shown to block signaling of the  ErbB2 receptor  which is overexpressed in certain aggressive types of breast cancer. [ 16 ]  A synthetic derivative of  bergapten , 5-(4-phenoxybutoxy)psoralen, shows promise as an immunosuppressant by inhibiting a specific  potassium channel . Its structure prevents intercalation into DNA, and it only very weakly produces singlet oxygen, majorly reducing unwanted toxicity and mutagenicity  in vivo . This has implications for the treatment of various autoimmune diseases (e.g.  multiple sclerosis ,  type-1 diabetes , and  rheumatoid arthritis ). [ 17 ]  While cell-surface modification and ion channel blocking are two newly discovered mechanisms of action, much research remains to be done.


Most furanocoumarins can be regarded as derivatives of either psoralen or  angelicin . Psoralen and its derivatives are often referred to as the  linear furanocoumarins , so called since they exhibit a linear chemical structure. Important linear furanocoumarins include xanthotoxin (also called  methoxsalen ),  bergapten ,  imperatorin , and  nodakenetin .


The structure of psoralen was originally deduced by identifying the products of its degradation reactions. It exhibits the normal reactions of the  lactone  of coumarin, such as ring opening by  alkali  to give a  coumarinic acid  or  coumaric acid  derivative.  Potassium permanganate  causes oxidation of the furan ring, while other methods of oxidation produce furan-2,3-carboxylic acid.


Psoralen is difficult to synthesize because  umbelliferone  undergoes  substitution  at the 8-position rather than at the desired 6 position.  Benzofuran  reacts preferentially in the  furan  ring rather than in the  benzene  ring. However, the 7-hydroxy derivative of 2,3-dihydrobenzofuran (also called coumaran) does undergo substitution at the desired 6-position allowing the following synthesis of the coumarin system via a  Gattermann–Koch reaction  followed by a  Perkin condensation  using  acetic anhydride . The synthesis is then completed by  dehydrogenation  of the five-membered ring to produce the furan ring.


Psoralen originates from  coumarins  in the  shikimate  pathway; its biosynthesis is shown in the figure below. The aromatic ring in 6 is activated at positions ortho to the hydroxyl group, and is alkylated by 5, an  alkylating agent . The dimethylallyl group in 7 then undergoes cyclization with the phenol group to give 8. This transformation is catalysed by a cytochrome P-450-dependent monooxygenase17 (psoralen 5-monooxygenase), and cofactors ( NADPH ) and molecular oxygen. [ 18 ]


A biosynthetic pathway in which psoralen is formed is shown in the figure below. A second  P-450 -dependent  monooxygenase  enzyme ( psoralen synthase ) then cleaves off 10 (in the form of 11) from 8 to give 1. This pathway does not involve any hydroxylated intermediate, and cleavage is postulated to be initiated by a  radical reaction . [ 18 ]


Ficus carica  (fig) is probably the most abundant source of psoralens. They are also found in small quantities in   Ammi visnaga  (bisnaga),  Pastinaca sativa  (parsnip),  Petroselinum crispum  ( parsley ),  Levisticum officinale  (lovage),  Foeniculum vulgare  (fruit, i.e., fennel seeds),  Daucus carota  (carrot),  Psoralea corylifolia  (babchi),  Apium graveolens  (celery),  bergamot oil  ( bergapten ,  bergamottin ). [ 19 ]


PUVA treatment  produces both  DNA interstrand crosslinks  (ICLs) and monoadducts. The ICLs introduced by psoralen are highly  genotoxic  to actively replicating cells.  The covalent linkage impedes  replication fork  progression. Thus unlinking the ICL is required before replication can resume.  The initial steps in repair ordinarily involve incisions in one parental strand on both sides of the crosslink. [ 20 ]   Subsequently, repair of the lesion can occur by an accurate or an inaccurate process.


The accurate process for repairing crosslinks is  homologous recombinational  repair (HRR). This involves replacing the damaged information using the intact information from another  homologous chromosome  in the same cell.   Escherichia coli  cells deficient in HRR are highly sensitive to PUVA compared to wild-type cells. [ 21 ]   HRR appears to be efficient.  In  E. coli , even though one or two unrepaired crosslinks are sufficient to inactivate a cell, a wild-type cell can repair and therefore recover from 53 to 71 psoralen crosslinks. [ 21 ]   In the yeast  Saccharomyces cerevisiae  HRR is a major pathway for accurately removing psoralen-crosslinks. [ 22 ]   In wild-type yeast, the recombination events associated with crosslink removal by HRR are predominantly non-crossover  gene conversion  events.  Psoralen crosslinks in virus DNA also appear to be removed by a recombinational repair process as occurs in SV40 virus infected cells, [ 23 ]  and in herpes simplex virus infected cells. [ 24 ]


One inaccurate process for repairing psoralen crosslinks appears to employ a  DNA polymerase  to fill in the gap formed in the strand with the two incisions.  This process is inaccurate because the complementary un-incised strand still retains a portion of the crosslink and thus cannot serve as an adequate template for accurate repair synthesis.  Inaccurate repair synthesis can cause  mutation .  Psoralen monoadducts in the template DNA strand may also cause inaccurate replication bypass ( translesion synthesis ) that can lead to mutation.  In  phage T4 , the increase in mutation observed after PUVA treatment was found to reflect translesion synthesis by wild-type DNA polymerase, likely due to imperfect proof reading capability.


Psoralens can reversibly crosslink nucleic acids double helices, and therefore have been used extensively for the analysis of interactions and structures for both DNA and RNA. [ 25 ] [ 26 ]


Sterigmatocystin  is a polyketide  mycotoxin  produced by certain species of  Aspergillus . The toxin is naturally found in some  cheeses .


Sterigmatocystin is a toxic metabolite structurally closely related to the  aflatoxins  as it is the penultimate precursor of aflatoxins B1 and G1. [ 1 ]  It contains a  xanthone  nucleus attached to a  bifuran  structure. Sterigmatocystin is mainly produced by the fungi  Aspergillus nidulans  and  A. versicolor .


It has been reported in mouldy grain, green coffee beans and cheese although information on its occurrence in foods is limited. It appears to occur much less frequently than the aflatoxins, although analytical methods for its determination have not been as sensitive, and so it is possible that small concentrations in food commodities may not always have been detected. Although it is a potent liver carcinogen similar to  aflatoxin B1 , current knowledge suggests that it is nowhere near as widespread in its occurrence. If this is the true situation it would be justified to consider sterigmatocystin as no more than a risk to consumers in special or unusual circumstances. A number of closely related compounds such as o-methyl sterigmatocystin are known, and some may also occur naturally.


Sterigmatocystin forms pale yellow needles and that are readily soluble in  methanol ,  ethanol ,  acetonitrile ,  benzene , and  chloroform . Sterigmatocystin reacts with a hot solution of potassium hydroxide and ethanol and is easily methylated by  methyl iodide . Treatment with ethanol in acid produces dihydroethoxysterigmatocystin. [ citation needed ]


The toxic effects of sterigmatocystin are much the same as those of  aflatoxin B1 . It is thus considered as a potent  carcinogen ,  mutagen , and  teratogen . It is less acutely toxic to rodents and monkeys but appears to be slightly more toxic to  zebra fish . The LD50 in mice is in excess of 800 mg/kg. The 10-day LD50 in Wistar rats is 166 mg/kg in males, 120 mg/kg in females, and 60–65 mg/kg for ip. administration in males. The ip. 10-day LD50 for vervet monkeys is 32 mg/kg. [ citation needed ]


Chronic symptoms include induction of hepatomas in rats, pulmonary tumours in mice, renal lesions and alterations in the liver and kidneys of African Green monkeys. Rats fed 5–10 mg/kg of sterigmatocystin for two years showed a 90% incidence of liver tumours. It has been suggested that sterigmatocystin is about 1/10 as potent a carcinogen as aflatoxin B1. [ citation needed ]


Toxic effects of sterigmatocystin-fed laboratory animals have included kidney and liver damage and diarrhoea. Skin and hepatic tumours are induced in rats by dermal application. Cattle exhibiting bloody diarrhoea, loss of milk production and in some cases death were found to have ingested feed containing Aspergillus versicolor and high levels of sterigmatocystin of about 8 mg/kg. The acute toxicity, carcinogenicity, and metabolism of sterigmatocystin has been compared with those for aflatoxin and several other hepatotoxic mycotoxins. [ citation needed ]


The  IARC-classification  of sterigmatocystin is group 2B, which means it is carcinogenic in other species and is possibly  carcinogenic  to humans, but that a definitive link between human exposure and cancer has not been proven.


Because sterigmatocystin (ST) is an intermediate of the aflatoxin biosynthesis pathway and is produced by the  BSL-1  organism  Aspergillus nidulans , it serves as a model for studying regulation of the aflatoxin  biosynthetic gene cluster  (BGC). Sterigmatocystin was shown to be produced only in the absence of glucose ( carbon catabolite repression ) but independent of CreA [ 2 ]  when glucose is used as sole carbon source. Instead, it was shown to be dependent on a regulator of  G 0  which transmits the glucose signal to downstream targets. [ 3 ]


The occurrence of sterigmatocystin in raw materials and foods has not been reported often. The instances reported have usually been on mouldy, or poor quality materials such as wheat, maize, animal feed, hard cheese, pecan nuts and green coffee beans. While this lack of information may be due to deficiencies in the analytical methods, where surveys of good quality products have been carried out with reliable methodology, sterigmatocystin has rarely if ever been found. However, further assurance is required before sterigmatocystin can finally be dismissed as a risk because A. versicolor has been isolated frequently from cereals, grain products, fruits and marmalade, dried meat products and grapefruit juice. Relatively high levels of sterigmatocystin have been formed in bread, cured ham and salami after inoculation with A. versicolor. More than in food, sterigmatocystin is frequently found in water-damaged buildings. [ 4 ]


Methods for extraction of sterigmatocystin have been commonly based on a mixture of  acetonitrile  and 4% aqueous  potassium chloride . Methods for detection using TLC are not very sensitive having a limit of detection in the range 20-50 microgrammes/kg. TLC plates must be sprayed with  aluminium chloride  and heated. Analytical methods for the determination of sterigmatocystin have been reported using  HPLC  but again these are not very sensitive because of lack of UV absorbance or  fluorescence , although a post column reaction with aluminium chloride has been used to increase sensitivity. Methods using HPLC linked with atmospheric pressure  ionisation mass spectrometric  detection have been developed for foods such as cheese, bread and corn products. [ citation needed ]


There appear to be no reports about the stability of sterigmatocystin, other than in solution, where it is similar to the aflatoxins. There is one report that phosphine gas significantly depresses the formation of sterigmatocystin when cereals are inoculated with A. versicolor. [ citation needed ]


No country has legislation for sterigmatocystin. Natural occurrence appears to be infrequent although only a limited number of surveys have been carried out. Soon after it was recognised as a highly toxic compound, the  California Department of Health Services  used TD50 values from the Cancer Potency Database to produce 'no significant risk' intake levels for humans. The level resulting was 8 microgrammes/kg body weight/day for a 70 kg adult [ citation needed ]


Sulfonamide  is a  functional group  (a part of a  molecule ) that is the basis of several groups of  drugs , which are called  sulphonamides ,  sulfa drugs  or  sulpha drugs . The original antibacterial sulfonamides  are synthetic  antimicrobial  agents that contain the  sulfonamide  group. Some sulfonamides are also devoid of antibacterial activity, e.g., the  anticonvulsant   sultiame . The  sulfonylureas  and  thiazide diuretics  are newer drug groups based upon the antibacterial sulfonamides. [ 1 ] [ 2 ]


Allergies  to sulfonamides are common. The overall incidence of  adverse drug reactions  to sulfa antibiotics is approximately 3%, close to  penicillin ; [ 3 ]  hence medications containing sulfonamides are prescribed carefully.


Sulfonamide drugs were the first broadly effective antibacterials to be used systemically, and paved the way for the antibiotic revolution in medicine.


In bacteria, antibacterial sulfonamides act as  competitive inhibitors  of the enzyme  dihydropteroate synthase  (DHPS), an enzyme involved in  folate synthesis . Sulfonamides are therefore bacteriostatic and inhibit growth and multiplication of bacteria, but do not kill them. Humans, in contrast to bacteria, acquire  folate  (vitamin B 9 ) through the diet. [ 4 ]


Sulfonamides are used to treat allergies and coughs, as well as having antifungal and antimalarial functions. The moiety is also present in other medications that are not antimicrobials, including  thiazide   diuretics  (including  hydrochlorothiazide ,  metolazone , and  indapamide , among others), loop diuretics (including  furosemide ,  bumetanide , and  torsemide ),  acetazolamide ,  sulfonylureas  (including  glipizide ,  glyburide , among others), and some  COX-2 inhibitors  (e.g.,  celecoxib ).


Sulfasalazine , in addition to its use as an antibiotic, is also used in the treatment of  inflammatory bowel disease . [ 5 ]


Sulfonamide drugs were the first broadly effective antibacterials to be used systemically, and paved the way for the antibiotic revolution in medicine. The first sulfonamide, trade-named  Prontosil , was a  prodrug . Experiments with Prontosil began in 1932 in the laboratories of  Bayer  AG, at that time a component of the huge German chemical trust  IG Farben . The Bayer team believed that  coal-tar dyes  which are able to bind preferentially to bacteria and parasites might be used to attack harmful organisms in the body. After years of fruitless trial-and-error work on hundreds of dyes, a team led by physician/researcher  Gerhard Domagk [ 6 ]  (working under the general direction of IG Farben executive  Heinrich Hörlein ) finally found one that worked: a red dye synthesized by Bayer chemist  Josef Klarer  that had remarkable effects on stopping some bacterial infections in mice. [ 7 ]  The first official communication about the breakthrough discovery was not published until 1935, more than two years after the drug was patented by Klarer and his research partner Fritz Mietzsch. [ citation needed ]


Prontosil, as Bayer named the new drug, was the first medicine ever discovered that could effectively treat a range of bacterial infections inside the body. It had a strong protective action against infections caused by  streptococci , including blood infections,  childbed fever , and  erysipelas , and a lesser effect on infections caused by other cocci. However, it had no effect at all in the test tube, exerting its antibacterial action only in live animals. Later, it was discovered by  Daniel Bovet , [ 8 ]  Federico Nitti, and  Jacques  and  Thérèse Tréfouël , a French research team led by  Ernest Fourneau  at the  Pasteur Institute , that the drug was metabolized into two parts inside the body, releasing from the inactive dye portion a smaller, colorless, active compound called  sulfanilamide . [ 9 ]  The discovery helped establish the concept of "bioactivation" and dashed the German corporation's dreams of enormous profit; the active molecule sulfanilamide (or sulfa) had first been synthesized in 1906 and was widely used in the dye-making industry; its patent had since expired and the drug was available to anyone. [ 10 ]


The result was a sulfa craze. [ 11 ]  For several years in the late 1930s, hundreds of manufacturers produced myriad forms of sulfa. This and the lack of testing requirements led to the  elixir sulfanilamide  disaster in the fall of 1937, during which at least 100 people were poisoned with  diethylene glycol . This led to the passage of the  Federal Food, Drug, and Cosmetic Act  in 1938 in the United States, giving authority to the U.S.  Food and Drug Administration  (FDA) to oversee the safety of food, drugs, medical devices, and cosmetics. As the first and only effective broad-spectrum antibiotic available in the years before  penicillin , heavy use of sulfa drugs continued into the early years of  World War II . [ 12 ]  They are credited with saving the lives of tens of thousands of patients, including  Franklin Delano Roosevelt Jr.  (son of US President  Franklin Delano Roosevelt ) and  Winston Churchill . [ 13 ] [ 14 ]  Sulfa had a central role in preventing wound infections during the war. American soldiers were issued a  first-aid kit  containing sulfa pills and powder and were told to sprinkle it on any open wound. [ 15 ]


The sulfanilamide compound is more active in the  protonated  form. The drug has very low solubility and sometimes can crystallize in the kidneys, due to its first pK a  of around 10. [ clarification needed ]  This is a very painful experience, so patients are told to take the medication with copious amounts of water. Newer analogous compounds prevent this complication because they have a lower pK a , around 5–6, [ citation needed ]  making them more likely to remain in a soluble form.


Many thousands of molecules containing the sulfanilamide structure have been created since its discovery (by one account, over 5,400 permutations by 1945), yielding improved formulations with greater effectiveness and less toxicity. Sulfa drugs are still widely used for conditions such as acne and urinary tract infections, and are receiving renewed interest for the treatment of infections caused by bacteria resistant to other antibiotics. [ citation needed ]


Sulfonamides are prepared by the reaction of a  sulfonyl chloride  with ammonia or an amine. Certain sulfonamides (sulfadiazine or  sulfamethoxazole ) are sometimes mixed with the drug  trimethoprim , which acts against  dihydrofolate reductase . As of 2013 [update] , the  Republic of Ireland  is the largest exporter worldwide of sulfonamides, accounting for approximately 32% of total exports. [ 16 ]


Sulfonamides have the potential to cause a variety of  adverse effects , including urinary tract disorders,  haemopoietic  disorders,  porphyria  and hypersensitivity reactions. When used in large doses, they may cause a strong allergic reaction. The most serious of these are classified as  severe cutaneous adverse reactions  (i.e. SCARs) and include the  Stevens–Johnson syndrome ,  toxic epidermal necrolysis  (also known as Lyell syndrome), the  DRESS syndrome , and a not quite as serious SCARs reaction,  acute generalized exanthematous pustulosis . Any one of these SCARs may be triggered by certain sulfonamides. [ 3 ]


Approximately 3% of the general population have adverse reactions when treated with sulfonamide antimicrobials. Of note is the observation that patients with HIV have a much higher prevalence, at about 60%. [ 17 ]


Hypersensitivity reactions are less common in nonantibiotic sulfonamides, and, though controversial, the available evidence suggests those with hypersensitivity to sulfonamide antibiotics do not have an increased risk of hypersensitivity reaction to the nonantibiotic agents. [ 18 ]  A key component to the allergic response to sulfonamide antibiotics is the arylamine group at N4, found in sulfamethoxazole, sulfasalazine, sulfadiazine, and the anti-retrovirals amprenavir and fosamprenavir. Other sulfonamide drugs do not contain this arylamine group; available evidence suggests that patients who are allergic to arylamine sulfonamides do not cross-react to sulfonamides that lack the arylamine group, and may therefore safely take non-arylamine sulfonamides. [ 19 ]  It has therefore been argued that the terms "sulfonamide allergy" or "sulfa allergy" are misleading and should be replaced by a reference to a specific drug (e.g., " cotrimoxazole  allergy"). [ 20 ]


Two regions of the sulfonamide antibiotic chemical structure are implicated in the hypersensitivity reactions associated with the class.


The nonantibiotic sulfonamides lack both of these structures. [ 21 ]


The most common manifestations of a hypersensitivity reaction to sulfa drugs are  rash  and  hives . However, there are several life-threatening manifestations of hypersensitivity to sulfa drugs, including  Stevens–Johnson syndrome ,  toxic epidermal necrolysis ,  agranulocytosis ,  hemolytic anemia ,  thrombocytopenia , fulminant hepatic necrosis, and  acute pancreatitis , among others. [ 22 ]


T-2 mycotoxin  is a  trichothecene   mycotoxin .  It is a naturally occurring  mold  byproduct of  Fusarium  spp.  fungus  which is toxic to humans and other animals. The clinical condition it causes is  alimentary toxic aleukia  and a host of symptoms related to organs as diverse as the skin, airway, and stomach. Ingestion may come from consumption of moldy whole  grains . T-2 can be  absorbed  through human skin. [ 2 ]  Although no significant systemic effects are expected after dermal contact in normal  agricultural  or residential environments, local skin effects can not be excluded. Hence, skin contact with T-2 should be limited.


Alimentary toxic aleukia (ATA), a disease which is caused by trichothecenes like T-2 mycotoxin, killed many thousands of USSR citizens in the  Orenburg District  in the 1940s. It was reported that the mortality rate was 10% of the entire population in that area. During the 1970s it was proposed that the consumption of  contaminated  food was the cause of this mass poisoning. Because of World War II, harvesting of grains was delayed and food was scarce in Russia. This resulted in the consumption of grain that was contaminated with  Fusarium  molds, which produce T-2 mycotoxin. [ 3 ]


In 1981, the  United States Secretary of State   Alexander Haig  and his successor  George P. Shultz  accused the Soviet Union of using T-2 mycotoxin as a chemical weapon known as " yellow rain " in Laos (1975–81), Kampuchea (1979–81), and  Afghanistan  (1979–81), where it allegedly caused thousands of casualties. [ 4 ]  Although several US chemical weapons experts claim to have identified "yellow rain" samples from Laos as trichothecenes, other experts believe that this exposure was due to naturally occurring T-2 mycotoxin in contaminated foods. [ 5 ]  Another alternative theory was developed by Harvard biologist  Matthew Meselson , who proposed that the "yellow rain" found in Southeast Asia originated from the excrement of jungle bees. [ 6 ]  The first indication for this theory came from finding high levels of  pollen  in the collected samples, giving the substance its yellow color. It was also found that jungle bees in this area fly collectively in great numbers, at altitudes too high to be easily seen, producing showers of feces that could have been mistaken for sprays from aircraft. [ 7 ]  Further testing later determined that the oily liquid was, in fact, the pollen-filled feces of jungle bees. [ 6 ]  A similar case in China was brought to light, and in this instance the cause of the phenomenon had also been bee excrement. [ 8 ]  Despite this conclusive analysis, the United States has not withdrawn its allegations and declares that the issue has not been fully resolved.


T-2 mycotoxin is also thought to be a cause of  Gulf War syndrome . US troops suffered from mycotoxicosis-like symptoms after an Iraqi missile detonated in a US military camp in Saudi Arabia during  Operation Desert Storm  in the Persian Gulf War, in 1991. It has been shown that Iraq researched trichothecene mycotoxins, among other substances, and thus was capable of its possession and employment in  chemical warfare . Nevertheless, much of the key information from these incidents remains classified, leaving these matters still unresolved. [ 9 ]


This compound has a tetracyclic  sesquiterpenoid  12,13-epoxytrichothene ring system, which relates it to the trichothecenes. [ 10 ]  These compounds are generally very stable and are not degraded during storage/milling and cooking/processing of food. They do not degrade at high temperatures either. This compound has an epoxide ring, and several acetyl and hydroxyl groups on its side chains. These features are mainly responsible for the biological activity of the compound and make it highly toxic. T-2 mycotoxin is able to inhibit  DNA  and  RNA synthesis   in vivo  and  in vitro [ 11 ]  and can induce  apoptosis . [ 12 ]  However, in vivo the compound rapidly metabolizes to HT-2 mycotoxin (a major  metabolite ). [ 13 ]


The  toxicity  of T-2 toxin is due to its 12,13-epoxy ring. [ 14 ]   Epoxides  are in general toxic compounds; these react with  nucleophiles  and then undergo further  enzymatic reactions . The  reactivity  of epoxides can lead to reactions with endogenous compounds and cellular constituents like DNA bases and proteins. [ 15 ]
These reactions could be the reason for the noticed actions and effects of T-2 mycotoxin. The toxic compound influences the  metabolism  of  membrane   phospholipids , leads to an increase of liver lipid  peroxidases  and has an inhibiting effect on DNA and RNA synthesis. In addition it can bind to an integral part of the 60s ribosomal subunit,  peptidyltransferase , thereby inhibiting  protein synthesis .
These effects are thought to be the explanation for T-2 toxin inducing apoptosis (cell death) in different tissues as the  immune system , the gastrointestinal tissue and also fetal tissue. With regard to apoptosis there has been noticed that the level of the pro-apoptotic factor Bas (Bcl-2-associated X protein) was increased and the level of Bcl-xl, an anti-apoptotic factor, was decreased in human chrondocytes ( cartilage  cells).  When exposed to T-2 mycotoxin. Furthermore, the level of Fas, an apoptosis-related cell-surface antigen and p53, a protein regulating the cell cycle, were increased.


T-2 mycotoxin is produced naturally by Fusarium fungi of which the most important species are:  F. sporotrichioides ,  F. langsethiae ,  F. acuminatum  and  F. poae .  These fungi are found in grains such as  barley ,  wheat  and  oats . The production of this compound for research and commercial purposes is generally accomplished by cultivating some strain of T-2 mycotoxin producing fungi on  agar plates . On these agar plates the fungi appear powdery and can yield substantial amounts of T-2 mycotoxin. For the isolation of the compound  high pressure liquid chromatography  is commonly used (HPLC). [ 16 ]


In the  Fusarium  species,  biosynthesis  of the T-2 mycotoxin often starts with trichodiene, and many of the species share a common route of  oxidizations  and  cyclizations . As an example, from the  F. sporotrichioides  species, the important oxidation steps that occur start from trichodiene and goes to isotrichodiol. From there, the eleventh carbon atom is oxidized to form isotrichotriol. The ninth carbon is then oxidized, and trichotriol is formed, which then cyclizes to make isotrichodermol. After that, the fifteenth carbon is oxidized to form didecalonectrin, which leads to the fourth carbon being oxidized, and diacetoxyscirpenol is formed. The second to last step is the oxidation of the eighth carbon to make neosolaniol, which then undergoes slight modification to create the T-2 toxin. [ 17 ]


Humans and animals are generally exposed to T-2 mycotoxins through food. Certain grains can contain the toxin which makes it a threat to human health and an economic burden. [ 18 ]  Unlike most biological toxins T-2 mycotoxin can be absorbed through intact skin. The compound can be delivered via food, water, droplets,  aerosols  and smoke from various dispersal systems. This makes it a potential  biological weapon , however large amounts of the compound are required for a  lethal dose . T-2 mycotoxin has an  LD 50  of approximately 1 milligram per kilogram of body weight.


The  EFSA  estimates that the mean exposure of T-2 in the EU lies between 12 and 43 ng/kg bw/day. [ 19 ]  This range is below the TDI of 100 ng/ kg body weight for the sum of HT-2 and T-2 toxins which is used by the EFSA.


T-2 mycotoxin is distributed uniformly throughout the body without preference to a specific organ or site. In rodents,  plasma  concentration levels peak around roughly thirty minutes after exposure, and in one study, the  half-life  of the T-2 toxin was seen to be less than twenty minutes. In a different study involving pigs, the distribution after four hours of IV injection was seen to be 15–24% in the GI tract and 4.7–5.2% in various other tissues. [ 20 ]


Once absorbed and distributed to various tissues, the T-2 mycotoxin goes through various metabolic reactions before it gets excreted. In vivo studies showed that the most occurring reactions are  ester   hydrolysis  and  hydroxylation  of the isovaleryl group. Deepoxidation and  glucuronide  conjugation do also occur. Ht-2 is the main metabolite. For the hydroxylation, the cytochrome p450 enzyme complex is suggested to be involved. T-2 triol and T-2 tetraol are most likely to be formed via  acetylcholine esterases . Some of the metabolic reactions of the mycotoxin are performed by the  microflora  in the gut.  The formed metabolites in these reactions are species- and pH-dependent. The ester cleavages are however performed by the mammal itself and not by the microflora. In  red blood cells  T-2 mycotoxin is metabolized to neosolaniol, and, in  white blood cells , to HT-2 via hydrolysis catalyzed by carboxylesterases.


Following absorption, distribution, and metabolism, T-2 mycotoxin is excreted fairly quickly, where 80–90% of it is excreted within 48 hours. [ 20 ]  The main methods of excretion seem to be from the urine and feces, [ 21 ]  where excretion through  bile  contributes heavily to the feces route of excretion. [ 14 ]  There is also very little of the parent T-2 mycotoxin in the excretions, meaning most of the initial compound is metabolized beforehand. [ 21 ]


T-2 is highly toxic when inhaled.  Acute toxic symptoms include vomiting, diarrhea, skin irritation, itching, rash, blisters, bleeding and  dyspnea . [ citation needed ]  If the individual is exposed to T-2 over a longer period alimentary toxic aleukia (ATA) develops.


At first the patient experiences a burning sensation in the mouth, throat and stomach. After a few days the person will suffer from an acute  gastroenteritis  that will last for 3 to 9 days. Within 9 weeks the  bone marrow  will slowly degenerate. Also the skin starts bleeding and the total number of  leukocytes  decreases. Problems with the nervous system can occur.


In the end the following symptoms might occur: a high fever,  petechial haemorrhage ,  necrosis  of muscles and skin, bacterial infections of the necrotic tissue,  enlarged lymph nodes . There is the possibility of  asphyxiation  because of  laryngeal   oedema  and  stenosis  of the  glottis . The lack of oxygen is then the cause of death.  Otherwise the patient will die of  bronchial pneumonia  and lung bleeding. [ 22 ]


T-2 mycotoxin is also toxic to animals. The compound is known for having lethal and sub-lethal effects on farm animals. It is often found in contaminated cereal grains that are fed to these animals. [ 23 ]  Most of the toxic effects are shared between humans and animals. After exposing  zebra fish  embryos to a concentration of 20 μmol/L or higher  malformation  and  mortality rates  increased. The malformations included tail deformities,  cardiovascular  defects and changes in behavior in early stages of life. This is the result of an increase in the amount of epoxides, which causes cell apoptosis. [ 24 ]  Other studies have shown that T-2-toxin causes lipid peroxidation in rats after feeding it to them. As the effect of T-2 toxin, elevated reactive oxygen species (ROS) levels were observed in several mammalian species. However, in spite of the general harmful effects caused by the toxin, in a study carried out in different chicken derived hepatic cell culture models, no alterations were found in the redox status of the cells. [ 25 ]


The compound also seems to reduce the fertility of ewes and heifers. Research has shown that a high dose of T-2 delays the  ovulation  due to a delayed  follicle  maturation. This possibly retards the following  luteinisation , which makes it impossible for female animals to conceive.


T-2 also has an effect on the fertility of bulls. In 1998 it was discovered that moldy hay influenced the quality of semen of bulls. Analysis of the moldy hay showed that T-2 was present. The compound decreased  sperm motility  and testosterone levels and increased the frequency of morphological abnormalities in the sperm cells.


The liver is another target for the mycotoxin. It is one of the first organs where the compound passes through after ingestion. Here it causes a reduced expression of  CYP1A  proteins in rabbits, pigs and rats.  CYP3A  activity decreases in pigs too. These enzymes help metabolize drugs that pass through the liver. Decrease in the activity could lead to an increase of unmetabolized drugs in the plasma. This can have a dangerous effect on an animal's health. [ 26 ]


All of the mentioned effects happen when T-2 is ingested in high doses. Animals are able to metabolize the compound with enzymes from the CYP3A family, just like humans.


At the moment, there is no specific therapy for T-2 mycotoxin poisonings. [ 21 ]  Exposure of the mycotoxin is typically followed by standardized treatment for toxic compounds in order to reduce the effect of the toxin. This includes using  activated charcoal , which has a high binding capacity of 0.48 mg of T-2 mycotoxin to 1 mg of charcoal. [ 21 ]  For dermal contact, soap and water is used to reduce the dermal effects. [ 21 ]  As a kind of  prophylaxis ,  antioxidants  are believed to have properties that may provide benefits. [ 20 ]


There are currently no applications, aside from war, for T-2 mycotoxins; however, there are some plausible therapeutic uses. Due to their abilities, research shows possible uses for the mycotoxin as growth promoters,  antibiotics ,  antivirals , as an  antileukemic , and as an  antimalarial . [ 20 ]


Tenoxicam , sold under the brand name  Mobiflex  among others, is a  nonsteroidal anti-inflammatory drug  (NSAID). It is used to relieve  inflammation ,  swelling , stiffness, and pain associated with  rheumatoid arthritis ,  osteoarthritis ,  ankylosing spondylitis  (a type of arthritis involving the  spine ),  tendinitis  (inflammation of a tendon),  bursitis  (inflammation of a  bursa , a  fluid -filled sac located around joints and near the bones), and  periarthritis  of the shoulders or hips (inflammation of tissues surrounding these joints). [ 1 ]


Tenoxicam belongs to the class of NSAIDs known as  oxicams .


It was patented in 1974 by  Roche  and approved for medical use in 1987. [ 2 ]  It is available as a  prescription-only drug  in the  United Kingdom  and other countries, but not in the  US .  Outside the United Kingdom, tenoxicam is also marketed under brand names including Tilatil, Tilcitin, and Alganex. [ 1 ] [ 3 ]


The drug is contraindicated for patients who are seniors who have been given  anesthesia  or  surgery ; are at risk of increased bleeding or kidney failure; have an active inflammatory disease involving the stomach or intestine (like  ulcerative colitis ); have an active stomach or  intestinal ulcer ; have had an acute asthmatic attack, hives, rhinitis (inflammation of the inner lining of the nasal passage), or other allergic reactions caused by  aspirin  or other nonsteroidal anti-inflammatory drugs (for example  diclofenac ,  ibuprofen ,  indomethacin ,  naproxen ). [ 4 ] [ 5 ]


Common side effects that have been observed with tenoxicam include peptic ulceration, dyspepsia, nausea, constipation, abdominal pain, diarrhea, rash, headache, edema, renal failure, and vertigo. [ 6 ] [ 5 ] [ 7 ]   In rare cases, tenoxicam and other NSAIDs can contribute to thrombotic events, Stevens-Johnson Syndrome, and toxic epidermal necrolysis. [ 8 ] [ 9 ] [ 10 ]


It is not recommended that women who are trying to conceive, who are pregnant, or who are breastfeeding take tenoxicam. Tenoxicam can be taken in the first and second trimester when necessary, but it is a contraindication in the third trimester.  Some studies have looked at whether or not NSAIDs are able to enter the breast milk and the first few studies have found evidence that NSAIDs can be found in breast milk.  Therefore, it is not recommended that women take tenoxicam while breastfeeding. [ 6 ] [ 5 ] [ 7 ]


Taking tenoxicam with other drugs can increase the chance of side effects or alter the therapeutic effect of tenoxicam or the other drug, depending on the combination.  Drug types the tenoxicam may interact with include: other analgesic NSAIDs,  salicylates  such as aspirin,  antacids , anticoagulants,  cardiac glycosides ,  ciclosporin ,  quinolone antibiotics ,  lithium therapy , diuretics and anti-hypertensives,  methotrexate , oral anti-diabetics,  colestyramine ,  dextromethorphan ,  mifepristone , corticosteroids, anti-platelet agents and  selective serotonin reuptake inhibitors  (SSRIs),  tacrolimus ,  zidovudine , and gold/ penicillamine . [ 6 ] [ 5 ] [ 7 ]


Like all NSAIDs, the exact mechanism of action of tenoxicam is unknown. [ dubious  –  discuss ]  Involved in the mechanism of action is inhibition of  cyclooxygenase  (COX-1 and COX-2) which leads to the potential adverse effect of increased bleeding. [ 6 ]


Tenoxicam is sold in the form of 20 mg tablets with the price of treatment ranging from US$1.29–2.73 per tablet. [ 11 ]   Recommended dosing calls for tenoxicam to be taken once daily with food.  One week is the typical length for treatment, but the treatment length may be extended. [ 6 ]


In 2008, the reported sales level for Tilcotil (tenoxicam) was 70 million SEK (approximately US$10.5 million). [ 11 ] [ 12 ]


The first members of the oxicam family of NSAIDs were brought to market in France in 1982. [ 13 ]   Shortly thereafter, tenoxicam went to phase III clinical trials for approval as use as an analgesic began in the 1980s.  The general consensus from clinical studies is that tenoxicam has about equal analgesic effect as other NSAIDs and does not elicit any important side effects.  More recent clinical trials for tenoxicam are examining the use of tenoxicam independently and in combination with other drugs for more specialized analgesic purposes in surgical operations such as third molar extraction and labor pains. [ 14 ] [ 15 ] [ 16 ]


Tetracycline , sold under various brand names, is an  antibiotic  in the  tetracyclines  family of medications, used to treat a number of  infections , [ 3 ]  including  acne ,  cholera ,  brucellosis ,  plague ,  malaria , and  syphilis . [ 3 ]  It is available in oral and topical formulations. [ 4 ] [ 5 ]


Common side effects include vomiting,  diarrhea , rash, and loss of appetite. [ 3 ]  Other side effects include poor  tooth  development if used by children less than eight years of age,  kidney problems , and  sunburning  easily. [ 3 ]  Use during  pregnancy  may harm the baby. [ 3 ]  It works by inhibiting protein synthesis in bacteria. [ 3 ]


Tetracycline was patented in 1953 [ 6 ]  and was approved for prescription use in 1954. [ 7 ] [ 8 ]  It is on the  World Health Organization's List of Essential Medicines . [ 9 ]  Tetracycline is available as a  generic medication . [ 3 ]   Tetracycline was originally made from bacteria of the genus  Streptomyces . [ 3 ]


Tetracyclines have a broad spectrum of antibiotic action. Originally, they possessed some level of bacteriostatic activity against almost all medically relevant  aerobic  and  anaerobic  bacterial genera, both  Gram-positive  and  Gram-negative , with a few exceptions, such as  Pseudomonas aeruginosa  and  Proteus  spp. , which display intrinsic resistance. However, acquired (as opposed to inherent) resistance has proliferated in many  pathogenic organisms  and greatly eroded the formerly vast versatility of this group of antibiotics. Resistance amongst  Staphylococcus  spp. ,  Streptococcus  spp. ,  Neisseria gonorrhoeae , anaerobes, members of the  Enterobacteriaceae , and several other previously sensitive organisms is now quite common. Tetracyclines remain especially useful in the management of infections by certain obligately intracellular bacterial pathogens such as  Chlamydia ,  Mycoplasma , and  Rickettsia . They are also of value in  spirochaetal  infections, such as  syphilis , and  Lyme disease . Certain rare or exotic infections, including  anthrax ,  plague , and  brucellosis , are also susceptible to tetracyclines. Tetracycline tablets were used in the plague outbreak in India in 1994. [ 10 ]   Tetracycline is first-line therapy for  Rocky Mountain spotted fever  ( Rickettsia ),  Lyme disease  ( B. burgdorferi ),  Q fever  ( Coxiella ),  psittacosis ,  Mycoplasma pneumoniae , and nasal carriage of  meningococci . [ citation needed ]


It is also one of a group of antibiotics which together may be used to treat  peptic ulcers  caused by bacterial infections. The mechanism of action for the antibacterial effect of tetracyclines relies on disrupting protein translation in bacteria, thereby damaging the ability of microbes to grow and repair; however, protein translation is also disrupted in eukaryotic  mitochondria  leading to effects that may  confound  experimental results. [ 11 ] [ 12 ]


The following list presents  MIC  susceptibility data for some medically significant microorganisms:


The tetracyclines also have activity against certain  eukaryotic  parasites, including those responsible for diseases such as  dysentery  caused by an  amoeba ,  malaria  (a  plasmodium ), and  balantidiasis  (a  ciliate ). [ citation needed ]


Since tetracycline is absorbed into bone, it is used as a marker of bone growth for  biopsies  in humans. Tetracycline labeling is used to determine the amount of bone growth within a certain period of time, usually a period around 21 days. Tetracycline is incorporated into mineralizing bone and can be detected by its  fluorescence . [ 14 ]  In "double tetracycline labeling", a second dose is given 11–14 days after the first dose, and the amount of bone formed during that interval can be calculated by measuring the distance between the two fluorescent labels. [ 15 ]


Tetracycline is also used as a biomarker in  wildlife  to detect consumption of medicine- or  vaccine -containing baits. [ 16 ]


Use of  tetracycline antibiotics  can: [ 17 ]


Caution should be exercised in long-term use when breastfeeding. Short-term use is safe;  bioavailability  in milk is low to nil. [ 23 ]  According to the U.S.  Food and Drug Administration  (FDA),  cases of  Stevens–Johnson syndrome ,  toxic epidermal necrolysis , and  erythema multiforme  associated with  doxycycline  use have been reported, but a causative role has not been established. [ 24 ]


Tetracycline inhibits protein synthesis by blocking the attachment of charged  tRNA  at the  P site  peptide chain. Tetracycline blocks the A-site so that a hydrogen bond is not formed between the amino acids. Tetracycline binds to the 30S and 50S subunit of microbial ribosomes. [ 3 ]  Thus, it prevents the formation of a peptide chain. [ 25 ]  The action is usually not inhibitory and irreversible even with the withdrawal of the drug. Mammalian cells are not vulnerable to the effect of Tetracycline as these cells contain no 30S ribosomal subunits so do not accumulate the drug. [ 26 ]  This accounts for the relatively small off-site effect of tetracycline on human cells. [ 27 ]


Bacteria usually acquire resistance to tetracycline from  horizontal transfer  of a  gene  that either encodes an  efflux pump  or a ribosomal protection protein. Efflux pumps actively eject tetracycline from the cell, preventing the build up of an inhibitory concentration of tetracycline in the  cytoplasm . [ 28 ]   Ribosomal protection proteins interact with the ribosome and dislodge tetracycline from the ribosome, allowing for translation to continue. [ 29 ]


The tetracyclines, a large family of antibiotics, were discovered by  Benjamin Minge Duggar  in 1948 as natural products, and first prescribed in 1948. [ 30 ]  Benjamin Duggar, working under  Yellapragada Subbarow  at  Lederle Laboratories , discovered the first tetracycline antibiotic,  chlortetracycline  (Aureomycin), in 1945. [ 31 ]  The structure of Aureomycin was elucidated in 1952 and published in 1954 by the Pfizer-Woodward group. [ 32 ]  After the discovery of the structure, researchers at  Pfizer  began chemically modifying aureomycin by treating it with hydrogen in the presence of a  palladized carbon catalyst . This  chemical  reaction replaced a chlorine moiety with a hydrogen, creating a compound named tetracycline via  hydrogenolysis . [ 33 ]  Tetracycline displayed higher potency, better solubility, and more favorable pharmacology than the other antibiotics in its class, leading to its FDA approval in 1954. The new compound was one of the first commercially successful semi-synthetic antibiotics that was used, and laid the foundation for the development of Sancycline,  Minocycline , and later the  Glycylcyclines . [ 7 ]


Tetracycline has a high affinity for calcium and is incorporated into bones during the active mineralization of  hydroxyapatite . When incorporated into bones, tetracycline can be identified using ultraviolet light. [ 34 ]


There is evidence that early inhabitants of Northeastern Africa consumed tetracycline antibiotics.  Nubian  mummies from between 350 and 550 A.D. were found to exhibit patterns of fluorescence identical with that of modern tetracycline labelled bone. [ 35 ]


It is conjectured that the beer brewed by the Nubians was the source of the tetracycline found in these bones. [ 36 ]


According to data from EvaluatePharma and published in the  Boston Globe , in the USA the price of tetracycline rose from $0.06 per 250- mg  pill in 2013 to $4.06 a pill in 2015. [ 37 ]  The  Globe  described the "big price hikes of some generic drugs" as a "relatively new phenomenon" which has left most pharmacists "grappling" with large upswings" in the "costs of generics, with 'overnight' price changes sometimes exceeding 1,000%." [ 37 ]


It is marketed under the brand names Sumycin, Tetracyn, and Panmycin, among others. Actisite is a thread-like fiber formulation used in dental applications. [ 38 ]


It is also used to produce several semisynthetic derivatives, which together are known as the  tetracycline antibiotics . The term "tetracycline" is also used to denote the four-ring system of this compound; "tetracyclines" are related substances that contain the same four-ring system. [ citation needed ]


Due to the drug's association with fighting infections, it serves as the main "commodity" in the science fiction series  Aftermath , with the search for tetracycline becoming a major preoccupation in later episodes. [ 39 ]


Tetracycline is also represented in  Bohemia Interactive 's survival sandbox,  DayZ . In the game, players may find the antibiotic to treat the common cold, influenza, cholera and infected wounds, but does not portray any side effects associated with tetracycline.


In  genetic engineering , tetracycline is used in  transcriptional activation . It has been used as an engineered "control switch" in  chronic myelogenous leukemia  models in mice. Engineers were able to develop a retrovirus that induced a particular type of leukemia in mice, and could then "switch" the cancer on and off through tetracycline administration. This could be used to grow the cancer in mice and then halt it at a particular stage to allow for further experimentation or study. [ 40 ]


A technique being developed for the control of the  mosquito  species  Aedes aegypti  (the infection  vector  for  yellow fever ,  dengue fever ,  Zika fever , and several other diseases) uses a strain that is  genetically modified  to require tetracycline to develop beyond the larval stage. Modified males raised in a laboratory develop normally as they are supplied with this chemical and can be released into the wild. Their subsequent offspring inherit this trait, but find no tetracycline in their environments, so never develop into adults. [ 41 ]


Urushiol   / ʊ ˈ r uː ʃ i . ɒ l /  is an oily mixture of  organic compounds  with  allergenic  properties found in  plants  of the  family   Anacardiaceae , especially  Toxicodendron   spp.  (e.g.,  poison oak ,  Chinese lacquer tree ,  poison ivy ,  poison sumac ),  Comocladia spp.  (maidenplums) ,  Metopium spp . (poisonwood) , and also in parts of the  mango tree  and the fruit of the  cashew  tree. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ]


In most individuals, urushiol causes an allergic  skin  rash on contact, [ 7 ]  known as  urushiol-induced contact dermatitis .


The name urushiol is derived from the  Japanese  word for the lacquer tree,  Toxicodendron vernicifluum  ( 漆 ,  urushi ) . [ 8 ]  The  oxidation  and polymerization of urushiol in the tree's sap in the presence of moisture allows it to form a hard  lacquer , which is used to produce traditional Chinese, Korean, and Japanese  lacquerware .


Although urushiol-containing  lacquers  and their skin-irritating properties were well known in East Asia for several millennia beforehand, its first recorded Western texts were in 1624 by  John Smith  where he initially likened poison ivy to  English ivy . [ 9 ]  He did not classify it as a poison at first due to the speed with which its rash disappeared and Smith hypothesized that there may actually be medicinal uses for the plant. [ 9 ]  In the 18th and 19th centuries, many experiments were done in this area to determine whether or not this theory was true. Because medicine was dominated by plant-based treatments at the time, physicians were hopeful that the strong effect this chemical produced on the body could be effective in some way.


André-Ignace-Joseph Dufresnoy was one of the first to come up with a medicinal use for this chemical in 1780 when he boiled poison ivy to produce an infusion for internal use. [ 9 ]  This led to a distilled extract of poison ivy which he prescribed to many people suffering from skin problems and even paralysis. He claimed this treatment to have yielded several positive results. [ 9 ]


For many years, poison ivy was thought to fall into the  Rhus  genus; however, in the 1900s, it was reclassified into a more appropriate genus,  Toxicodendron , meaning  poison tree . [ 9 ]  There were many documented cases of irritations and allergic reactions from the plant, and its prevalence in medicinal use quickly dwindled. After this new categorization, scientists began attempts to determine what it was that rendered plants of this genus noxious, starting with a hypothesis of a volatile oil present in the plants. [ 9 ]


While this proved incorrect, Rikou Majima from Japan was able to determine that the chemical urushiol was the irritant. Further, he determined that the substance was a type of alkyl catechol, and due to its structure it was able to penetrate the skin and survive on surfaces for months to years. [ 9 ]  Urushiol's ability to polymerise into a hard glossy coating is the chemical basis for traditional lacquerware in many Asian countries. [ 10 ]  After urushiol comes in contact with oxygen, under certain conditions it becomes a black lacquer and has been named  urushi lacquer . [ 11 ]


Urushiol in its pure form is a pale-yellow  liquid  with a  density  of about 0.968 g/mL and a  boiling point  of 200 °C (392 °F).  It is soluble in  diethyl ether ,  acetone ,  ethanol ,  carbon tetrachloride , and  benzene . [ 12 ] [ 13 ]


Urushiol is a mixture of several closely related  organic compounds . Each consists of a  catechol  substituted in the 3 position with a  hydrocarbon  chain that has 15 or 17 carbon atoms. The hydrocarbon group may be  saturated  or unsaturated. The exact composition of the mixture varies, depending on the plant source. Whereas  western poison oak  urushiol contains chiefly catechols with C 17  side-chains, [ 14 ]  poison ivy and poison sumac contain mostly catechols with C 15  sidechains.


The likelihood and severity of allergic reaction to urushiol is dependent on the degree of  unsaturation  of the  hydrocarbon  chain. Less than half of the general population experience a reaction with the saturated urushiol alone, but over 90% do so with urushiol that contains at least two  degrees of unsaturation  (double bonds). Longer side chains tend to produce a stronger reaction. [ 15 ]


Urushiol is an  oleoresin  contained within the sap of  poison ivy  and related plants, and after injury to the plant, or late in the fall, the sap leaks to the surface of the plant, where under certain temperature and humidity conditions the urushiol becomes a blackish  lacquer  after being in contact with  oxygen . [ 15 ] [ 16 ] [ 11 ]  Urushi lacquer is very stable. It is able to withstand disturbances from alkali, acid, and alcohol, while also being able to resist temperatures of over 300 °C. However, the lacquer can be degraded by UV rays from the sun and other sources. [ 10 ]


Within the United States, urushiol-containing plants are widely distributed. Poison ivy can be found in all states except California, Alaska, and Hawaii. Poison oak can be found on the west coast or in some states in the southeast, while poison sumac can be found only in the eastern half of the country. [ 17 ]


These plants all have distinguishing features that will help in identification. Poison ivy always grows with groups of three glossy, pointed leaflets on leaves that alternate along the branch (in contrast to similar looking leaves of boxelder which has opposite leaves). Poison oak has a similar appearance, but with larger and more rounded lobes, with a light, velvety  pubescence  and grow in groups of 3, 5, or 7. Poison sumac grows in groups of 7 to 13 leaflets, always an odd number. The leaflets are ovate-lanceolate and glossy. [ 18 ]


Before the urushiol has been absorbed by the skin, it can be removed with a washcloth using soap and water. Substantial amounts of urushiol may be absorbed within minutes. Once urushiol has penetrated the skin, attempting to remove it with water is ineffective. [ 15 ]  After being absorbed by the skin, it is recognized by the  immune system 's  dendritic cells , otherwise called  Langerhans cells . These cells then migrate to the  lymph nodes , where they present the urushiol to  T-lymphocytes  and thus recruit them to the skin, and the T-lymphocytes cause pathology through the production of  cytokines  and  cytotoxic  damage to the skin. [ 19 ]  This causes the painful rash, blisters, and itching.


Once this response starts, only a few treatments, such as  cortisone  or  prednisone , are effective. [ 9 ]  Medications that can reduce the irritation include  antihistamines  ( diphenhydramine  (Benadryl) or  cetirizine  (Zyrtec)). Other treatments include applying cold water or  calamine lotion  to soothe the pain and stop the itching. [ 9 ]


Research conducted on urushiol by  Mahmoud ElSohly  led to the development of  PDC-APB , a candidate for a vaccine against skin irritation from  poison ivy . [ 20 ]