It is not known how many people have TFOHS. [ 6 ]  Males are affected more frequently than females. [ 3 ]  Athlete's foot is the most common fungal disease, with possibly more than 50% of the population affected at some time. [ 2 ] [ 4 ]  Tinea manuum accounts for less than 2% of all superficial fungal infections. [ 2 ]  Tinea manuum  is rare in both hands. [ 2 ]  Scenarios with one foot and two hands, and one foot and one hand, have been described. [ 15 ]  One study showed that 65% of cases with tinea manuum were part of TFOHS. [ 6 ]


The condition was first described by Curtis in 1964. [ 11 ]  It was later designated a syndrome. [ 11 ]


Uremic frost  is a colloquial description for crystallized  urea  deposits that can be found on the skin of those affected by  chronic kidney disease  (CKD). [ 1 ]   Uremic frost was first described in 1865 by  Harald Hirschsprung  (1830-1916), a Danish pediatrician. He was also the first to describe  Hirschsprung's disease  in 1886. The disease now carries his name. [ 2 ]  Uremic frost has become increasingly uncommon with the advent of dialysis in the 1950s. Uremic frost is a classical pre-dialysis era description of crystallized urea deposits over the skin of patients with prolonged kidney failure and severe uremia. High blood urea level leads to high secretion of urea by sweat glands as a component of sweat. As water evaporates off the skin, it results in crystallization of the remaining urea which appear as white salts over the skin. [ 3 ]
This condition is more common in severe, untreated uremia and is associated with serum  BUN  levels >200. It is becoming rare in people with chronic kidney disease managed on long-term  hemodialysis , with estimated prevalence between 0.8 and 3%. [ 4 ] [ 5 ] [ 6 ]


This article about an endocrine, nutritional, or metabolic disease is a  stub . You can help Wikipedia by  expanding it .


Verrucous carcinoma  is a type of  squamous cell carcinoma  that may be associated with HPV infection (may be subtypes 16 or 18, but types 6 and 11 have also been reported, as have HPV negative variants).  Several subtypes of verrucous carcinoma have been described.  Treatment of verrucous carcinoma with radiation therapy should be avoided due to the risk of anaplastic transformation.


Warts  are non-cancerous viral growths usually occurring on the hands and feet but which can also affect other locations, such as the  genitals  or face. [ 1 ] [ 3 ]  One or many warts may appear. [ 3 ]  They are distinguished from  cancerous  tumors as they are caused by a viral infection, such as a  human papillomavirus ,  rather than a  cancer growth . [ 3 ]


Factors that increase the risk include the use of public showers and pools, working with meat,  eczema , and a  weak immune system . [ 1 ] [ 3 ]  The virus is believed to infect the host through the entrance of a skin  wound . [ 1 ]  A number of types exist, including  plantar warts , " filiform warts ", and  genital warts . [ 3 ]  Genital warts are often  sexually transmitted . [ 5 ]


Without treatment, most types of warts resolve in months to years. [ 1 ]  A number of treatments may speed resolution, including  salicylic acid  applied to the skin and  cryotherapy . [ 1 ]  In those who are otherwise healthy, they do not typically result in significant problems. [ 1 ]  Treatment of genital warts differs from that of other types. [ 3 ]  Infection of a virus, such as  HIV , can cause warts. This is prevented through careful handling of needles or sharp objects that could infect the individual through physical trauma of the skin, plus the practice of  safe sex  or  sexual abstinence . Viruses that are not sexually transmitted, or are not transmitted in the case of a wart, can be prevented through a number of behaviors, such as wearing shoes outdoors and avoiding unsanitized areas without proper shoes or clothing, such as public restrooms or locker rooms.


Warts are very common, with most people being infected at some point in their lives. [ 2 ]  The estimated current rate of non-genital warts among the general population is 1–13%. [ 1 ]  They are more common among young people. [ 1 ]  Prior to widespread adoption of the  HPV vaccine , the estimated rate of genital warts in sexually active women was 12%. [ 5 ]  Warts have been described as far back as 400 BC by  Hippocrates . [ 4 ]


A range of types of wart have been identified, varying in shape and site affected, as well as the type of human papillomavirus involved. [ 6 ] [ 7 ]  These include:


Warts are caused by the  human papillomavirus  (HPV). There are about 130 known types of human papillomaviruses. [ 9 ]  HPV infects the  squamous epithelium , usually of the skin or genitals, but each HPV type is typically only able to infect a few specific areas of the body. Many HPV types can produce a  benign  growth, often called a "wart" or "papilloma", in the area they infect. [ 10 ]  Many of the more common HPV and wart types are listed below.


Common warts have a characteristic appearance under the microscope.  They have thickening of the  stratum corneum  (hyperkeratosis), thickening of the  stratum spinosum  (acanthosis), thickening of the  stratum granulosum ,  rete ridge  elongation, and large  blood vessels  at the  dermoepidermal junction . [ citation needed ]


On  dermatoscopic  examination, warts will commonly have fingerlike or knoblike extensions. [ 16 ]


Gardasil  6 is an  HPV vaccine  aimed at preventing cervical cancers and genital warts.  Gardasil is designed to prevent infection with HPV types 16, 18, 6, and 11. HPV types 16 and 18 currently cause about 70% of  cervical cancer  cases, [ 13 ] [ 14 ]  and also cause some  vulvar ,  vaginal , [ 11 ]   penile  and  anal cancers . [ 12 ]  HPV types 6 and 11 are responsible for 90% of documented cases of genital warts. [ 17 ]


Gardasil 9 protects against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. [ 18 ]


HPV vaccines do not currently protect against the virus strains responsible for  plantar warts  (verrucae). [ 19 ]


The virus is relatively hardy and immune to many common  disinfectants . Exposure to 90%  ethanol  for at least 1 minute, 2%  glutaraldehyde , 30%  Savlon , and/or 1%  sodium hypochlorite  can disinfect the pathogen. [ 20 ]


The virus is resistant to drying and heat, but killed by 100 °C (212 °F) temperature and  ultraviolet  radiation. [ 20 ]


There are many treatments and procedures associated with wart removal. [ 21 ]  A review of various skin wart treatments concluded that topical treatments containing  salicylic acid  were more effective than  placebo . [ 22 ]   Cryotherapy  appears to be as effective as salicylic acid, but there have been fewer trials. [ 22 ]


Daily application of the  latex  of  Chelidonium majus  is a traditional treatment. [ 48 ]


The acrid yellow  sap  of  Greater Celandine  is used as a traditional wart remedy. [ 49 ]


According to English  folk belief , touching  toads  causes warts; according to a  German  belief, touching a toad under a  full moon  cures warts. [ 50 ]  The most common  Northern Hemisphere  toads have glands that protrude from their skin that superficially resemble warts. Warts are caused by a virus, and toads do not harbor it. [ 51 ]  A variety of traditional  folk remedies  and rituals claim to be able to remove warts.


In  The Adventures of Tom Sawyer ,  Mark Twain  has his characters discuss a variety of such remedies.  Tom Sawyer proposes "spunk-water" (or "stump-water", the water collecting in the hollow of a tree stump) as a remedy for warts on the hand.  You put your hand into the water at midnight and say:


Barley-corn, barley-corn, injun-meal shorts,
Spunk-water, spunk-water, swaller these warts


You then "walk away quick, eleven steps, with your eyes shut, and then turn around three times and walk home without speaking to anybody. Because if you speak the charm's busted."  This is given as an example of  Huckleberry Finn 's planned remedy, which involves throwing a dead cat into a graveyard as a devil or devils comes to collect a recently buried wicked person.  Another remedy involved splitting a bean, drawing blood from the wart and putting it on one of the halves, and burying that half at a  crossroads  at midnight.  The  theory of operation  is that the blood on the buried bean will draw away the wart. [ 52 ]  Twain is recognized as an early collector and recorder of genuine  American folklore . [ 53 ]


Similar practices are recorded elsewhere.  In  Louisiana , one remedy for warts involves rubbing the wart with a  potato , which is then buried; when the "buried potato dries up, the wart will be cured". [ 54 ]  Another remedy similar to Twain's is reported from  Northern Ireland , where water from a specific well on  Rathlin Island  is credited with the power to cure warts. [ 55 ]


Surviving ancient medical texts show that warts were a documented disease since at least the time of  Hippocrates , who lived  c.  460  –  c.  370 BC . In the book  De Medecia  by the Roman physician  Aulus Cornelius Celsus , who lived  c.  25 BC  –  c.  50 AD , different types of warts were described. Celsus described  Myrmecia , today recognized as  plantar wart , and categorized  acrochordon  (a skin tag) as a wart. In the 13th century, warts were described in books published by the surgeons  William of Saliceto  and  Lanfranc of Milan . The word  verruca  to describe a wart was introduced by the physician  Daniel Sennert , who described warts in his 1636 book  Hypomnemata physicae . [ 56 ]


The cause of warts was initially disputed in the medical profession. In the early 18th century the physician  Daniel Turner , who published the first book on  dermatology , suggested that warts were caused by damaged  nerves  close to the skin. In the mid-18th century, the surgeon  John Hunter  popularized the belief that warts were caused by a bacterial  syphilis
infection. The surgeon  Benjamin Bell  documented that warts were caused by a disease entirely unrelated to syphilis, and established a  causal link  between warts and cancer. In the 19th century, the  chief physician  of Verona Hospital established a link between warts and  cervical cancer . But in 1874 it was noted by the dermatologist  Ferdinand Ritter von Hebra  that while various theories were advanced by the medical profession, the "influences causing warts are still very obscure". [ 56 ]


In 1907 the physician Giuseppe Ciuffo was the first to demonstrate that warts were caused by a virus infection. In 1976 the virologist  Harald zur Hausen  was the first to discover that warts were caused by the  human papillomavirus  (HPV). His continuous research established the evidence necessary to develop a  HPV vaccine , which first became available in 2006. [ 56 ]


When the  cholesterol  levels in the body  rise above the normal level , a number of  skin lesions  can occur.  Xanthomas  are one of types of skin lesions that may occur in this situation.


Other systemic conditions may also occur with increased levels of cholesterol in the blood.


Allopurinol  is a  medication  used to decrease  high blood uric acid levels . [ 5 ]  It is specifically used to prevent  gout , prevent specific types of  kidney stones  and for the high uric acid levels that can occur with  chemotherapy . [ 6 ] [ 7 ]  It is taken  orally  (by mouth) or  intravenously  (injected into a vein). [ 7 ]


Common side effects when used orally include itchiness and rash. [ 7 ]  Common side effects when used by injection include  vomiting  and  kidney problems . [ 7 ]  While not recommended historically, starting allopurinol during an attack of gout appears to be safe. [ 8 ] [ 9 ]  In those already on the medication, it should be continued even during an acute gout attack. [ 8 ] [ 6 ]  While use during  pregnancy  does not appear to result in harm, this use has not been well studied. [ 1 ]  Allopurinol is in the  xanthine oxidase inhibitor  family of medications. [ 7 ]


Allopurinol was approved for medical use in the United States in 1966. [ 7 ]  It is on the  World Health Organization's List of Essential Medicines . [ 10 ]  Allopurinol is available as a  generic medication . [ 7 ]  In 2022, it was the 39th most commonly prescribed medication in the United States, with more than 15   million prescriptions. [ 11 ] [ 12 ]


Allopurinol is used to reduce urate formation in conditions where urate deposition has already occurred or is predictable.  The specific diseases and conditions where it is used include gouty arthritis, skin  tophi , kidney stones, idiopathic gout; uric acid lithiasis; acute uric acid nephropathy; neoplastic disease and myeloproliferative disease with high cell turnover rates, in which high urate levels occur either spontaneously, or after cytotoxic therapy; certain enzyme disorders which lead to overproduction of urate, for example:  hypoxanthine-guanine phosphoribosyltransferase , including  Lesch–Nyhan syndrome ;  glucose 6-phosphatase  including  glycogen storage disease ;  phosphoribosyl pyrophosphate synthetase ,  phosphoribosyl pyrophosphate amidotransferase ;  adenine phosphoribosyltransferase .


It is also used to treat kidney stones caused by deficient activity of  adenine phosphoribosyltransferase .


Allopurinol was also commonly used to treat  tumor lysis syndrome  in chemotherapeutic treatments, as these regimens can rapidly produce severe acute hyperuricemia; [ 13 ]  however, it has gradually been replaced by  urate oxidase  therapy. [ 14 ]   Intravenous  formulations are used in this indication when people are unable to swallow medication. [ 4 ]


Allopurinol cotherapy is used to improve outcomes for people with  inflammatory bowel disease  and  Crohn's disease  who do not respond to thiopurine monotherapy. [ 15 ] [ 16 ]  Cotherapy has also been shown to greatly improve hepatoxicity side effects in treatment of IBD. [ 17 ]  Cotherapy invariably requires dose reduction of the thiopurine, usually to one-third of the standard dose depending upon the patient's genetic status for  thiopurine methyltransferase . [ 18 ]


Allopurinol has been tested as an augmentation strategy for the treatment of  mania  in  bipolar disorder . Meta-analytic evidence showed that adjunctive allopurinol was superior to placebo for acute mania (both with and without mixed features). [ 19 ]  Its efficacy was not influenced by dosage, follow-up duration, or concurrent standard treatment. [ 19 ]


There is a correlation between uric acid levels and cardiovascular disease and mortality, and so allopurinol has been explored as a potential treatment to reduce risk of cardiac disease. [ 20 ]  However, the data is inconsistent and conflicting, and the use of allopurinol for use in cardiovascular disease is controversial. Independently of its effects on uric acid, it may also have effects on oxidative stress and inflammation. [ 21 ]


Because allopurinol is not a  uricosuric , it can be used in people with poor  kidney  function.  However, for people with impaired kidney function, allopurinol has two disadvantages. First, its dosing is complex. [ 22 ]  Second, some people are hypersensitive to the drug; therefore, its use requires careful monitoring. [ 23 ] [ 24 ]


Allopurinol has rare but potentially fatal adverse effects involving the skin. The most serious adverse effect is a hypersensitivity syndrome consisting of fever, skin rash,  eosinophilia ,  hepatitis , and worsened renal function, collectively referred to as  DRESS syndrome . [ 23 ]  Allopurinol is one of the drugs commonly known to cause  Stevens–Johnson syndrome  and  toxic epidermal necrolysis , two life-threatening  dermatological  conditions. [ 23 ]  More common is a less-serious rash that leads to discontinuing this drug. [ 23 ]


More rarely, allopurinol can also result in the depression of bone marrow elements, leading to  cytopenias , as well as  aplastic anemia . Moreover, allopurinol can also cause  peripheral neuritis  in some patients, although this is a rare side effect. Another side effect of allopurinol is  interstitial nephritis . [ 25 ]


Drug interactions are extensive, and are as follows: [ 13 ]


Allopurinol may also increase the activity or half-life of the following drugs, in order of seriousness and certainty of the interaction: [ 13 ]


Co-administration of the following drugs may make allopurinol less active or decrease its half-life: [ 13 ]


Co-administration of the following drugs may cause hypersensitivity or skin rash: [ 13 ]


A common misconception is that allopurinol is metabolized by its target,  xanthine oxidase , but this action is principally carried out by  aldehyde oxidase . [ 26 ]  The active  metabolite  of allopurinol is  oxipurinol , which is also an inhibitor of xanthine oxidase. Allopurinol is almost completely metabolized to oxipurinol within two hours of oral administration, whereas oxipurinol is slowly excreted by the kidneys over 18–30 hours. For this reason, oxipurinol is believed responsible for the majority of allopurinol's effect. [ 27 ]


Allopurinol is a purine analog; it is a structural  isomer  of  hypoxanthine  (a naturally occurring  purine  in the body) and is an  inhibitor  of the enzyme  xanthine oxidase . [ 5 ]  Xanthine (1H-Purine-2,6-dione) oxidase is responsible for the successive oxidation of hypoxanthine to  xanthine  and subsequently  uric acid , the product of human purine metabolism. [ 5 ]  In addition to blocking uric acid production, inhibition of xanthine oxidase causes an increase in hypoxanthine and xanthine. While xanthine cannot be converted to purine ribonucleotides, hypoxanthine can be salvaged to the purine  ribonucleotides   adenosine  and  guanosine monophosphates . Increased levels of these ribonucleotides may cause feedback inhibition of  amidophosphoribosyl transferase , the first and rate-limiting enzyme of purine biosynthesis. Allopurinol, therefore, decreases uric acid formation and may also inhibit purine synthesis. [ 28 ]


The HLA-B*5801 allele is a  genetic marker  for allopurinol-induced severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). [ 29 ] [ 30 ]  The frequency of the HLA-B*5801 allele varies between ethnicities: Han Chinese and Thai populations have HLA-B*5801  allele frequencies  of around 8%, as compared to European and Japanese populations, who have allele frequencies of around 1.0% and 0.5%, respectively. [ 31 ]  The increase in risk for developing allopurinol-induced SJS or TEN in individuals with the HLA-B*5801 allele (as compared to those who do not have this allele) is very high, ranging from a 40-fold to a 580-fold increase in risk, depending on ethnicity. [ 29 ] [ 30 ]  As of 2011 the FDA-approved drug label for allopurinol did not contain any information regarding the HLA-B*5801 allele, though FDA scientists did publish a study in 2011 which reported a strong, reproducible and consistent association between the allele and allopurinol-induced SJS and TEN. [ 32 ]  However, the American College of Rheumatology recommends screening for HLA-B*5801 in high-risk populations ( e.g.  Koreans with stage 3 or worse chronic kidney disease and those of Han Chinese and Thai descent), and prescribing patients who are positive for the allele an alternative drug. [ 33 ]  The Clinical Pharmacogenetics Implementation Consortium (CPIC) [ 34 ]  guidelines state that allopurinol is contraindicated in known carriers of the HLA-B*5801 allele. [ 35 ] [ 36 ]


Allopurinol was first synthesized and reported in 1956 by Roland K. Robins (1926–1992), in a search for  antineoplastic agents . [ 5 ] [ 37 ]    Allopurinol inhibits the breakdown ( catabolism ) of the  thiopurine  drug  mercaptopurine , and was later tested by Wayne Rundles in collaboration with  Gertrude Elion 's lab at  Wellcome Research Laboratories  to see if it could improve treatment of  acute lymphoblastic leukemia  by enhancing the action of mercaptopurine. [ 5 ] [ 38 ]   However, no improvement in leukemia response was noted with mercaptopurine-allopurinol co-therapy, so that work turned to other compounds and the team then started testing allopurinol as a potential therapeutic for gout. [ 39 ]   Allopurinol was first marketed as a treatment for gout in 1966. [ 38 ]


Allopurinol is sold as an injection for intravenous use [ 4 ]  and as a tablet. [ 13 ]


Allopurinol has been marketed in the United States since 19 August 1966, when it was first approved by FDA under the trade name Zyloprim. [ 40 ]   Allopurinol was marketed at the time by  Burroughs Wellcome .  Allopurinol is a generic drug sold under a variety of brand names, including Allohexal, Allosig, Milurit, Alloril, Progout, Ürikoliz, Zyloprim, Zyloric, Zyrik, and Aluron. [ 41 ]


Ampiroxicam  ( INN ) is a  non-steroidal anti-inflammatory drug  (NSAID). It is a  prodrug  of  piroxicam . [ 1 ]  It has been studied for potential  anticancer activity , but preliminary results did not show evidence of such activity. [ 2 ] [ 3 ]


This  drug  article relating to the  musculoskeletal system  is a  stub . You can help Wikipedia by  expanding it .


This  analgesic -related article is a  stub . You can help Wikipedia by  expanding it .


Barbiturates [ a ]  are a class of  depressant drugs  that are chemically derived from  barbituric acid . [ 2 ]  They are effective when used  medically  as  anxiolytics ,  hypnotics , and  anticonvulsants , but have physical and psychological  addiction  potential as well as  overdose  potential among other possible adverse effects. They have been  used recreationally  for their anti-anxiety and sedative effects, and are thus  controlled  in most countries due to the risks associated with such use.


Barbiturates have largely been replaced by  benzodiazepines  and  nonbenzodiazepines  ("Z-drugs") in routine medical practice, particularly in the treatment of  anxiety disorders  and  insomnia , because of the significantly lower risk of overdose, and the lack of an  antidote  for  barbiturate overdose . Despite this, barbiturates are still in use for various purposes: in  general anesthesia ,  epilepsy , treatment of acute  migraines  or  cluster headaches , acute  tension headaches ,  euthanasia ,  capital punishment , and  assisted suicide . [ 3 ]


Barbiturates, such as  phenobarbital , were long used as  anxiolytics  and  hypnotics . Intermediate-acting barbiturates reduce time to fall asleep, increase total sleep time, and reduce REM sleep time. Today they have been largely replaced by  benzodiazepines  for these purposes because the latter are less toxic in drug  overdose . [ 4 ] [ 5 ] [ 6 ]  However, barbiturates are still used as anticonvulsants (e.g.,  phenobarbital  and  primidone ) and general anesthetics (e.g.,  sodium thiopental ).


Barbiturates in high doses are used for  medical aid in dying , and in combination with a  muscle relaxant  for  euthanasia  and for  capital punishment  by  lethal injection . [ 7 ] [ 8 ]  Barbiturates are frequently employed as euthanizing agents in small-animal  veterinary medicine .


Sodium thiopental  is an ultra-short-acting barbiturate that is marketed under the name Sodium Pentothal. It is often mistaken for " truth serum ", or  sodium amytal , an intermediate-acting barbiturate that is used for sedation and to treat insomnia, but was also used in so-called sodium amytal "interviews" where the person being questioned would incorrectly be thought to be more likely to provide the truth whilst under the influence of the drug. [ 9 ]   When dissolved in water, sodium amytal can be swallowed, or it can be administered by intravenous injection. The drug does not itself force people to tell the truth, but is thought to decrease inhibitions and slow creative thinking, making subjects more likely to be caught off guard when questioned, and increasing the possibility of the subject revealing information through emotional outbursts. Lying is somewhat more complex than telling the truth, especially under the influence of a sedative-hypnotic drug. [ 10 ]


The memory-impairing effects and cognitive impairments induced by sodium thiopental are thought to reduce a subject's ability to invent and remember lies. This practice is no longer considered legally admissible in court, owing to findings that subjects undergoing such interrogations may form false memories, putting the reliability of all information obtained through such methods into question. Nonetheless, it is still employed in certain circumstances by defense and law enforcement agencies as a "humane" alternative to torture interrogation when the subject is believed to have information critical to the security of the state or agency employing the tactic. [ 11 ]


In 1988, the synthesis and binding studies of an artificial receptor binding barbiturates by six complementary  hydrogen bonds  was published. [ 12 ]  Since this first article, different kind of receptors were designed, as well as different barbiturates and  cyanurates , not for their efficiencies as drugs but for applications in  supramolecular chemistry , in the conception of materials and molecular devices.


The preferred IUPAC name of the base compound, barbituric acid, is  1,3-diazinane-2,4,6-trione. Different barbiturates have different substituents in the basic structure, mainly in position 5 on the ring. [ 13 ]  In modern chemistry the barbiturates are often presented by its Hirshfeld surface representations showing its intermolecular interactions  [1]   calculated with  CrystalExplorer  Program.
Sodium barbital and  barbital  have also been used as  pH buffers  for biological research, e.g., in immuno-electrophoresis or in fixative solutions. [ 14 ] [ 15 ]


Barbiturates are classified based on the duration of action. Examples of each class include: [ 16 ]


Indications  for the use of barbiturates include: [ 17 ]


There are special risks to consider for older adults, and women who are pregnant. When a person ages, the body becomes less able to rid itself of barbiturates. As a result, people over the age of 65 are at higher risk of experiencing the harmful effects of barbiturates, including drug dependence and accidental overdose. [ 19 ]  When barbiturates are taken during pregnancy, the drug passes through the placenta to the fetus. After the baby is born, it may experience withdrawal symptoms and have trouble breathing. In addition, nursing mothers who take barbiturates may transmit the drug to their babies through breast milk. [ 20 ]  A rare adverse reaction to barbiturates is  Stevens–Johnson syndrome , which primarily affects the mucous membranes.


With regular use,  tolerance  to the effects of barbiturates develops. Research shows tolerance can develop with even one administration of a barbiturate. As with all GABAergic drugs, barbiturate withdrawal produces potentially fatal effects such as seizures, in a manner reminiscent of  delirium tremens  and  benzodiazepine withdrawal  although its more direct mechanism of GABA agonism makes barbiturate withdrawal even more severe than that of  alcohol  or benzodiazepines.  It is considered one of the most dangerous withdrawals of any known addictive substance. Similarly to benzodiazepines, the longer acting barbiturates produce a less severe withdrawal syndrome than short acting and ultra-short acting barbiturates. Withdrawal symptoms are dose-dependent with heavier users being more affected than lower-dose addicts.


The pharmacological treatment of barbiturate withdrawal is an extended process often consisting of converting the patient to a long-acting benzodiazepine (i.e.  Valium ), followed by slowly tapering off the benzodiazepine. Mental cravings for barbiturates can last for months or years in some cases and counselling/support groups are highly encouraged by addiction specialists. Patients should never try to tackle the task of discontinuing barbiturates without consulting a doctor, owing to the high lethality and relatively sudden onset of the withdrawal. Attempting to quit "cold turkey" may result in neurological damage due to excitotoxicity, severe physical injuries received during convulsions, and even death resulting from arrhythmias during grande Mal seizures, paralleling death caused by delirium tremens. [ citation needed ]


Some symptoms of an overdose typically include sluggishness, incoordination, difficulty in thinking, slowness of speech, faulty judgement, drowsiness, shallow breathing, staggering, and, in severe cases, coma or death. The lethal dosage of barbiturates varies greatly with tolerance and from one individual to another. The  lethal dose  is highly variable among different members of the class, with superpotent barbiturates such as pentobarbital being potentially fatal in considerably lower doses than the low-potency barbiturates such as butalbital. Even in inpatient settings, the development of tolerance is still a problem, as dangerous and unpleasant withdrawal symptoms can result when the drug is stopped after dependence has developed. Tolerance to the anxiolytic and sedative effects of barbiturates tends to develop faster than tolerance to their effects on smooth muscle, respiration, and heart rate, making them generally unsuitable for a long time psychiatric use. Tolerance to the anticonvulsant effects tends to correlate more with tolerance to physiological effects, however, meaning that they are still a viable option for long-term epilepsy treatment.


Barbiturates in overdose with other CNS (central nervous system) depressants (e.g. alcohol, opiates, benzodiazepines) are even more dangerous owing to additive CNS and respiratory depressant effects. In the case of benzodiazepines, not only do they have additive effects, barbiturates also increase the binding affinity of the benzodiazepine binding site, leading to exaggerated benzodiazepine effects. (ex. If a benzodiazepine increases the frequency of channel opening by 300%, and a barbiturate increases the duration of their opening by 300%, then the combined effects of the drugs increases the channels' overall function by 900%, not 600%).


The longest-acting barbiturates have half-lives of a day or more, and subsequently result in  bioaccumulation  of the drug in the system. The therapeutic and recreational effects of long-acting barbiturates wear off significantly faster than the drug can be eliminated, allowing the drug to reach toxic concentrations in the blood following repeated administration (even when taken at the therapeutic or prescribed dose) despite the user feeling little or no effects from the plasma-bound concentrations of the drug. Users who consume alcohol or other sedatives after the drug's effects have worn off, but before it has cleared the system, may experience a greatly exaggerated effect from the other sedatives which can be incapacitating or even fatal.


Barbiturates induce a number of hepatic  CYP  enzymes (most notably  CYP2C9 ,  CYP2C19 , and  CYP3A4 ), [ 22 ]  leading to exaggerated effects from many  prodrugs  and decreased effects from drugs which are metabolized by these enzymes to inactive metabolites. This can result in fatal overdoses from drugs such as  codeine ,  tramadol , and  carisoprodol , which become considerably more potent after being metabolized by CYP enzymes. Although all known members of the class possess relevant enzyme induction capabilities, the degree of induction overall as well as the impact on each specific enzyme span a broad range, with phenobarbital and secobarbital being the most potent enzyme inducers and butalbital and talbutal being among the weakest enzyme inducers in the class.


People who are known to have killed themselves by barbiturate overdose include  Stefan Zweig ,  Charles Boyer ,  Ruan Lingyu ,  Dalida ,  Jeannine Deckers ,  Felix Hausdorff ,  Abbie Hoffman ,  Phyllis Hyman ,  Carole Landis ,  C. P. Ramanujam ,  George Sanders ,  Jean Seberg ,  Lupe Vélez  and the members of   Heaven's Gate  cult. Others who have died as a result of barbiturate overdose include  Pier Angeli ,  Brian Epstein ,  Judy Garland ,  Jimi Hendrix ,  Marilyn Monroe ,  Inger Stevens ,  Dinah Washington ,  Ellen Wilkinson , and  Alan Wilson ; in some cases these have been speculated to be suicides as well. Those who died of a combination of barbiturates and other drugs include  Rainer Werner Fassbinder ,  Dorothy Kilgallen ,  Malcolm Lowry ,  Edie Sedgwick  and  Kenneth Williams .  Dorothy Dandridge  died of either an overdose or an unrelated  embolism .  Ingeborg Bachmann  may have died of the consequences of barbiturate withdrawal (she was hospitalized with burns, the doctors treating her not being aware of her barbiturate addiction).


The use of Barbiturates is contraindicated in the following conditions:


Barbiturates act as positive  allosteric modulators  and, at higher doses, as  agonists  of  GABA A  receptors . [ 24 ]   GABA  is the principal inhibitory  neurotransmitter  in the  mammalian   central nervous system  (CNS). Barbiturates bind to the GABA A  receptor at multiple homologous transmembrane pockets located at subunit interfaces, [ 25 ]  which are binding sites distinct from  GABA  itself and also distinct from the  benzodiazepine  binding site. Like benzodiazepines, barbiturates potentiate the effect of GABA at this receptor. In addition to this GABAergic effect, barbiturates also block  AMPA  and  kainate receptors , subtypes of  ionotropic glutamate receptor . Glutamate is the principal excitatory neurotransmitter in the mammalian CNS. Taken together, the findings that barbiturates potentiate inhibitory GABA A  receptors and inhibit excitatory AMPA receptors can explain the superior CNS-depressant effects of these agents to alternative GABA potentiating agents such as benzodiazepines and  quinazolinones . At higher concentration, they inhibit the  Ca 2+ -dependent release of neurotransmitters such as glutamate via an effect on  P / Q-type   voltage-dependent calcium channels . [ 26 ]
Barbiturates produce their pharmacological effects by increasing the duration of chloride ion channel opening at the GABA A  receptor (pharmacodynamics: This increases the efficacy of GABA), whereas benzodiazepines increase the frequency of the chloride ion channel opening at the  GABA A  receptor (pharmacodynamics: This increases the potency of GABA). The direct gating or opening of the chloride ion channel is the reason for the increased toxicity of barbiturates compared to  benzodiazepines  in overdose. [ 27 ] [ 28 ]


Further, barbiturates are relatively non-selective compounds that bind to an entire superfamily of ligand-gated ion channels, of which the GABA A  receptor channel is only one of several representatives. This  Cys-loop receptor  superfamily of ion channels includes the neuronal  nACh receptor  channel, the  5-HT 3  receptor  channel, and the  glycine receptor  channel. However, while GABA A  receptor currents are increased by barbiturates (and other general anesthetics), ligand-gated ion channels that are predominantly permeable for cationic ions are blocked by these compounds. For example, neuronal nAChR channels are blocked by clinically relevant anesthetic concentrations of both thiopental and pentobarbital. [ 29 ]  Such findings implicate (non-GABA-ergic) ligand-gated ion channels, e.g. the neuronal nAChR channel, in mediating some of the (side) effects of barbiturates. [ 30 ]  This is the mechanism responsible for the (mild to moderate) anesthetic effect of barbiturates in high doses when used in anesthetic concentration.


Drug interactions with barbiturates are: [ 21 ]


Caution is needed in people using: [ 21 ]


Caution is also required in patients with:


Barbituric acid  was first synthesized 27 November 1864, by  German  chemist  Adolf von Baeyer . This was done by  condensing   urea  with  diethyl malonate . There are several stories about how the substance got its name. The most likely story is that Baeyer and his colleagues went to celebrate their discovery in a  tavern  where the town's  artillery   garrison  were also celebrating the feast of  Saint Barbara  – the patron saint of artillerymen. An artillery officer is said to have christened the new substance by amalgamating  Barbara  with  urea . [ 31 ]  Another story holds that Baeyer synthesized the substance from the collected urine of a Munich waitress named Barbara. [ 32 ]  No substance of medical value was discovered, however, until 1903 when two German scientists working at  Bayer ,  Emil Fischer  and  Joseph von Mering , discovered that  barbital  was very effective in putting dogs to sleep. Barbital was then marketed by Bayer under the  trade name   Veronal . It is said that Mering proposed this name because the most peaceful place he knew was the  Italian  city of  Verona . [ 31 ]  In 1912, Bayer introduced another barbituric acid derivative,  phenobarbital , under the trade name Luminal, as a  sedative – hypnotic . [ 33 ]


It was not until the 1950s that the behavioral disturbances and physical dependence potential of barbiturates became recognized. [ 34 ]


Since the 1970s, most barbiturates were replaced by  benzodiazepines . [ 35 ]


Barbituric acid itself does not have any direct effect on the  central nervous system  and chemists have derived over 2,500 compounds from it that possess pharmacologically active qualities. The broad class of barbiturates is further broken down and classified according to speed of onset and duration of action. Ultrashort-acting barbiturates are commonly used for  anesthesia  because their extremely short duration of action allows for greater control. These properties allow doctors to rapidly put a patient "under" in emergency surgery situations. Doctors can also bring a patient out of anesthesia just as quickly, should complications arise during surgery. The middle two classes of barbiturates are often combined under the title "short/intermediate-acting." These barbiturates are also employed for anesthetic purposes, and are also sometimes prescribed for  anxiety  or  insomnia . This is not a common practice anymore, however, owing to the dangers of long-term use of barbiturates; they have been replaced by the  benzodiazepines  and  Z-drug  such as zolpidem, zaleplon and eszopiclone for sleep. The final class of barbiturates are known as long-acting barbiturates (the most notable one being phenobarbital, which has a half-life of roughly 92 hours). This class of barbiturates is used almost exclusively as  anticonvulsants , although on rare occasions they are prescribed for daytime sedation. Barbiturates in this class are not used for insomnia, because, owing to their extremely long half-life, patients would awake with a residual "hang-over" effect and feel groggy.


Barbiturates can in most cases be used either as the free acid or as salts of sodium, calcium, potassium, magnesium, lithium, etc.  Codeine - and  dionine -based salts of barbituric acid have been developed.


During  World War II , military personnel in the Pacific region were given "goofballs" to improve their tolerance of the heat and humidity of daily working conditions. Goofballs reduced the demand on the respiratory system, as well as maintaining blood pressure. Many soldiers returned with addictions that required several months of rehabilitation before discharge. This led to growing dependency problems, often exacerbated by indifferent physicians prescribing high doses to unknowing patients through the 1950s and 1960s.  [ citation needed ]


In the late 1950s and 1960s, an increasing number of published reports of barbiturate  overdoses  and dependence problems led physicians to reduce their prescription, particularly for spurious requests. This eventually led to the scheduling of barbiturates as controlled drugs.


In the Netherlands, the  Opium Law  classifies all barbiturates as  List II  drugs, with the exception of  secobarbital , which is on  List I .


There is a small group of List II drugs for which physicians have to write the prescriptions according to the same, tougher guidelines as those for List I drugs (writing the prescription in full in letters, listing the patients name, and have to contain the name and initials, address, city and telephone number of the licensed prescriber issuing the prescriptions, as well as the name and initials, address and city of the person the prescription is issued to). Among that group of drugs are the barbiturates  amobarbital ,  butalbital ,  cyclobarbital , and  pentobarbital .


In the United States, the  Controlled Substances Act  of 1970 classified most barbiturates as controlled substances—and they remain so as of August 2023 [update] .  Barbital ,  methylphenobarbital  (also known as  mephobarbital ), and  phenobarbital  are designated  schedule IV  drugs, and "Any substance which contains any quantity of a derivative of barbituric acid, or any salt of a derivative of barbituric acid" [ 36 ]  (all other barbiturates) were designated as being  schedule III . Under the original CSA, no barbiturates were placed in schedule I, II, or V; [ 37 ]  however, amobarbital, pentobarbital, and secobarbital are now schedule II controlled substances unless they are in a suppository dosage form. [ 38 ]


In 1971, the  Convention on Psychotropic Substances  was signed in  Vienna . Designed to regulate  amphetamines , barbiturates, and other synthetics, the 34th version of the  treaty , as of 25 January 2014 [update] , regulates secobarbital as schedule II, amobarbital, butalbital, cyclobarbital, and pentobarbital as schedule III, and  allobarbital ,  barbital ,  butobarbital ,  mephobarbital ,  phenobarbital ,  butabarbital , and  vinylbital  as schedule IV on its "Green List". [ 39 ]  The combination medication  Fioricet , consisting of butalbital, caffeine, and  paracetamol  (acetaminophen), however, is specifically exempted from controlled substance status, while its sibling  Fiorinal , which contains aspirin instead of paracetamol and may contain  codeine  phosphate, remains a schedule III drug.


Recreational users report that a barbiturate high gives them feelings of relaxed contentment and  euphoria . Physical and psychological dependence may also develop with repeated use. [ 40 ]  Chronic misuse of barbiturates is associated with significant morbidity. One study found that 11% of males and 23% of females with a  sedative - hypnotic  misuse die by suicide. [ 41 ]  Other effects of barbiturate  intoxication  include  drowsiness ,  lateral  and  vertical   nystagmus ,  slurred speech  and  ataxia , decreased anxiety, and loss of inhibitions. Barbiturates are also used to alleviate the adverse or withdrawal effects of illicit drug use, in a manner similar to long-acting  benzodiazepines  such as  diazepam  and  clonazepam . [ 42 ] [ 43 ]  Often polysubstance use occurs and barbiturates are consumed with or substituted by other available substances, most commonly alcohol.


People who use substances tend to prefer short-acting and intermediate-acting barbiturates. [ 44 ]  The most commonly used are  amobarbital  (Amytal),  pentobarbital  (Nembutal), and  secobarbital  (Seconal). A combination of amobarbital and secobarbital (called  Tuinal ) is also highly used. Short-acting and intermediate-acting barbiturates are usually prescribed as sedatives and sleeping pills. These pills begin acting fifteen to forty minutes after they are swallowed, and their effects last from five to six hours.


Slang terms for barbiturates include barbs, barbies, bluebirds, dolls, wallbangers, yellows, downers, goofballs, sleepers, 'reds & blues', and tooties. [ 45 ]


(it lacks oxygen at #2 position of generic barbiturate structure)


(the oxygen at #2 position is replaced by a sulfur)


Thiopental  is a barbiturate with one of the C=O double bonds (with the carbon being labelled 2 in the adjacent diagram) replaced with a C=S double bond, R 1  being  CH 2 CH 3  (ethyl) and R3) being  CH(CH 3 )CH 2 CH 2 CH 3  ( sec -pentyl). Thiopental is no longer available in the United States. [ 47 ]


Bupropion , formerly called  amfebutamone , [ 16 ]  and sold under the brand name  Wellbutrin  among others, is an  atypical antidepressant  that is US FDA-approved to treat  major depressive disorder ,  seasonal affective disorder  and to support  smoking cessation . [ 17 ] [ 18 ]  It is also popular as an  add-on  medication in the cases of "incomplete response" to the first-line  selective serotonin reuptake inhibitor  (SSRI) antidepressant. [ 18 ] [ 19 ]  Bupropion has several features that distinguish it from other antidepressants: it does not usually cause sexual dysfunction, [ 18 ]  it is not associated with weight gain [ 18 ]  and  sleepiness , [ 20 ]  and it is more effective than SSRIs at improving symptoms of  hypersomnia  and fatigue. [ 21 ]  Bupropion, particularly the immediate-release formulation, carries a higher risk of seizure than many other antidepressants, hence caution is recommended in patients with a history of seizure disorder. [ 22 ]  The medication is taken  by mouth . [ 2 ] [ 3 ]


Common  adverse effects  of bupropion with the greatest difference from  placebo  are  dry mouth ,  nausea ,  constipation ,  insomnia ,  anxiety ,  tremor , and  excessive sweating . [ 10 ] [ 11 ]  Raised  blood pressure  is notable. [ 23 ]  Rare but serious side effects include  seizures , [ 10 ] [ 11 ]   liver toxicity , [ 24 ]   psychosis , [ 25 ]  and risk of  overdose . [ 26 ]  Bupropion use during  pregnancy  may be associated with increased likelihood of  congenital heart defects . [ 27 ]


Bupropion acts as a  norepinephrine–dopamine reuptake inhibitor  (NDRI) and a  nicotinic receptor antagonist . [ 2 ]  However, its effects on  dopamine  are weak and clinical significance is contentious. [ 28 ] [ 29 ] [ 30 ] [ 31 ] [ 32 ]  Chemically, bupropion is an  aminoketone  that belongs to the  class  of  substituted cathinones  and more generally that of  substituted amphetamines  and  substituted phenethylamines . [ 33 ] [ 34 ]


Bupropion was invented by  Nariman Mehta , who worked at  Burroughs Wellcome , in 1969. [ 35 ]  It was first approved for medical use in the United States in 1985. [ 36 ]  Bupropion was originally called by the generic name amfebutamone, before being renamed in 2000. [ 16 ]  In 2022, it was the 21st most commonly prescribed medication in the United States, with more than 25   million prescriptions. [ 37 ] [ 38 ]  It is on the  World Health Organization's List of Essential Medicines . [ 39 ]  In 2022, the US  Food and Drug Administration  (FDA) approved the combination  dextromethorphan/bupropion  to serve as a rapid-acting  antidepressant  in patients with  major depressive disorder . [ 40 ]


The evidence overall supports the  effectiveness  of bupropion over  placebo  for the treatment of depression. [ 41 ] [ 18 ] [ 42 ]  Some peer-reviewed studies suggest the  quality of evidence  is low. [ 42 ] [ 18 ]  Some  meta-analyses  report that bupropion has an at-most small  effect size  for depression. [ 43 ] [ 44 ] [ 42 ] [ 45 ]  One meta-analysis reported a large effect size. [ 18 ]  However, there were methodological limitations with this meta-analysis, including using a subset of only five trials for the effect size calculation, substantial  variability  in effect sizes between the selected trials—which led the authors to state that their findings in this area should be interpreted with "extreme caution"—and general lack of inclusion of  unpublished  trials in the meta-analysis. [ 18 ]  Unpublished trials are more likely to be negative in findings, [ 46 ] [ 47 ]  and other meta-analyses have included unpublished trials. [ 43 ] [ 44 ] [ 42 ] [ 45 ]  Evidence suggests that the effectiveness of bupropion for depression is similar to that of other antidepressants. [ 43 ] [ 44 ] [ 18 ]


Over the autumn and winter months, bupropion prevents the development of depression in those who have recurring  seasonal affective disorder : 15% of participants on bupropion experienced a major depressive episode vs. 27% of those on placebo. [ 48 ]  Bupropion also improves depression in  bipolar disorder , with the efficacy and risk of an affective switch being similar to other antidepressants. [ 49 ]


Bupropion has several features that distinguish it from other antidepressants: for instance, unlike the majority of antidepressants, it does not usually cause sexual dysfunction, and the occurrence of sexual side effects is not different from placebo. [ 18 ] [ 50 ]  Bupropion treatment is not associated with weight gain; on the contrary, the majority of studies observed significant weight loss in bupropion-treated participants. [ 18 ]  Bupropion treatment also is not associated with the  sleepiness  that may be produced by other antidepressants. [ 20 ]  Bupropion is more effective than  selective serotonin reuptake inhibitors  (SSRIs) at improving symptoms of  hypersomnia  and fatigue in depressed patients. [ 21 ]  Bupropion is effective in the treatment of anxious depression and, contrary to common belief, does not exacerbate anxiety in this context. [ 51 ] [ 52 ]  The effectiveness of bupropion for anxious depression is equivalent to that of SSRIs in the case of depression with low or moderate anxiety, whereas SSRIs show a modest effectiveness advantage in terms of response rates for depression with high anxiety. [ 51 ]


The addition of bupropion to a prescribed SSRI is a common strategy when people do not respond to the SSRI, [ 19 ]  and it is supported by clinical trials; [ 18 ]  however, it appears to be inferior to the addition of atypical antipsychotic  aripiprazole . [ 53 ] [ further explanation needed ]


Prescribed as an aid for smoking cessation, bupropion reduces the severity of  craving  for nicotine and  withdrawal  symptoms [ 54 ] [ 55 ] [ 56 ]  such as depressed
mood, irritability, difficulty concentrating, and increased appetite. [ 57 ]  Initially, bupropion slows the weight gain that often occurs in the first weeks after quitting smoking. With time, however, this effect becomes negligible. [ 57 ]


The bupropion treatment course lasts for seven to twelve weeks, with the patient halting the use of tobacco about ten days into the course. [ 57 ] [ 10 ]  After the course, the effectiveness of bupropion for maintaining abstinence from smoking declines over time, from 37% of tobacco abstinence at 3 months to 20% at one year. [ 58 ]  It is unclear whether extending bupropion treatment helps to prevent relapse of smoking. [ 59 ]


Overall, six months after the therapy, bupropion increases the likelihood of quitting smoking by approximately 1.6-fold as compared to placebo. In this respect, bupropion is as effective as  nicotine replacement therapy  but inferior to  varenicline . Combining bupropion and nicotine replacement therapy does not improve the quitting rate. [ 60 ]


In children and adolescents, the use of bupropion for smoking cessation does not appear to offer any significant benefits. [ 61 ]  The evidence for its use to aid smoking cessation in pregnant women is insufficient. [ 62 ]


In the United States, the treatment of  attention deficit hyperactivity disorder  (ADHD) is not an approved indication of bupropion, and it is not mentioned in the 2019 guideline on ADHD treatment from the  American Academy of Pediatrics . [ 63 ]  Systematic reviews of bupropion for the treatment of ADHD in both adults and children note that bupropion may be effective for ADHD but warn that this conclusion has to be interpreted with caution, because clinical trials were of low quality due to small sizes and risk of bias. [ 30 ] [ 64 ] [ 65 ] [ 66 ]  Similarly to  atomoxetine , bupropion has a delayed  onset of action  for ADHD, and several weeks of treatment are required for therapeutic effects. [ 30 ] [ 67 ]  This is in contrast to  stimulants , such as  amphetamine  and  methylphenidate , which have an immediate onset of effect in the condition. [ 67 ]


Bupropion is less likely than other antidepressants to cause  sexual dysfunction . [ 68 ]  A range of studies indicate that bupropion not only produces fewer sexual side effects than other antidepressants but can actually help to alleviate sexual dysfunction [ 69 ]  including sexual dysfunction induced by  SSRI  antidepressants. [ 70 ]  There have also been small studies suggesting that bupropion or a bupropion/ trazodone  combination may improve some measures of sexual function in women who have  hypoactive sexual desire disorder  (HSDD) and are not depressed. [ 71 ]  According to an expert consensus recommendation from the International Society for the Study of Women's Sexual Health, bupropion can be considered as an off-label treatment for HSDD despite limited safety and efficacy data. [ 72 ]  Likewise, a 2022  systematic review  and  meta-analysis  of bupropion for sexual desire disorder in women reported that although data were limited, bupropion appeared to be dose-dependently effective for the condition. [ 73 ]


Bupropion, when used for treating long-term weight gain over six to twelve months, results in an average weight loss of 2.7 kilograms (6.0 lb) over placebo. [ 74 ]  This is not much different from the weight loss produced by several other weight-loss medications such as  sibutramine  or  orlistat . [ 74 ]  The combination drug  naltrexone/bupropion  has been approved by the US  Food and Drug Administration  (FDA) for the treatment of obesity. [ 75 ] [ 76 ]


Bupropion is not effective in the treatment of  cocaine dependence , [ 77 ]  but it is showing promise in reducing drug use in treating amphetamine-type stimulant use and cravings. [ 78 ] [ 79 ]  Based on studies indicating that bupropion lowers the level of the inflammatory mediator  TNF-alpha , there have been suggestions that it might be useful in treating  inflammatory bowel disease ,  psoriasis , and other autoimmune conditions, but very little clinical evidence is available. [ 80 ] [ 81 ] [ 82 ]  Bupropion is not effective in treating chronic low back pain. [ 83 ]  The drug may be useful in the treatment of  excessive daytime sleepiness  (EDS) and  narcolepsy . [ 84 ] [ 85 ] [ 86 ] [ 87 ]


Bupropion has been used to treat  disorders of diminished motivation , like  apathy ,  abulia , and  akinetic mutism . [ 88 ] [ 89 ]  Accordingly, the drug has been found to increase  effort expenditure  and improve  motivational deficits  in  animal models . [ 88 ]  However, only limited benefits of bupropion in the treatment of apathy have been observed in  clinical trials  in various conditions. [ 88 ]


Bupropion has been used in the treatment of  postural orthostatic tachycardia syndrome  (POTS). [ 90 ] [ 91 ]


Bupropion is available as an  oral   tablet  in several different formulations. [ 10 ] [ 11 ]  It is mainly formulated as the  hydrochloride   salt [ 10 ] [ 11 ]  but also as the  hydrobromide  salt. [ 12 ]  In addition to single-drug formulations, bupropion is formulated in  combinations  including  naltrexone/bupropion  (Contrave) for obesity and  dextromethorphan/bupropion  (Auvelity) for depression. [ 92 ] [ 93 ]


The US  Food and Drug Administration  (FDA) prescription label advises that bupropion should not be prescribed to individuals with  epilepsy  or other conditions that lower the  seizure threshold , such as  anorexia nervosa ,  bulimia nervosa , or  benzodiazepine  or  alcohol withdrawal . It should be avoided in individuals who are taking  monoamine oxidase inhibitors  (MAOIs). The label recommends that caution should be exercised when treating people with liver damage, severe  kidney disease , and severe  hypertension , and in children, adolescents, and young adults due to the increased risk of  suicidal ideation . [ 10 ]


The common adverse effects of bupropion with the greatest difference from placebo are dry mouth, nausea, constipation, insomnia, anxiety, tremor, and excessive sweating. [ 10 ] [ 11 ]  Bupropion has the highest incidence of insomnia of all second-generation antidepressants, apart from  desvenlafaxine . [ 94 ]  It is also associated with about 20% increased risk of headache. [ 95 ]


Bupropion raises blood pressure in some people. One study showed an average rise of 6 mm Hg in systolic blood pressure in 10% of patients. [ 23 ]  The prescribing information notes that  hypertension , sometimes severe, is observed in some people taking bupropion, both with and without pre-existing hypertension. [ 10 ] [ 11 ]  The safety of bupropion in people with cardiovascular conditions and its general cardiovascular safety profile remains unclear due to the lack of data. [ 96 ] [ 97 ]


Seizure  is a rare but serious adverse effect of bupropion. It is strongly dose-dependent: for the immediate release preparation, the seizure incidence is 0.4% at the dose 300–450 mg per day; the incidence climbs almost ten-fold for the higher than recommended dose of 600 mg. [ 10 ] [ 11 ]  For comparison, the incidence of unprovoked seizure in the general population is 0.07–0.09%, and the risk of seizure for a variety of other antidepressants is generally 0–0.5% at the recommended doses. [ 98 ]


Cases of  liver toxicity  leading to death or  liver transplantation  have been reported for bupropion. It is considered to be one of several antidepressants with a greater risk of hepatotoxicity. [ 24 ]


The prescribing information warns about bupropion triggering an angle-closure  glaucoma  attack. [ 10 ]  On the other hand, bupropion may decrease the risk of development of  open angle glaucoma . [ 99 ]


Bupropion use by mothers in the first trimester of pregnancy is associated with a 23% increase in the odds of  congenital heart defects  in their children. [ 27 ]


Bupropion has rarely been associated with instances of  Stevens–Johnson syndrome . [ 100 ] [ 101 ]


Bupropion has not been associated with  QT prolongation  at therapeutic doses but has been associated with QT prolongation in  overdose . [ 102 ] [ 103 ] [ 104 ]


The US  Food and Drug Administration  (FDA) requires all antidepressants, including bupropion, to carry a  boxed warning  stating that antidepressants may increase the risk of suicide in people younger than 25. This warning is based on a statistical analysis conducted by the FDA which found a 2-fold increase in  suicidal thought  and behavior in children and adolescents, and a 1.5-fold increase in the 18–24 age group. [ 105 ]  For this analysis the FDA combined the results of 295 trials of 11 antidepressants to obtain statistically significant results. Considered in isolation, bupropion was not statistically different from placebo. [ 105 ]


Bupropion prescribed for smoking cessation results in a 25% increase in the risk of psychiatric side effects, in particular,  anxiety  (about 40% increase) and  insomnia  (about 80% increase). The evidence is insufficient to determine whether bupropion is associated with suicides or suicidal behavior. [ 55 ]


In rare cases, bupropion-induced  psychosis  may develop. It is associated with higher doses of bupropion; many cases described are at higher than recommended doses. Concurrent antipsychotic medication appears to be protective. [ 25 ]  In most cases the psychotic symptoms are eliminated by reducing the dose, ceasing treatment or adding antipsychotic medication. [ 10 ] [ 25 ]


Although studies are lacking, a handful of case reports suggest that abrupt discontinuation of bupropion may cause  antidepressant discontinuation syndrome . [ 106 ]


Bupropion is considered moderately dangerous in overdose. [ 107 ] [ 108 ]  According to an analysis of  US National Poison Data System , adjusted for the number of prescriptions, bupropion and  venlafaxine  are the two new generation antidepressants (that is excluding  tricyclic antidepressants ) that result in the highest  mortality  and  morbidity . [ 26 ]  For significant overdoses, seizures have been reported in about a third of all cases; other serious effects include hallucinations, loss of consciousness, and  abnormal heart rhythms . When bupropion was one of several kinds of pills taken in an overdose, fever, muscle rigidity, muscle damage, hypertension or hypotension, stupor, coma, and respiratory failure have been reported. While most people recover, some people have died, having had multiple uncontrolled seizures and myocardial infarction. [ 10 ]


Since bupropion is metabolized to  hydroxybupropion  by the enzyme  CYP2B6 , drug interactions with CYP2B6 inhibitors are possible: this includes such medications as  paroxetine ,  sertraline ,  norfluoxetine  (active metabolite of  fluoxetine ),  diazepam ,  clopidogrel , and  orphenadrine . The expected result is an increase of bupropion and a decrease in hydroxybupropion blood concentration. The reverse effect (decrease of bupropion and increase of hydroxybupropion) can be expected with CYP2B6  inducers  such as  carbamazepine ,  clotrimazole ,  rifampicin ,  ritonavir ,  St John's wort , and  phenobarbital . [ 109 ]  Indeed, carbamazepine decreases exposure to bupropion by 90% and increases exposure to hydroxybupropion by 94%. [ 110 ]  Ritonavir,  lopinavir/ritonavir , and  efavirenz  have been shown to decrease levels of bupropion and/or its metabolites. [ 111 ]   Ticlopidine  and clopidogrel, both potent CYP2B6 inhibitors, have been found to considerably increase bupropion levels as well as decrease levels of its metabolite hydroxybupropion. [ 111 ]


Bupropion and its metabolites are inhibitors of  CYP2D6 , with hydroxybupropion responsible for most of the inhibition. Additionally, bupropion and its metabolites may decrease the expression of CYP2D6 in the liver. The end effect is a significant slowing of the clearance of other drugs metabolized by this enzyme. [ 2 ]  For instance, bupropion has been found to increase  area-under-the-curve  of  desipramine , a CYP2D6 substrate, by 5-fold. [ 111 ]  Bupropion has also been found to increase levels of  atomoxetine  by 5.1-fold, while decreasing the exposure to its main metabolite by 1.5-fold. [ 112 ]  As another example, the ratio of  dextromethorphan  (a drug that is mainly metabolized by CYP2D6) to its major  metabolite   dextrorphan  increased approximately 35-fold when it was administered to people being treated with 300 mg/day bupropion. [ 109 ]  When people on bupropion are given  MDMA , about 30% increase of exposure to both drugs is observed, with enhanced mood but decreased  heart rate  effects of MDMA. [ 113 ] [ 114 ]  Interactions with other CYP2D6 substrates, such as  metoprolol ,  imipramine ,  nortriptyline , [ 114 ]   venlafaxine , [ 109 ]  and  nebivolol [ 2 ]  have also been reported. However, in a notable exception, bupropion does not seem to affect the concentrations of CYP2D6 substrates fluoxetine and paroxetine. [ 109 ] [ 115 ]  Bupropion prevents  norepinephrine  and  dopamine  release induced by  amphetamines  and has been found to reduce the subjective and  sympathomimetic  effects of  methamphetamine  in humans. [ 116 ] [ 117 ] [ 118 ]


Bupropion lowers the  seizure  threshold, and therefore can potentially interact with other medications that also lower it, such as  antipsychotics ,  tricyclic antidepressants ,  theophylline , and systemic  corticosteroids . [ 10 ]  The prescribing information recommends minimizing the use of  alcohol , since in rare cases bupropion reduces alcohol tolerance. [ 10 ]


Caution should be observed when combining bupropion with a  monoamine oxidase inhibitor  (MAOI), as it may result in  hypertensive crisis . [ 119 ]


The  mechanism of action  of bupropion in the treatment of depression and for other indications is unclear. [ 2 ]  However, it is thought to be related to the fact that bupropion is a  norepinephrine–dopamine reuptake inhibitor  (NDRI) and  negative allosteric modulator  of several  nicotinic acetylcholine receptors . [ 2 ]  Bupropion does not act as a  norepinephrine–dopamine releasing agent . [ 129 ]  Pharmacological actions of bupropion, to a substantial degree, are due to its active metabolites  hydroxybupropion ,  threo -hydrobupropion , and  erythro -hydrobupropion  that are present in the blood plasma at comparable or much higher levels. [ 2 ]  In fact, bupropion could accurately be conceptualized as a  prodrug  of these metabolites. [ 2 ]  Overall action of these metabolites, and particularly one enantiomer  S,S -hydroxybupropion , is also characterized by inhibition of norepinephrine and dopamine reuptake and nicotinic inhibition (see the chart on the right). [ 2 ]  Bupropion has no meaningful direct activity at a variety of  receptors , including  α-  and  β-adrenergic ,  dopamine ,  serotonin ,  histamine , and  muscarinic acetylcholine receptors . [ 20 ]


The occupancy of  dopamine transporter  (DAT) by bupropion (300   mg/day) and its metabolites in the human brain as measured by several  positron emission tomography  (PET) studies is approximately 20%, with a mean occupancy range of about 14 to 26%. [ 130 ] [ 28 ] [ 29 ] [ 30 ]  For comparison, the NDRI  methylphenidate  at therapeutic doses is thought to occupy greater than 50% of DAT sites. [ 30 ]  In accordance with its low DAT occupancy, no measurable dopamine release in the human brain was detected with bupropion (one 150   mg dose) in a PET study. [ 130 ] [ 28 ] [ 29 ] [ 131 ]  Bupropion has also been shown to increase striatal  VMAT2 , though it is unknown if this effect is more pronounced than other DRIs. [ 132 ]  These findings raise questions about the role of  dopamine reuptake inhibition  in the pharmacology of bupropion, and suggest that other actions may be responsible for its therapeutic effects. [ 130 ] [ 28 ] [ 30 ] [ 29 ]  No data are available on occupancy of the  norepinephrine transporter  (NET) by bupropion and its metabolites. [ 130 ] [ 28 ]  However, due to the increased exposure of hydroxybupropion over bupropion itself, which has higher  affinity  for the NET than the DAT, [ 133 ]  bupropion's overall pharmacological profile in humans may end up making it effectively more of a  norepinephrine reuptake inhibitor  than a dopamine reuptake inhibitor. [ 31 ] [ 32 ]  Accordingly, the clinical effects of bupropion are more consistent with noradrenergic activity than with dopaminergic actions. [ 31 ] [ 32 ]


Bupropion has been claimed to be a  sigma   σ 1  receptor   agonist . [ 134 ] [ 135 ]  Its antidepressant-like effects in rodents depend on σ 1  receptor activation. [ 134 ] [ 135 ] [ 136 ]  They are enhanced and inhibited by σ 1  receptor agonists and antagonists, respectively. [ 134 ] [ 135 ] [ 136 ]  However, no data on the binding or functional effects of bupropion at the human sigma receptors seem to be available. [ 120 ] [ 121 ] [ 122 ]  In any case, bupropion has been reported to bind to rodent σ 1  receptors with  IC 50 Tooltip half-maximal inhibitory concentration  values of 580 to 2,100   nM. [ 137 ]  In contrast to many other  phenethylamines  and  amphetamines , [ 138 ]  bupropion is not an  agonist  of the  trace amine-associated receptor 1  (TAAR1). [ 139 ] [ 140 ] [ 141 ] [ 142 ]


Bupropion has been found to have a mixture of  anti-inflammatory  and  pro-inflammatory  activity through  modulation of the immune system . [ 143 ] [ 144 ] [ 145 ] [ 146 ] [ 147 ] [ 148 ] [ 149 ]  One such mechanism underlying these effects may be reduced levels of the pro-inflammatory  cytokine   tumor necrosis factor alpha  (TNFα). [ 143 ] [ 149 ] [ 150 ]  The catecholaminergic actions of bupropion may be involved in its immunomodulatory effects. [ 150 ]


After oral administration, bupropion is rapidly and completely absorbed reaching the peak blood plasma concentration after 1.5 hours ( t max ). Sustained-release (SR) and extended-release (XL) formulations have been designed to slow down absorption resulting in t max  of 3 hours and 5 hours, respectively. [ 109 ]  Absolute  bioavailability  of bupropion is unknown but is presumed to be low, at 5–20%, due to the  first-pass metabolism . As for the relative bioavailability of the formulations, XL formulation has lower bioavailability (68%) compared to SR formulation and immediate release bupropion. [ 2 ]


Bupropion is metabolized in the body by a variety of pathways. The  oxidative  pathways are by  cytochrome P450  isoenzymes  CYP2B6  leading to  R,R - and  S,S -hydroxybupropion  and, to a lesser degree,  CYP2C19  leading to 4'-hydroxybupropion. The  reductive  pathways are by  11β-hydroxysteroid dehydrogenase type 1  in the liver and  AKR7A2 / AKR7A3  in the intestine leading to  threo -hydrobupropion  and by yet unknown enzyme leading to  erythro -hydrobupropion . [ 2 ]


The metabolism of bupropion is highly variable: the effective doses of bupropion received by persons who ingest the same amount of the drug may differ by as much as 5.5 times (with a  half-life  of 12–30 hours), while the effective doses of  hydroxybupropion  may differ by as much as 7.5 times (with a half-life of 15–25 hours). [ 10 ] [ 158 ] [ 159 ]  Based on this, some researchers have advocated monitoring of the blood level of bupropion and hydroxybupropion. [ 160 ]


The metabolism of bupropion also seems to follow biphasic pharmacokinetics: the redistribution alpha phase with half-life of about 1 hour [ 161 ]  precedes the metabolism beta phase of about 12-30 hours. This might explain why abuse is unfeasible due to a short "high", as well as support the use of extended-release formulas to maintain a consistent concentration of bupropion.


The metabolism of bupropion is highly species-dependent. [ 162 ] [ 163 ] [ 164 ]  As an example, oral bupropion results in hydroxybupropion levels that are 16-fold higher than those of bupropion itself in humans, whereas in rats, oral bupropion results in levels of bupropion that are 3.4-fold higher than those of hydroxybupropion. [ 162 ]  The species-dependent metabolism of bupropion is thought to be involved in species differences in its pharmacodynamic effects. [ 162 ] [ 163 ] [ 164 ]  For example, bupropion produces  psychostimulant -like and  reinforcing  effects in rodents, whereas oral bupropion at therapeutic doses seems to have much less or no potential for such effects in humans. [ 165 ]


Bupropion is an  aminoketone  that belongs to the  class  of  substituted cathinones  and the more general class of  substituted phenethylamines . [ 33 ] [ 34 ]  It is also known structurally as 3-chloro- N - tert -butyl-β-keto-α-methylphenethylamine, 3-chloro- N - tert -butyl-β-ketoamphetamine, or 3-chloro- N - tert -butylcathinone. The clinically used bupropion is  racemic , which is a mixture of two  enantiomers :  S -bupropion and  R -bupropion. Although the  optical isomers  on bupropion can be separated, they rapidly  racemize  under physiological conditions. [ 2 ] [ 166 ]


Bupropion is a  small-molecule   compound  with the  molecular formula  C 13 H 18 ClNO and a  molecular weight  of 239.74   g/mol. [ 167 ] [ 168 ]  It is a highly  lipophilic  compound, [ 2 ]  with an experimental  log P  of 3.6. [ 167 ] [ 168 ]  Pharmaceutically, bupropion is used mainly as the  hydrochloride   salt  but also to a lesser extent as the  hydrobromide  salt. [ 10 ] [ 11 ] [ 169 ]


A number of  analogues  of bupropion exist, such as  hydroxybupropion ,  radafaxine , and  manifaxine , among others. [ 162 ]


There have been reported cases of false-positive urine amphetamine tests in persons taking bupropion. [ 170 ] [ 171 ] [ 172 ]


It is synthesized in two chemical steps starting from 3'-chloro- propiophenone . The alpha position adjacent to the ketone is first  brominated  followed by  nucleophilic displacement  of the resulting alpha-bromoketone with  t -butylamine  and treated with  hydrochloric acid  to give bupropion as the hydrochloride salt in 75–85% overall yield. [ 35 ] [ 173 ]


Bupropion was invented by  Nariman Mehta  of Burroughs Wellcome (now  GlaxoSmithKline ) in 1969, and the US patent for it was granted in 1974. [ 35 ]  It was approved by the US  Food and Drug Administration  (FDA) as an antidepressant on 30 December 1985, and marketed under the name Wellbutrin. [ 36 ] [ 174 ]  However, a significant incidence of  seizures  at the originally recommended dosage (400–600 mg/day) caused the withdrawal of the drug in 1986. Subsequently, the risk of seizures was found to be highly dose-dependent, and bupropion was re-introduced to the market in 1989 with a lower maximum recommended daily dose of 450 mg/day. [ 175 ]


In 1996, the US  Food and Drug Administration  (FDA) approved a  sustained-release  formulation of alcohol-resistant bupropion called Wellbutrin SR, intended to be taken twice a day (as compared with three times a day for immediate-release Wellbutrin). [ 176 ]  In 2003, the FDA approved another sustained-release formulation called Wellbutrin XL, intended for once-daily dosing. [ 177 ]  Wellbutrin SR and XL are available in  generic  form in the United States and Canada. In 1997, bupropion was approved by the FDA for use as a smoking cessation aid under the name Zyban. [ 178 ] [ 176 ]  In 2006, Wellbutrin XL was similarly approved as a treatment for seasonal affective disorder. [ 179 ] [ 180 ]


In October 2007, two providers of consumer information on nutritional products and supplements, ConsumerLab.com and The People's Pharmacy, released the results of comparative tests of different brands of bupropion. [ 181 ]  The People's Pharmacy received multiple reports of increased side effects and decreased efficacy of generic bupropion, which prompted it to ask ConsumerLab.com to test the products in question. The tests showed that "one of a few generic versions of Wellbutrin XL 300 mg, sold as Budeprion XL 300 mg, didn't perform the same as the brand-name pill in the lab." [ 182 ]  The FDA investigated these complaints and concluded that Budeprion XL is equivalent to Wellbutrin XL in regard to bioavailability of bupropion and its main active metabolite hydroxybupropion. The FDA also said that coincidental natural mood variation is the most likely explanation for the apparent worsening of depression after the switch from Wellbutrin XL to Budeprion XL. [ 183 ]  On 3 October 2012, however, the FDA reversed this opinion, announcing that "Budeprion XL 300 mg fails to demonstrate therapeutic equivalence to Wellbutrin XL 300 mg." [ 184 ]  The FDA did not test the bioequivalence of any of the other generic versions of Wellbutrin XL 300 mg, but requested that the four manufacturers submit data on this question to the FDA by March 2013. [ 184 ]  As of October 2013 [update]  the FDA has made determinations on the formulations from some manufacturers not being bioequivalent. [ 184 ]


In April 2008, the FDA approved a formulation of bupropion as a hydrobromide salt instead of a hydrochloride salt, to be sold under the name Aplenzin by  Sanofi-Aventis . [ 12 ] [ 185 ] [ 186 ]


In 2009, the FDA issued a health advisory warning that the prescription of bupropion for smoking cessation has been associated with reports of unusual behavior changes, agitation, and hostility. Some people, according to the advisory, have become depressed or have had their depression worsen, have had thoughts about suicide or dying, or have attempted suicide. [ 187 ]  This advisory was based on a review of anti-smoking products that identified 75 reports of "suicidal adverse events" for bupropion over ten years. [ 188 ]  Based on the results of follow-up trials this warning was removed in 2016. [ 189 ]


In 2012, the US Justice Department announced that GlaxoSmithKline had agreed to plead guilty and pay a $3 billion fine, in part for promoting the unapproved use of Wellbutrin for weight loss and sexual dysfunction. [ 190 ]


In 2017, the  European Medicines Agency  (EMA) recommended suspending a number of nationally approved medicines due to misrepresentation of bioequivalence study data by Micro Therapeutic Research Labs in India. [ 191 ]  The products recommended for suspension included several 300 mg modified-release bupropion tablets. [ 192 ]


Following EMA's call for an industry-wide review of medicines for the possible presence of nitrosamines, [ 193 ]  GlaxoSmithKline paused batch release and distribution of bupropion 150 mg tablets in November 2022. In July 2023, EMA raised the acceptable daily intake of nitrosamine impurities, leading GlaxoSmithKline to announce that distribution of bupropion 150 mg tablets would resume "across the EU and Europe" by the end of 2023. [ 194 ]


While bupropion demonstrates some potential for misuse, this potential is less than of other commonly used stimulants, being limited by features of its pharmacology. [ 195 ]  Case reports describe the misuse of bupropion as producing a "high" similar to cocaine or amphetamine usage but with less intensity. Bupropion misuse is uncommon. [ 195 ]  There have been some anecdotal and case-study reports of bupropion abuse, but the bulk of evidence indicates that the subjective effects of bupropion when taken orally are markedly different from those of addictive stimulants such as cocaine or amphetamine. [ 196 ]  However, bupropion, by non-conventional routes of administration like injection or insufflation, has been reported to be misused in the United States and Canada, notably in prisons. [ 197 ] [ 198 ] [ 199 ] [ 200 ]


In Russia bupropion is banned as a  narcotic drug , due to it being a derivative of  methcathinone . [ 201 ]
In Australia, France, and the UK, smoking cessation is the only licensed use of bupropion, and no generics are marketed. [ 202 ] [ 203 ] [ 204 ]


Brand names include Wellbutrin, [ 10 ] [ 11 ]  Aplenzin, [ 12 ]  Budeprion, Buproban, buprapan, Forfivo, Voxra, Zyban, [ 8 ]  Bupron, Bupisure, Bupep, Smoquite, Elontril, Oribion and Buxon. [ citation needed ]


Bupropion has been studied limitedly in the treatment of  social anxiety disorder . [ 205 ] [ 206 ] [ 207 ]


Cantharidin  is an odorless, colorless fatty substance of the  terpenoid  class, which is secreted by many species of  blister beetles . [ a ]  Its main current use in pharmacology is treating  molluscum contagiosum  and  warts  topically. [ 2 ]  It is a burn agent and  poisonous  in large doses, and has been historically used as  aphrodisiacs  ( Spanish fly ). In its natural form, cantharidin is secreted by the male blister beetle, and given to the female as a copulatory gift during mating. Afterwards, the female beetle covers her eggs with it as a defense against predators.


Poisoning from cantharidin is a significant veterinary concern, especially in horses, but it can also be poisonous to humans if taken internally (where the source is usually experimental self-exposure). Externally, cantharidin is a potent  vesicant  (blistering agent), exposure to which can cause severe  chemical burns . Properly dosed and applied, the same properties have also been used therapeutically, for instance, for treatment of skin conditions, such as  molluscum contagiosum  infection of the skin.


Cantharidin is classified as an  extremely hazardous substance  in the  United States , and is subject to strict reporting requirements by facilities that produce, store, or use it in significant quantities. [ 3 ]


Cantharidin, from the Greek  kantharis , for beetle, [ 4 ]  is an odorless, colorless  natural product  with solubility in various organic solvents, [ specify ]  but only slight solubility in water. [ 5 ]  Its skeleton is  tricyclic , formally, a tricyclo-[5.2.1.0 2,6 ]decane skeleton. Its functionalities include a  carboxylic acid anhydride  (−CO−O−CO−) substructure in one of its rings, as well as a bridging  ether  in its  bicyclic  ring system.


The complete mechanism of the  biosynthesis  of cantharidin is unknown. Its framework formally consists of two  isoprene  units. [ 6 ]  However,  feeding studies  indicate that the biosynthetic process is more complicated, and not a simple product of  geranyl pyrophosphate  or related ten-carbon parent structure, as the seeming  monoterpene  nature would suggest. Instead, there is a  farnesol  (15-carbon) precursor from which certain carbon segments are later excised. [ 7 ]


The level of cantharidin in blister beetles can be quite variable. Among blister beetles of the genus  Epicauta  in  Colorado ,  E. pennsylvanica  contains about 0.2 mg,  E. maculata  contains 0.7 mg, and  E. immaculata  contains 4.8 mg per beetle; males also contain higher levels than females. [ 8 ]


Males of  Berberomeloe majalis  have higher level of cantharidin per beetle: 64.22 ± 51.28 mg/g (dry weight) and 9.10 ± 12.64 mg/g (d. w.). Cantharidin content in  haemolymph  is also higher in males (80.9 ± 106.5 μg/g) than in females (20.0 ± 41.5 μg/g). [ 9 ]


Preparations made from  blister beetles  (particularly " Spanish fly ") have been used since ancient times as an  aphrodisiac , possibly because their physical effects were perceived to mimic those of sexual arousal, [ 10 ]  and because they can cause prolonged erection or  priapism  in men. [ 11 ]  These preparations were known as  cantharides , from the Greek word for "beetle".


Examples of such use found in historical sources include:


Cantharidin was first isolated as a chemically pure substance in 1810 by  Pierre Robiquet , [ 23 ]  a French chemist then living in  Paris . Robiquet isolated cantharidin as the active ingredient in pharmacological preparations of  Lytta vesicatoria , a.k.a. " Spanish fly ", a species of  blister beetle . This was one of the first historical instances of the identification and extraction of a simple active principle from a complex medicine.


Robiquet found cantharidin to be an odorless and colorless solid at  room temperature . He demonstrated that it was the active principle responsible for the aggressively  blistering properties  of the coating of the eggs of the blister beetle, and additionally established that cantharidin had toxic properties comparable in degree to those of the most virulent poisons known in the 19th century, such as  strychnine . [ 24 ]


Poisoning by  Epicauta  species from cantharidin is a significant veterinary concern, especially in horses; species infesting feedstocks depend on region—e.g.,  Epicauta pennsylvanica  (black blister beetle) in the U.S. midwest; and  E. occidentalis, temexia, and vittata  species (striped blister beetles) in the U.S. southwest—where the concentrations of the agent in each can vary substantially. [ 5 ]  Beetles feed on  weeds , and occasionally move into crop fields used to produce livestock feeds (e.g.,  alfalfa ), where they are found to cluster and find their way into  baled hay , e.g., a single flake (4–5 in. section [ 29 ] ) may have several hundred insects, or none at all. [ 5 ]  Horses are very sensitive to the cantharidin produced by beetle infestations: the  LD 50  for horses is roughly 1 mg/kg of the horse's body weight. Horses may be accidentally poisoned when fed bales of fodder with blister beetles in them. [ 30 ]


Great bustards , a strongly  polygynous  bird species, [ 31 ]  are not immune to the toxicity of cantharidin; they become intoxicated after ingesting blister beetles. However, cantharidin has activity also against parasites that infect them. [ 32 ] [ 33 ]  Great bustards may eat toxic  blister beetles  of the genus  Meloe  to increase the sexual arousal of males. [ 34 ]


As a blister agent, cantharidin has the potential to cause adverse effects when used medically; for this reason, it has been included in a list of "problem drugs" used by dermatologists and emergency personnel. [ 35 ]  However, this references unregulated sources of cantharidin. [ 36 ]  In July 2023, the US FDA approved a topical formulation of cantharidin (Ycanth) for the treatment of  molluscum contagiosum . [ 37 ]


When  ingested  by humans, the  LD 50  is unknown, but fatal doses have been
recorded between 10 mg and 65 mg. [ 38 ]  The median lethal dose appears to be around 1 mg/kg [ 39 ]  but individuals have survived after consuming oral doses as high as 175 mg. [ 40 ]  Ingesting cantharidin can initially cause severe damage to the lining of the  gastrointestinal  and  urinary tracts , and may also cause permanent  renal  damage. Symptoms of cantharidin poisoning include  blood in the urine , abdominal pain, and (rarely)  prolonged erections . [ 36 ]


The extreme toxicity of cantharidin makes any use as an aphrodisiac highly dangerous. [ 41 ] [ 42 ]   As a result, it is illegal to sell (or use) cantharidin or preparations containing it without a prescription in many countries. [ 35 ]


Topical cantharidin is absorbed by the lipid membranes of  epidermal cells , causing the release of  serine proteases ,  enzymes  that break the  peptide bonds  in proteins. This causes the disintegration of  desmosomal plaques , cellular structures involved in cell-to-cell adhesion, leading to detachment of the  tonofilaments  that hold cells together. The process leads to the loss of cellular connections ( acantholysis ), and ultimately results in blistering of the skin. Lesions heal without scarring. [ 43 ] [ 44 ]


VP-102, an experimental drug-device combination that includes cantharidin delivered via a single-use applicator, is being studied for the treatment of  molluscum contagiosum ,  common warts , and  genital warts . [ 45 ]


Cantharidin appears to have some effect in the topical treatment of  cutaneous leishmaniasis  in animal models. [ 46 ]  In addition to topical medical applications, cantharidin and its analogues may have activity against cancer cells. [ 47 ] [ 48 ] [ 49 ]
Laboratory studies with cultured tumor cells suggest that this activity may be the result of  PP2A  inhibition. [ 50 ] [ 51 ]


Carbamazepine , sold under the brand name  Tegretol  among others, is an  anticonvulsant medication  used in the treatment of  epilepsy  and  neuropathic pain . [ 4 ] [ 1 ]  It is used as an adjunctive treatment in  schizophrenia  along with other medications and as a  second-line  agent in  bipolar disorder . [ 6 ] [ 1 ]  Carbamazepine appears to work as well as  phenytoin  and  valproate  for focal and generalized seizures. [ 7 ]  It is not effective for  absence  or  myoclonic seizures . [ 1 ]


Carbamazepine was discovered in 1953 by Swiss chemist Walter Schindler. [ 8 ] [ 9 ]  It was first marketed in 1962. [ 10 ]  It is available as a  generic medication . [ 11 ]  It is on the  World Health Organization's List of Essential Medicines . [ 12 ]  In 2020, it was the 185th most commonly prescribed medication in the United States, with more than 2   million prescriptions. [ 13 ] [ 14 ]


Photoswitchable analogues of carbamazepine have been developed to control its pharmacological activity locally and on demand using light ( photopharmacology ), with the purpose of reducing the adverse systemic effects of the drug. [ 15 ]  One of these light-regulated compounds (carbadiazocine, based on a bridged  azobenzene  or  diazocine ) has been shown to produce analgesia with noninvasive illumination  in vivo  in a rat model of  neuropathic pain .


Carbamazepine is typically used for the treatment of  seizure disorders  and  neuropathic pain . [ 1 ]  It is used  off-label  as a second-line treatment for bipolar disorder and in combination with an  antipsychotic  in some cases of  schizophrenia  when treatment with a conventional antipsychotic alone has failed. [ 1 ] [ 16 ]  However, evidence does not support its usage for schizophrenia. [ 17 ]  It is not effective for  absence seizures  or  myoclonic seizures . [ 1 ]  Although carbamazepine may have a similar effectiveness (as measured by people continuing to use a medication) and efficacy (as measured by the medicine reducing seizure recurrence and improving remission) when compared to  phenytoin  and  valproate , choice of medication should be evaluated on an individual basis as further research is needed to determine which medication is most helpful for people with newly-onset seizures. [ 7 ]


In the United States, carbamazepine is  indicated  for the treatment of  epilepsy  (including  partial seizures , generalized  tonic-clonic seizures  and  mixed seizures ), and  trigeminal neuralgia . [ 4 ] [ 18 ]  Carbamazepine is the only medication that is approved by the  Food and Drug Administration  for the treatment of trigeminal neuralgia. [ 19 ]


As of 2014, a  controlled release  formulation was available for which there is tentative evidence showing fewer side effects and unclear evidence with regard to whether there is a difference in efficacy. [ 20 ]


It has also been shown to improve symptoms of "typewriter tinnitus", a type of tinnitus caused by the neurovascular compression of the cochleovestibular nerve.  [ 21 ]


In the US, the label for carbamazepine contains warnings concerning: [ 4 ]


Common  adverse effects  may include drowsiness, dizziness, headaches and migraines,  ataxia , nausea, vomiting, and/or constipation.  Alcohol  use while taking carbamazepine may lead to enhanced depression of the  central nervous system . [ 5 ]   Less common side effects may include increased risk of seizures in people with  mixed seizure disorders , [ 25 ]   abnormal heart rhythms , blurry or  double vision . [ 5 ]   Also, rare case reports of an auditory side effect have been made, whereby patients perceive sounds about a  semitone  lower than previously; this unusual side effect is usually not noticed by most people, and disappears after the person stops taking carbamazepine. [ 26 ]


Serious skin reactions such as  Stevens–Johnson syndrome  (SJS) or  toxic epidermal necrolysis  (TEN) due to carbamazepine therapy are more common in people with a particular  human leukocyte antigen  gene-variant ( allele ),  HLA-B*1502 . [ 5 ]   Odds ratios  for the development of SJS or TEN in people who carry the allele can be in the double, triple or even quadruple digits, depending on the population studied. [ 27 ] [ 28 ]   HLA-B*1502  occurs almost exclusively in people with ancestry across broad areas of Asia, but has a very low or absent frequency in European, Japanese, Korean and African populations. [ 5 ] [ 29 ]  However, the HLA-A*31:01 allele has been shown to be a strong predictor of both mild and severe adverse reactions, such as the  DRESS  form of severe cutaneous reactions, to carbamazepine among Japanese, Chinese, Korean, and Europeans. [ 28 ] [ 30 ]  It is suggested that carbamazepine acts as a potent antigen that binds to the antigen-presenting area of HLA-B*1502 alike, triggering an everlasting activation signal on immature CD8-T cells, thus resulting in widespread cytotoxic reactions like SJS/TEN. [ 31 ]


Carbamazepine has a potential for  drug interactions . [ 18 ]  Drugs that decrease breaking down of carbamazepine or otherwise increase its levels include  erythromycin , [ 32 ]   cimetidine ,  propoxyphene , and  calcium channel blockers . [ 18 ]  Grapefruit juice raises the  bioavailability  of carbamazepine by inhibiting the enzyme  CYP3A4  in the gut wall and in the liver. [ 5 ]  Lower levels of carbamazepine are seen when administered with  phenobarbital ,  phenytoin , or  primidone , which can result in breakthrough seizure activity. [ 33 ]


Valproic acid  and  valnoctamide  both inhibit  microsomal epoxide hydrolase  (mEH), the enzyme responsible for the breakdown of the  active metabolite  carbamazepine-10,11-epoxide into inactive metabolites. [ 34 ]  By inhibiting mEH, valproic acid and valnoctamide cause a build-up of the active metabolite, prolonging the effects of carbamazepine and delaying its excretion.


Carbamazepine, as an inducer of  cytochrome P450  enzymes, may increase clearance of many drugs, decreasing their concentration in the blood to subtherapeutic levels and reducing their desired effects. [ 33 ]  Drugs that are more rapidly metabolized with carbamazepine include  warfarin ,  lamotrigine ,  phenytoin ,  theophylline ,  valproic acid , [ 18 ]  many  benzodiazepines , [ 35 ]  and  methadone . [ 36 ]  Carbamazepine also increases the metabolism of the hormones in  birth control pills  and can reduce their effectiveness, potentially leading to unexpected pregnancies. [ 18 ]


Carbamazepine is a  sodium channel blocker . [ 37 ]   It binds preferentially to  voltage-gated sodium channels  in their inactive conformation, which prevents repetitive and sustained firing of an  action potential .  Carbamazepine has effects on serotonin systems but the relevance to its antiseizure effects is uncertain. There is evidence that it is a  serotonin releasing agent  and possibly even a  serotonin reuptake inhibitor . [ 38 ] [ 39 ] [ 40 ]  It has been suggested that carbamazepine can also block  voltage-gated calcium channels , which will reduce neurotransmitter release. [ 41 ]


Carbamazepine is relatively slowly but practically completely absorbed after administration by mouth. Highest concentrations in the  blood plasma  are reached after 4 to 24 hours depending on the dosage form.  Slow release  tablets result in about 15% lower absorption and 25% lower peak plasma concentrations than ordinary tablets, as well as in less fluctuation of the concentration, but not in significantly lower  minimum concentrations . [ 42 ] [ 43 ]


In the circulation, carbamazepine itself comprises 20 to 30% of total residues. The remainder is in the form of  metabolites ; 70 to 80% of residues is bound to  plasma proteins . Concentrations in breast milk are 25 to 60% of those in the blood plasma. [ 43 ]


Carbamazepine itself is not pharmacologically active. It is activated, mainly by CYP3A4, to carbamazepine-10,11- epoxide , which is solely responsible for the drug's anticonvulsant effects. The epoxide is then inactivated by microsomal epoxide hydrolase (mEH) to carbamazepine- trans -10,11- diol  and further to its  glucuronides . Other metabolites include various  hydroxyl  derivatives and carbamazepine- N -glucuronide. [ 43 ]


The  plasma half-life  is about 35 to 40 hours when carbamazepine is given as single dose, but it is a strong  inducer  of liver enzymes, and the plasma half-life shortens to about 12 to 17 hours when it is given repeatedly. The half-life can be further shortened to 9–10 hours by other enzyme inducers such as  phenytoin  or  phenobarbital . About 70% are excreted via the urine, almost exclusively in form of its metabolites, and 30% via the faeces. [ 42 ] [ 43 ]


Carbamazepine was discovered by chemist Walter Schindler at J.R. Geigy AG (now part of  Novartis ) in  Basel ,  Switzerland , in 1953. [ 44 ] [ 45 ]   It was first marketed as a  drug to treat epilepsy in Switzerland in 1963 under the brand name Tegretol; its use for  trigeminal neuralgia  (formerly known as tic douloureux) was introduced at the same time. [ 44 ]  It has been used as an anticonvulsant and antiepileptic in the United Kingdom since 1965, and has been approved in the United States since 1968. [ 1 ]


Carbamazepine was studied for bipolar disorder throughout the 1970s. [ 46 ]


Carbamazepine and its bio-transformation products have been detected in wastewater treatment plant  effluent [ 47 ] : 224   and in streams receiving treated wastewater. [ 48 ]  Field and laboratory studies have been conducted to understand the accumulation of carbamazepine in food plants grown in soil treated with  sludge , which vary with respect to the concentrations of carbamazepine present in sludge and in the concentrations of sludge in the soil. Taking into account only studies that used concentrations commonly found in the environment, a 2014 review concluded that "the accumulation of carbamazepine into plants grown in soil amended with biosolids poses a  de minimis  risk to human health according to the approach." [ 47 ] : 227


Carbamazepine is available worldwide under many brand names including Tegretol. [ 49 ]


Cefixime , sold under the brand name  Suprax  among others, is an  antibiotic  medication used to treat a number of  bacterial infections . [ 5 ]  These infections include  otitis media ,  strep throat ,  pneumonia ,  urinary tract infections ,  gonorrhea , and  Lyme disease . [ 5 ]  For gonorrhea typically only one dose is required. [ 6 ]  In the United States it is a second-line treatment to  ceftriaxone  for gonorrhea. [ 5 ]  It is taken by mouth. [ 5 ]


Common side effects include  diarrhea ,  abdominal pain , and  nausea . [ 5 ]  Serious side effects may include  allergic reactions  and  Clostridioides difficile  diarrhea . [ 5 ]  It is not recommended in people with a history of a severe  penicillin allergy . [ 6 ]  It appears to be relatively safe during  pregnancy . [ 7 ]  It is in the  third-generation cephalosporin  class of medications. [ 5 ]  It works by disrupting the bacteria's  cell wall  resulting in its death. [ 5 ]


Cefixime was patented in 1979 and approved for medical use in the United States in 1989. [ 5 ] [ 8 ]  It is on the  World Health Organization's List of Essential Medicines . [ 9 ]  It is available as a  generic medication  in the United States. [ 10 ]


Cefixime treats infections of the:


It is also used to treat  typhoid fever . [ 13 ] [ 14 ] [ 5 ]


Cefixime is a broad spectrum cephalosporin antibiotic and is commonly used to treat bacterial infections of the ear, urinary tract, and upper respiratory tract. The following represents MIC susceptibility data for a few medically significant microorganisms: [ 15 ]


The bactericidal action of Cefixime is due to the inhibition of cell wall synthesis. [ medical citation needed ]  It binds to one of the  penicillin binding proteins  (PBPs) which inhibits the final transpeptidation step of the peptidoglycan synthesis in the bacterial cell wall, thus inhibiting biosynthesis and arresting cell wall assembly resulting in bacterial cell death. [ medical citation needed ]


Absorption
Only 40–50% is absorbed from the GI tract (oral  bioavailability ). Absorption may be slowed but not decreased when taken with food. Average peak concentration after administration of oral suspension is approximately 25–50% greater than the peak concentration following oral tablet or capsules administration. [ 11 ]


Distribution
It has high concentrations in  bile  and  urine . It can cross the placenta and its protein binding capacity is 65%. [ medical citation needed ]


Cefixime is contraindicated in patients with known sensitivity or allergies to  cephalosporin  class of  antibiotics . [ 11 ] [ 16 ]  As Cefixime is a third generation cephalosporin, it is not contraindicated for patients with a true penicillin allergy.


Adverse drug reactions include  diarrhea ,  dyspepsia ,  nausea  and vomiting. [ 5 ]  Hypersensitivity reactions like skin rashes,  urticaria  and  Stevens–Johnson syndrome  have been reported. [ medical citation needed ]  There is no specific  antidote  for cefixime overdosage. [ medical citation needed ]


It was sold under the trade name Suprax 125 in the United States until 2003, when it was taken off the market by drug manufacturer  Wyeth  after its  patent  expired. [ citation needed ]  Lupin started selling Suprax in the United States in 2007, [ 18 ]  and it is available in different formulations and strengths. [ 18 ] [ 19 ] [ 20 ] [ 21 ]


Cefixime is marketed under many  brand names  worldwide; examples include Fixacef, Pancef, Caricef, Taxim o, Texit, Ofex, Ceftid, Cef-3, Denvar, 3-C, Cefim, Magnett, Oroken, Ofiken, Fix-A, and Zifi. [ 1 ] [ 22 ]  In India it is marketed as Zifi 200 and is commonly  counterfeited . [ 23 ]