B&O Supprettes  is the  brand name  for a  prescription  medication containing powdered  opium  and  belladonna   alkaloids  in a  suppository  form.  They are indicated for the treatment of moderate to severe  pain  from  urethral   spasm , and for extending the interval(s) between injections of opiates. [ 1 ]  The drug has various "off label" uses, including  renal colic ,  intestinal   cramps ,  tenesmus  and  diarrhea . They are also often prescribed after urinary bladder  surgery . [ 2 ]   B&O Supprettes was unique in the  United States  because they were the only drug containing opium that is for suppository use sold in the US  and, in fact, one of the very few medications that contains opium in any form in the US along with  paregoric  and  opium tincture  ( laudanum ). [ 3 ]


B&O Supprettes (the name is derived from the generic term 'belladonna/opium suppository') is an "unapproved" drug according to the  Food and Drug Administration  (FDA) – that is, the drug existed before the  Food, Drug and Cosmetic Act of 1938 . Accordingly, the compound has never undergone specific medical trials, and its  efficacy  has never been required to be demonstrated. The FDA has put pressure on the manufacturers of this drug for this reason. The original manufacturer of the Supprettes,  Eli Lilly and Company , has long since lost any patent to the drug. Amerifit, which manufactured generic Supprettes prior to 2008, was cautioned by the FDA due to the unapproved nature of the drug combination. [ 4 ]   Since 2008, Paddock Laboratories has manufactured a generic version of the Supprettes after working with the FDA on marketing issues related to the unapproved nature of the drug.


The drug and its  generic  counterparts are supplied in packages of 12, and available in two strengths:


Each B&O Supprettes suppository  #15 A  contains 16.2 mg (1/4  grain ) of belladonna and 30 mg (1/2 grain) of opium.


Each B&O Supprettes suppository  #16 A  contains 16.2 mg of belladonna and 60 mg (1 grain) of opium.


The usual dose is one suppository  rectally  once or twice daily  PRN  - (as needed), not to exceed four Supprettes in a 24-hour period. [ 1 ]


In the United States, B&O Supprettes is a  Schedule II  drug under the  Controlled Substances Act  of 1970; a written prescription is mandatory, and no refills are permitted. [ 5 ]  Refrigerated storage is preferable, but not required. Most pharmacies consider B&O Supprettes to be a "special order" item, and as such are not normally kept in inventory.  Compounding  pharmacies have the capability of producing a generic form of the medication, and can modify the dosage(s) of the active ingredients (for pediatric or elderly patients, and those with  chronic kidney disease ) or the carrier (usually substituting  cocoa butter ) to best meet the needs of the patient at the request of the prescriber.


Biodyl  is a  trademark  of  Merial  for a  dietary supplement  used in animals.  It is manufactured in two formulations: a powder for use in an individual animal's drinking water, and an  injectable  solution.  The injectable solution is available by  veterinary   prescription  in some countries and  over the counter  in others.


Biodyl is formulated as a powder to be given in water, and as an injectable solution.  The injectable solution is given  under the skin ,  in the muscle , or  in a vein , depending on the species of animal. [ 1 ]   Its intended uses include reducing physiological stress such as due to being transported, and preventing  azoturia  in performance animals.  The manufacturer's own product information describes Biodyl as an "injection solution containing metabolic constituents ( adenosine triphosphoric acid  or ATP, magnesium aspartate,  potassium aspartate ,  sodium selenite  and vitamin B 12) for debility, convalescence and myopathies." [ 2 ]


Composition: [ 1 ] [ 3 ]


In the United States, Biodyl is not  FDA approved , "in that there is not in effect an approval of an application filed with respect to its intended use or uses". [ 4 ]


The manufacturer however, states that "Biodyl is safe when used as directed. It has been around from the 1950s and adverse reactions have been exceedingly rare over many years of tracking. Less than one animal in over 2 million doses." [ 5 ]


In April 2009, the sudden deaths of 21  polo ponies  at  Palm Beach International Polo Club  in  Florida  were attributed by a polo team captain to error or tampering in the team's supply of Biodyl. [ 6 ] [ 7 ]   A newspaper in Argentina reported 3 similar deaths of horses at an international competition in Uruguay. [ 6 ]


In the United States, concerns about a possible manufacturing error or tampering were lost amid a media outcry about the "illegal" use of "illegal" drugs not approved by the FDA, even "banned" by the FDA. [ 8 ]   In the US, Biodyl is neither an illegal drug nor a banned drug, but it is an unapproved drug.  Although Biodyl is a  dietary supplement , a type of product that normally is not subject to FDA approval, FDA approval is required to market injectable solutions (except animal vaccines, which are subject to USDA approval).  An Associated Press story misreported an October 2008 FDA refusal to permit commercial importation of the solution as a refusal to approve the solution.  In fact, Biodyl is not FDA-approved because the manufacturer has never submitted an application for FDA approval. [ 9 ]   Also, the FDA may permit the importation of unapproved drugs for personal use for pets. [ 10 ]


However, on April 23 a new concern emerged when a reputable pharmacy in  Ocala, Florida  disclosed that in  compounding  a preparation for the polo ponies which may have been intended to substitute for Biodyl, the pharmacy accidentally used an incorrect quantity of one of the ingredients. [ 11 ]   Compounding of drugs for use in animals is a subject of concern for the FDA. [ 12 ]


Daflon  is an oral micronized purified phlebotonic  flavonoid  fraction containing 90%  diosmin  and 10%  hesperidin . It is manufactured by  Laboratoires Servier  and often used to treat or manage disorders of the blood vessels. [ 1 ] [ 2 ]  Flavonoids are a type of  phytochemical  that have been associated with various effects on human health and are a component of many different  pharmaceutical ,  nutraceutical , and  cosmetic  preparations. [ 3 ]  Diosmin is a flavone  glycoside  that is derived from hesperidin. Hesperidin is a flavone that is extracted from citrus fruits. [ 4 ]


Daflon is not an FDA-approved medication, and therefore it cannot be advertised for treatment of diseases in the United States. Daflon is under preliminary research for its potential use in treating  vein  diseases, [ 5 ]  or  hemorrhoids . [ 6 ]  It is sold as a drug in  France , [ 7 ] [ 8 ]  Spain, [ 9 ]   Malaysia [ 10 ] [ 11 ]  and Belgium.


There is moderate certainty evidence for the effectiveness of daflon for slightly reducing oedema compared to placebo in the treatment of  chronic venous insufficiency . [ 12 ]   Little to no differences in quality of life after treatment with Daflon were found and there is low certainty evidence that this class of drugs do not influence ulcer healing. [ 12 ]   Diosmiplex, a micronized purified flavonoid fraction of daflon, with similar venous insufficiency indication, is sold as a prescription  medical food  in the US. [ 13 ]


Daflon plays a crucial role in the prevention of  perivascular   edema  formation and treatment of  venous stasis . This activity can be explained by its antagonist activity against  prostaglandin E2  (PgE2) and  thromboxane  (TxA2) biosynthesis leading to inhibition of inflammatory process. Moreover, it also has a contraction activity on the lymphatic vessels which cause the lymphatic flow maximal. [ 14 ]


For venous insufficiency, the dosage is 2 tablets of 500mg daily. For acute hemorrhoidal attack, the dosage is 6 tablets daily for 4 days, followed by 4 tablets daily over the next 3 days. [ 15 ]  For chronic venous disease, the dosage is 2 tablets a day for at least 2 months. [ 16 ]


Possible side effects include routine  gastric disorders  and neurovegetative disorders, however, toxicology studies indicate that diosmin is quite safe. [ 2 ]  Diosmin interacts in an inhibitory manner with some metabolic enzymes so  drug-interactions  are probable. [ 2 ]


Excedrin  is an  over-the-counter   headache   pain reliever , typically in the form of  tablets or caplets . It contains  paracetamol, aspirin and caffeine . It was manufactured by  Bristol-Myers Squibb  until it was purchased by  Novartis  in July 2005 along with other products from BMS's over-the-counter business. As of March 2015,  GSK  holds majority ownership of Excedrin through a joint venture transaction with  Novartis . [ 1 ]  On July 18, 2022, GSK spun off its consumer healthcare business (including Excedrin) to  Haleon .


The brand became known for advertisements where it cured especially unpleasant and excruciating headaches (called "Excedrin headaches" in the ads of 1970s, [ 2 ]  and later called "Excedrin  tension headaches "). In 2007, the brand branched out into marketing for other types of pains with the introduction of Excedrin Back & Body, without caffeine.


Excedrin is a combination medication composed of  acetaminophen ,  aspirin , and  caffeine . These medications treat migraine headache in a variety of ways.


Acetaminophen  is a fever reducer and painkiller. Its precise mechanism is unknown. It is known that it mostly affects the  brain  and  spinal cord , which are parts of the central nervous system. By lowering the quantity of  prostaglandins  the body produces, acetaminophen raises the threshold for pain.


Aspirin  is a nonsteroidal anti-inflammatory drug (NSAID). It lessens irritation and swelling as well as discomfort and inflammation. The amount of prostaglandins the body produces is also decreased by aspirin, but not in the same way that acetaminophen does.


Caffeine  acts as a  vasoconstrictor , [ 3 ]  causing blood vessels to become smaller. This helps to restrict the blood vessels in the brain. As a result, the amount of blood that may pass through the blood arteries at once is reduced. There are several theories regarding the cause and exacerbation of headaches, and it is thought by some that  vasodilation  may contribute to symptoms. [ 4 ]  If a headache is brought on by caffeine withdrawal, the caffeine content of Excedrin may relieve it. [ 3 ]


Over the years, different forms of the drug have been introduced: [ 5 ] [ 6 ]


Excedrin is no longer sold in Canada. [ 11 ]


Previously, Excedrin Migraine and Excedrin Extra Strength sold in Canada had a different formulation compared to the United States. In Canada the product sold with those names contained 500 mg of acetaminophen and 65 mg of caffeine per tablet. The reason was that the  combination of acetaminophen with aspirin  creates the risk of  renal papillary necrosis  if large doses are taken chronically.


In 2005, Bristol-Myers Squibb announced the sale of its North American consumer medicine business (including Excedrin,  Comtrex  and Keri brands) to  Novartis  for $660 million, in order to focus on drugs for the ten most profitable disease areas. [ 12 ]  As of March 2015,  GlaxoSmithKline  held majority ownership through a joint venture transaction with  Novartis . [ 1 ]


On January 9, 2012, Novartis announced that it was voluntarily recalling all lots of select bottle-packaging configurations of Excedrin products with expiration dates of December 20, 2014, or earlier as a precautionary measure because the products may contain stray tablets, capsules, or caplets from other Novartis products, or contain broken or chipped tablets. The recall was conducted with the knowledge of the U.S.  Food and Drug Administration . [ 13 ]  Wholesalers and retailers were instructed to stop distribution and return the affected product. Consumers in possession of recalled Excedrin were instructed to stop using the product and contact Novartis. Novartis stated that Excedrin would be shipping to stores on October 15, 2012, and that customers would start seeing it by the first of November. [ 14 ]


On January 21, 2020, GlaxoSmithKline announced that production and distribution of caplets and gel tabs of Excedrin Extra Strength and Excedrin Migraine would be stopped temporarily. Their statement said, "Through routine quality control and assurance measures, we discovered inconsistencies in how we transfer and weigh ingredients" for the recalled products, and that production would restart "shortly". [ 15 ] [ 16 ]  However, GSK acknowledged that they "cannot confirm a definite date as to when supply will resume". [ 17 ]


On December 26, 2020,  the U.S. Consumer Product Safety Commission  announced the recall of 400,000 bottles of Excedrin due to the containers of the drug allegedly having holes in the bottom. The concern behind the recall was that the plastic bottles, if they had a hole, could allow children to access the painkiller caplets and lead to dangerous overdose or poisoning. [ 18 ]  The recall involved bottles containing 50, 80, 100, 152, 200, 250, or 300 caplets. [ 19 ]


Levolet  may refer to:


The  Merck Group , branded and commonly known as  Merck , is a German  multinational  science and technology company headquartered in  Darmstadt , with about 60,000 employees and a presence in 66 countries. The group includes around 250 companies; the main company is Merck  KGaA  in Germany. The company is divided into three business lines: Healthcare, Life Sciences and Electronics. Merck was founded in 1668 and is the world's oldest operating chemical and pharmaceutical company, as well as one of the largest pharmaceutical companies globally. [ 6 ] [ 7 ]


Merck operates in  Europe ,  Africa ,  Asia ,  Oceania  and the  Americas . It has major  research and development  centres in  Darmstadt ,  Boston ,  Tokyo  and  Beijing , as well as other Research and Development units in  Taiwan ,  France ,  Israel ,  South Korea ,  India , and the  UK . [ 8 ]  Merck pioneered the commercial manufacture of  morphine  in the 19th century and for a time held a virtual monopoly on  cocaine .


Merck was privately owned until going public on the  Frankfurt Stock Exchange  in 1995 and is listed on the  DAX  index of Germany's top companies. The  Merck family  still controls a majority of 70.3% of the company's shares. The Merck Group includes around 250 companies in 180 countries; the current main parent company of the group, since 1995, is named  Merck  KGaA , and is itself mainly owned by the former main parent company,  E. Merck  oHG , which now operates as a  holding company .


The American pharmaceutical company  Merck & Co.  was established as a subsidiary of Merck in 1891, but was  nationalized  by the United States in 1917, before being privatized again when  George W. Merck , a member of an American branch of the Merck family, repurchased the stock in 1919. [ 9 ]  It is known as MSD ( Merck Sharp and Dohme ) outside of North America. The original Merck of Darmstadt holds the rights to the name Merck in all countries except the U.S. and Canada, where it is known as EMD ( Emanuel Merck, Darmstadt ), and the life science business specifically is known as MilliporeSigma. In 2015 Merck adopted a uniform brand identity for all its subsidiaries, and the company has stressed its intention to protect the brand of "the real Merck" globally and initiated litigation against its former subsidiary over use of the name. [ 10 ]


In 2018, the company celebrated their 350th anniversary. [ 11 ]  Merck has formed a strategic alliance with the  Technische Universität Darmstadt , which is located in the same town as Merck. [ 12 ]


The roots of Merck reach back as far as the 17th century in the  Landgraviate of Hesse-Darmstadt  (now a part of Germany). In 1668,  Friedrich Jacob Merck , an  apothecary , assumed ownership of the  Engel-Apotheke  ( lit.   ' Angel Pharmacy ' ) in  Darmstadt . [ citation needed ]


In 1816,  Emanuel Merck , a descendant of the original founder, took over the pharmacy. Thanks to his scientific education he was successful in isolating and characterizing several different  alkaloids  in the  pharmacy 's laboratory, and by doing so also invented a number of drugs. He began the manufacture of these substances "in bulk" in 1827, touting them as a "Cabinet of Pharmaceutical and Chemical Innovations". He and his successors gradually built up a  chemical - pharmaceutical  factory that produced — in addition to raw materials for pharmaceutical preparations — a multitude of other chemicals and (from 1890) medicines. [ 13 ]


In 1891, Georg(e) Merck established himself in the United States and set up  Merck & Co.  with Theodore Weicker in New York. Merck & Co. was confiscated following the  First World War  and set up as an independent company in the United States. [ 14 ] [ 15 ]   Today, the US company, which operates as Merck Sharp and Dohme (MSD) outside the U.S. and Canada, has about 68,000 employees (December 2021) in 120 countries. It is one of the top 5 pharmaceutical companies worldwide, larger than its German ancestor, which employs 60,334 people in 67 countries (December 2021). While Merck in Darmstadt is the legal successor of the original Merck and retains the rights to the name "Merck" in all countries except the U.S. and Canada, it is sometimes known as the "German Merck" or "Merck Darmstadt" in North America. The company was formerly also referred to as "E. Merck" (Emanuel Merck). [ citation needed ]


In the years of the  Nazi rule , the company was led by Karl Emanuel Merck who became a member of the  Nazi Party  in 1933 and subsequently received the title of  Wehrwirtschaftsführer . In addition, Merck was president of the Hessian Chamber of Commerce and Industry as well as performing an advisory function in the Expert Advisory Council for National Health ("Sachverständigenrat für  Volksgesundheit ") of the  Nazi Party . [ 16 ]  During World War II, Merck was manufacturing war essential products such as narcotics, vitamins,  biocides  and other chemicals. According to the company's account, 265  forced laborers  were working in the plant in Darmstadt, most of them women from Russia and Poland. [ 17 ]  Additionally, several hundred  Fremdarbeiter  ("foreign workers") from France and Belgium were employed throughout the war years. An air raid on 12 December 1944 destroyed nearly 70 percent of the plant and killed 55 employees. [ 18 ]


In 1973, Merck Ltd. acquired BDH Chemicals [ 19 ]  from the  Glaxo Group .


In the early 1980s Merck Group built a visitor center at its Darmstadt headquarters that featured a pyramid. [ citation needed ]


Merck was legally named  E. Merck  oHG  until 1995. In 1995 it was listed on the  Frankfurt Stock Exchange  and became a  KGaA , legally named  Merck KGaA . [ citation needed ]


On 13 March 2006, Merck announced a takeover bid for  Schering AG , the world's largest producer of oral contraceptives. On 23 March 2006,  Bayer  AG made a supported offer for Schering and Merck decided to drop out of the bidding for the company. [ 20 ]  Schering is not to be confused with  Schering-Plough  which was once part of Schering AG but was acquired by Merck & Co. in 2009. In September 2006 the company announced a takeover bid of $13.2 billion for  Serono  SA, Switzerland's largest biotech firm. The deal included a buy-out of the  Bertarelli  family's 64.5% stake in Serono to be followed by a public tender offer for the remaining shares starting in November 2006. [ 21 ] [ 22 ]  The combined company has an R&D budget of approximately $1.1 billion and sales of approximately $4.6 billion. Its approximately $2 billion in sales of  biologics  would make it seventh among pharmaceutical/biotech companies. The new entity,  Merck Serono , began operations in 2007.


Merck KGaA established its philanthropic foundation in 2008 called Merck Foundation.  Rasha Kelej  currently serves as its CEO. [ 23 ] [ 24 ]


In 2010, Merck took over  Billerica  (MA) based  Millipore Corporation  for EUR 5.3 billion (US$7.2 billion). [ 25 ] [ 26 ]  It is now Merck's life science business unit. With the acquisition of Millipore, Merck is consolidating its US holdings and shutting down the Gibbstown facility and warehouse. Gibbstown operations will be transferred to the new Philadelphia office and Millipore headquarters. [ 27 ]


Merck Korea received the "Leading Investor Award" at the 5th Korea-EU  Industrial Cooperation Day  in 2011. [ citation needed ]


In December 2013, the company bought  AZ Electronic Materials  SA (AZEM) for about $2.6 billion in cash to increase its offering of specialty chemicals to the electronics industry. [ 28 ]


In September 2014 Merck halted the clinical development of two drug candidates in development with  Oxygen Biotherapeutics . One drug candidate suffered a lack of success in  patient recruitment , with its MUC1 antigen-specific cancer  immunotherapy  drug,  tecemotide  (L-BLP25), missing its Phase I/II endpoint of increasing overall survival in patients with Stage III  non-small cell lung cancer . [ 29 ]  Later in September it was announced that the company would acquire  Sigma-Aldrich  for $17 billion. [ 30 ]  After the acquisition was completed in 2015, Merck had around 50,000 employees. [ 31 ]  In November 2014, Merck and  Pfizer  agreed a deal for the latter to sell the former sharing rights to develop an experimental immunotherapy drug for a fee of $850 million. [ 32 ]


In October 2015, Merck revealed it would return the rights of the Kuvan drug to  BioMarin Pharmaceutical Inc.  The drug is effective in the treatment of the rare genetic disorder  PKU , however Merck is moving away from genetics into  cancer treatment ,  immunology  and  neurology . [ 33 ]  In October, it was announced that  Karl-Ludwig Kley , CEO of Merck since April 2007, would retire in April 2016, and be succeeded by  Stefan Oschmann , who has been a member of the executive board since 2011. [ 34 ]  The company started building new facilities for its R&D operations and a new visitor center at its Darmstadt site in the early 2010s. By 2015 the site's pyramid had been torn down as part of the renovations. [ 35 ]


In April 2017, the company announced it had completed the acquisition of food safety testing company,  BioControl Systems Inc. [ 36 ]  In August of the same year the company announced the acquisition of Natrix Separations for an undisclosed sum. [ 37 ]


In April 2019, Merck announced it would acquire  Versum Materials . [ 38 ]  The acquisition was completed in October 2019 and represented an equity value of about U$5.8 billion. [ 39 ]  In the same year, Merck has also announced the acquisition of Intermolecular Inc, the California-based company for advanced materials. The acquisition was completed in September 2019 and represented an equity value of U$62 million. [ 40 ]


In February 2020, Merck announced the divestment of its Allergopharma Business to Dermapharm, under an unspecified fee. The deal includes Merck's Portfolio in Europe and parts of Asia, including China and India. [ 41 ]


In January 2021,  MilliporeSigma  announced it would acquire AmpTec to expand and enhance the businesses mRNA vaccine capabilities as well as its treatment and diagnostics offerings. [ 42 ]  In March, its Performance Materials division changed name to Electronics division. [ 43 ]  In December of the same year, EMD Serono (Merck Group operations in the US and Canada) announced it would acquire Swiss-based  Chord Therapeutics  and its lead drug  cladribine , used in generalised  myasthenia gravis  and  neuromyelitis optica spectrum disorder . [ 44 ]


In September 2017, Merck said it is considering options for its consumer-health division, including a potential full or partial sale, or strategic partnership. An  equity analyst  estimated the unit could command a purchase price of €1.8 billion to €2.7 billion from a full sale. [ 45 ]  In December  Reuters  reported that both  Nestlé  and private equity owners of  Stada [ 46 ]  were preparing bids for Merck's consumer health group. Days later, Reuters again reported that  Perrigo  was also preparing a bid for the division in the region of €4 billion ($4.7 billion to $4.8 billion). [ 47 ]  In April 2018, Reuters reported that generic drug manufacturer,  Mylan  was in advanced discussions to acquire the consumer health business for between  €3.5–4 billion (£3–3.4 billion). [ 48 ]  Later in the month, Reuters reported that  Procter & Gamble  would purchase the division for €3.4 billion euros (£2.96 billion; $4.2 billion). [ 49 ]


Merck in Darmstadt is the sole legal successor of the original Merck and retains the rights to the trademark "Merck" in all countries except the U.S. and Canada, where "EMD" brand is mostly used (it was introduced alongside Merck's 2001 logo [ 50 ] ). In recent branding campaigns, the company has referred to itself as "the original Merck" and "the real Merck". The company was legally known as  E. Merck  oHG  until 1995, when  Merck  KGaA  became the main parent company and the former a  holding company . Both oHG and KGaA are generic business entity type designations and not used in everyday speech or branding. [ citation needed ]


In 2015 Merck adopted a new logo to increase the visual differences between both companies, while also visualizing "vibrant science and technology" as the new company's brand. [ 51 ]  It has initiated litigation in several countries against its former subsidiary  Merck & Co.  (MSD) over infringing use of the Merck name. In 2016, the  High Court of Justice  in the United Kingdom ruled that MSD had breached an agreement with its former parent company and that only Merck of Darmstadt is entitled to use the Merck name in the United Kingdom; the judge also held that MSD's use of "Merck" as part of branding on its global websites were directed to the UK and infringed Merck's trade mark rights in the UK. [ 52 ]  In response, MSD has initiated counter-litigation in the United States. [ 53 ]


After those controversies, Merck also adopted a new logo for EMD. The same look was also given to the logos of EMD Serono, MilliporeSigma, and EMD Performance Materials (renamed EMD Electronics in March 2021) divisions. Its corporate website is  merckgroup.com  in the world excluding U.S. and Canada, displaying normal Merck logo in the header, and  emdgroup.com  in U.S. and Canada, displaying use of its corporate name, Merck KGaA, Darmstadt, Germany, in the header and additionally displaying a disclaimer about trademark ownership in the footer. [ citation needed ]


On 7 December 2021, Merck, which uses the name EMD Electronics in North America, announced they would be investing $1 billion in a U.S. operations joint venture with  Palantir Technologies  to assist in solving some of the chip industries supply chain problems. The plan is for sites in Pennsylvania, Texas, California, and Arizona. [ 54 ]


Generics UK (Merck's former British subsidiary, the global Generics business being sold on 2 October 2007) paid a £12M  out-of-court settlement  with the  Department of Health and Social Care  of the UK over involvement in an alleged  price and supply fixing  cartel. [ 55 ]


The  NHS  alleges various drugs companies exploited the  oligopolistic market  conditions, forcing the NHS to pay inflated prices. NHS fraud investigators believe there was a  conspiracy  to limit the supply of 30 of its most commonly prescribed drugs, including a class of  penicillin   antibiotics  and to a  generic  version of best-selling  ulcer  treatment  Zantac . [ 56 ]  The NHS has so far filed claims in relation to just three drugs, seeking damages of more than £150m, while the  Serious Fraud Office  (SFO) is conducting a parallel investigation into the price-fixing allegations limited to the supply of blood-thinning pill  warfarin  and  penicillin -based  antibiotics . Homes and offices of  executives  at six firms, including  Ranbaxy , Generics UK,  Norton Healthcare , Goldshield and Regent-GM were raided by the SFO in May 2002. [ citation needed ]


The following is an illustration of the company's mergers, acquisitions,  spin-offs  and historical predecessors:


After Wilhelm Adam Sertürner's isolation of  morphine  from  opium  in 1805, Merck pioneered (from 1827) the commercial manufacture of morphine for an expanding global market. From 1884 onwards, Merck also played role in the production and marketing of  cocaine .  Sigmund Freud , author of  Über Coca  (1884), was an enthusiastic collaborator in Merck's cocaine research, though the methodological sophistication of his  self-experimentation  studies has been challenged.
Attention was directed at  vitamins  as a new  product  category, and  Vigantol  was introduced in 1927, followed by Cebion in 1934. [ citation needed ]


Following the defeat of Germany in  World War II , Merck was granted permission by the military government to produce drugs, pesticides, food preservatives, reagents, and fine chemicals for laboratory use. Soon afterward the boom that is commonly known as the " Wirtschaftswunder " (economic miracle) set in. For Merck, this meant two-digit sales-growth figures for many years. Products of this time included  corticoid  preparations — for example  Fortecortin , which is still used today — the cold remedy Nasivin or the hormone preparations Gestafortin and Mantova. [ citation needed ]


Merck currently employs over 2,500 people in its 4 R&D hubs via.  Boston ,  Darmstadt , Beijing and Tokyo. [ 57 ] [ 58 ]  In the year 2018, Merck invested over €1,6 billion in its R&D operations. [ 59 ]
The focus of Merck's current pharmaceutical R&D is on  oncology , neurology and immunology. In oncology, its first marketed product is  Erbitux  ( cetuximab ), for which it has marketing rights worldwide, apart from North America. [ 60 ]  (Cetuximab was discovered by  Imclone Systems , and is marketed in North America by  Bristol-Myers Squibb .) Other areas of Expertise from Merck Healthcare include Fertility, Endocrinology and General Medicine, the later focusing on treatments for Diabetes, Thyroid disease and Cardiovascular diseases. Some products from Merck include  Metformin ,  Bisoprolol ,  Levothyroxine  and  Digitoxin . Merck's  clinical research  strategy consists of a partnership with  Quintiles  in which the latter helps the former in the clinical development of all its compounds. [ 61 ]  In February 2019, Merck also announced a partnership with GSK to develop and commercialize M7824 (bintrafusp alfa*), a new Immunotherapy with potential in various difficult-to-treat cancers. [ 62 ]  In 2020, Merck launched partnership with  Pechoin  in China to develop "high-tech herbal"  skincare products . [ 63 ]


The life science business of Merck, formerly known as Merck Millipore, was created in July 2010 following the completed acquisition of the US company Millipore. It employs around 19,000 people in 66 countries and runs 65 manufacturing sites and uses the brands Sigma-Aldrich, Milli-Q and Millipore. [ 64 ]  This division comprises all Millipore activities and major segments of the former Merck division Performance & Life Science Chemicals.Merck Millipore had three business units: Bioscience, Lab Solutions and Process Solutions. The Bioscience business unit is dedicated to  solutions  and reagents for protein research and cell biology, cell culture  solutions , as well as to products and services for the development of biopharmaceutical agents. The scope of activities of Lab Solutions included laboratory chemicals and other materials for research, science and industry, products and services for sampling, and test kits for the pharmaceutical, foods and diagnostics industries, along with products, consumables and services surrounding highly purified laboratory water for science and industry. Process Solutions focused on products and services for the production of chemical and biopharmaceutical agents. In 2022 the business was restructured and consisted afterwards of the entities Life Science Services, Science & Lab Solutions, and Process Solutions. The Life Science Services include the Contract Development and Manufacturing Organization (CDMO) and contract testing services. Science & Lab Solutions includes products for Laboratories and Quality Control organizations. Process Solutions supports the biopharma manufacturing processes of its clients with single-use products. [ 65 ]


In 2015, Merck acquired  SigmaAldrich  and combined it with Merck Millipore. [ 66 ]  The company was branded Merck globally and MilliporeSigma in the United States and Canada [ 64 ]  The newly established life science business of Merck has 300,000 products and three business units: Research Solutions, Process Solutions and Applied Solutions. The company serves customers in biotech, pharma, diagnostics, food safety, academia, and environmental. Matthias Heinzel serves as the CEO of the life science business of Merck.


The Life Science business sponsors several award programs for graduate students. One of these awards, the Alfred R. Bader Award for Student Innovation recognizes advanced chemistry graduate students, typically in the field of synthetic organic chemistry. [ citation needed ]


Semiconductor Solutions is the largest business unit within Merck's Electronics business sector. It provides materials, delivery systems, and services for the semiconductor industry. The business unit supplies products for every major production step in the wafer processing, including doping, lithography, patterning, deposition, planarization, etching, and cleaning. After the acquisition of Intermolecular, its capabilities allow material combinations to be tested directly in the specific application environment accelerating learning cycles. Since the acquisition of Versum and Intermolecular, inc., the company's portfolio in electronic materials was significantly expanded. The launch of the integrated organization was done on 1 June 2020. [ citation needed ]


Merck started working on effect pigments in 1957. The business unit is called Surface Solutions. The core markets for Surface Solutions are automotive coatings, cosmetics, and, to a smaller extent, industrials. An example of its pigments is alumina effect pigments sold under the brand name  Xirallic . Currently, this business unit pools all activities for pigments in lacquering, printing, and plastic applications, in the field of security technology (for instance counterfeiting protection), pigments for applications in the food and pharmaceutical areas, functional materials, and active substances and pigments for cosmetics. [ citation needed ]


M Ventures  is a  venture capital  fund of Merck. In 2021, the funds available for investment were increased by Eur 600M to enable investments Biotechnology and Technology. [ 67 ]


The award was jointly established by Merck and the  Technische Universität Darmstadt  in 1992. It recognizes scientists who have made contributions to chemical and pharmaceutical research. [ citation needed ]


During the company's 350th anniversary in 2018, Merck announced the Future Insight Prize The prize consists of a research grant of €1,000,000 ($1.1 million) every year through the next 35 years, to motivate innovation in areas that could solve humanity's most pressing issues. [ 68 ]


Nurofen  is a  brand  of range of pain-relief medication containing  ibuprofen  made by the  English - Dutch  company  Reckitt Benckiser . [ 1 ]   Introduced in 1983, the Nurofen brand was acquired following Reckitt Benckiser's acquisition of  Boots healthcare international  in 2005 for £1.93 billion, which included Nurofen,  Strepsils , and  Clearasil . [ 2 ]   The brand is primarily marketed and sold in the  United Kingdom , [ 1 ]  other parts of  Europe ,  South Africa ,  Australia  and  New Zealand .  In 2016, it was the biggest selling branded over-the-counter medication sold in Great Britain, with sales of £116.8 million. [ 3 ]


There are 11 variants of Nurofen, all of which contain ibuprofen as an active ingredient. [ 4 ]   The ibuprofen is variously formulated as the  free acid , or the  lysine   salt .  For oral formulations, i.e., taken by mouth, it is available in the conventional solid round tablet, a torpedo-shaped solid caplet, or may alternatively be in the form of a soft gel cap.  It is also available as a  topical gel , which is applied directly to the surface of the skin. [ 5 ]   In some cases these are marketed as being useful for treating specific types of pain; such as  back pain  or  period pain . The primary difference among the various formulations is speed and duration of ibuprofen absorption.  According to the UK  Medicines and Healthcare products Regulatory Agency  (UK MHRA), the form of ibuprofen in 'Nurofen Tension Headache' ( ibuprofen lysine ) is absorbed nearly twice as fast as the form in 'Nurofen Period Pain' (ibuprofen free acid), with the former reaching peak blood concentrations in 38 minutes, compared to 80 minutes for the latter. [ 6 ]


Some variants of Nurofen contain additional active ingredients; for example, 'Nurofen Cold & Flu' contains the non- sedating   decongestant   pseudoephedrine .  Others are advertised as being targeted for specific pain types, for example  period pain . [ 1 ]


Nurofen Plus is a pain relief medication based on  codeine  and  ibuprofen . [ 7 ]  It contains 12.8  mg  of  codeine phosphate  (a mild  opioid analgesic ) and 200 mg of ibuprofen, [ 7 ]  which is an  NSAID . Nurofen Plus is the only product in the Nurofen range that contains codeine.


The original Nurofen Plus tablet was manufactured in two equal parts, joined, and then coated.  One part contained 12.8 mg of codeine phosphate, and the other part contained 200 mg of ibuprofen. The tablets could be forcefully split into their two constituent active ingredients, thus isolating the codeine for recreational use. Such drugs have a potential for misuse because they are available freely to the public. [ 8 ]


On 25 August 2011, it was reported that several packs of Nurofen Plus were found to contain  Seroquel XR  — an  anti-psychotic  drug used to treat  schizophrenia  — in  Boots  stores across London. [ 9 ] [ 10 ] [ 11 ]   The next day, a safety alert was issued by the  Medicines and Healthcare products Regulatory Agency  (MHRA). Pharmacists were told to check each package of Nurofen Plus to look for anti-psychotic drugs. Three batches of Nurofen Plus were affected by the alert. Reckitt Benckiser, manufacturer of Nurofen Plus, said that it did not know where the drugs had been switched. The product was re-released in October in cellophane-sealed packs. [ 12 ]


In 2010, the Australian consumer advocate  Choice  awarded Nurofen a "Shonky award" for charging more for "targeted" products, all of which had the same active ingredient as the base product. [ 13 ]


In 2012, the Australian  Therapeutic Goods Administration  upheld a complaint that Nurofen's advertising of different products for different pain was "misleading or likely to be misleading", and ordered that "any representation that refers to two or more Nurofen products that contain equivalent quantities of ibuprofen and include the same product specific indications on the Australian Register of Therapeutic Goods must clearly indicate, in the body of the advertisement, that the two products can be used for the same purposes and are interchangeable (or words to that effect)". [ 14 ]


In April 2013, the Australian consumer affairs television programme  The Checkout  ran a story about Nurofen's claims about targeting specific pain.  Edelman , the PR company for Reckitt Benckiser provided a statement, some of which was used in the programme. Included in the information provided by Edelman were photocopies of some 'sciencey looking documents' that confirmed that Ibuprofen was 'Non-selective'. [ citation needed ]


In March 2015, the  Australian Competition & Consumer Commission  (ACCC) launched proceedings against Reckitt Benckiser; for misleading advertising for its targeted pain range. In December 2015, the  Federal Court of Australia  found that Reckitt Benckiser, which makes Nurofen, had misled consumers with its "Nurofen Specific pain range", and ordered that all Nurofen specific pain products be removed from retail sale within three months. [ 15 ]   A spokeswoman for Reckitt Benckiser argued that, "[This] specific-pain range" was intended "to help consumers navigate their pain relief options, particularly within the grocery environment where there is no healthcare professional to assist decision making". [ 16 ]   The ACCC said that the products were found to be "no more effective at treating the type of pain described on its packaging than any of the other Nurofen specific pain products", and sold for almost twice the price. [ 17 ]   Specific pain range painkillers include Nurofen Back Pain, Nurofen Period Pain, Nurofen Migraine Pain and Nurofen Tension; and all contain the "same active ingredient, 342 milligrams of ibuprofen lysine". [ 16 ]


In April 2016, the Federal Court imposed a $1.7 million fine on Reckitt Benckiser. [ 18 ]  The ACCC appealed the decision in May arguing that $1.7 million in penalties did not act as an adequate deterrent for a company the size of Reckitt Benckiser. [ 19 ]  In December 2016, the Federal Court increased the fine to $6 million, the highest corporate penalty ever awarded for misleading conduct under the  Australian Consumer Law . [ 20 ]


Following the 2015 Australian decision, the UK  Advertising Standards Authority  (ASA) said that it was investigating earlier complaints about a television advertisement for Nurofen Express, which was alleged to be misleading, as it implied that the medicine targeted muscles in the head. [ 21 ]


Tiger Balm  ( Chinese :  虎 標 萬 金 油 ;  pinyin :  Hǔbiao Wànjīnyóu ;  Pe̍h-ōe-jī :  Hó͘-phiau Bān-kim-iû ) is an  analgesic   heat rub  manufactured and distributed by  Singaporean  company  Haw Par Healthcare . It is used for external pain relief.


A precursor to Tiger Balm called Ban Kin Yu ( Chinese :  萬金油 ;  lit.  'Ten Thousand Golden Oil') was developed in the 1870s in  Rangoon ,  Burma , during the  British colonial era  by the practising Chinese herbalist  Aw Chu Kin , [ 1 ]  son of Aw Leng Fan, a Chinese  Hakka  herbalist in  Zhongchuan ,  Fujian Province ,  China . [ 2 ]  His father had sent him to Rangoon in the 1860s to help in his uncle's herbal shop. Eventually, Aw Chu Kin himself set up a family business named Eng Aun Tong 永安堂 ("Hall of Everlasting Peace"). On his deathbed in 1908, he asked his sons  Aw Boon Haw  and  Aw Boon Par  to perfect the product. In 1918, the product was renamed "Tiger Balm" in order to gain broader appeal. [ 2 ]  By 1918, the Aw family had become one of the wealthiest families in Rangoon. [ 3 ]  By the 1920s, the brothers had turned Eng Aun Tong into a very successful business empire that produced and marketed pharmaceutical products, including the Tiger Balm medicinal ointment. [ 4 ]  Tiger Balm sold well in Burma, and was exported to China, Japan, and Southeast Asia. [ 5 ]


The brothers moved to Singapore in the 1920s due to problems with the  colonial British government . [ 5 ]  They set up a branch first at  Amoy Street , then moved to Cecil Street and finally to  89 Neil Road  between 1924 and 1926, at the junction of Neil and Craig Road. The Aw family founded the  Tiger Balm Gardens  in Hong Kong in 1935, Singapore in 1937 and Fujian Province in 1946 [ 6 ]  to promote the product. Boon Haw also established newspapers in China and Singapore; his daughter said that he spent so much money on advertising that "he thought it would be cheaper to just open a few newspapers". [ 7 ]


In 2013, a lawsuit filed by Haw Par against the Indian company  Rangoon Chemical Works , asserting that the latter's "Flying Tiger" balm with similar branding infringed on the Tiger Balm trademark, reached the  Supreme Court of India . [ 8 ]  As a result, Rangoon Chemical Works made changes in the branding of its product and redesigned packaging. [ 9 ]


In 2018, there were 10 products being sold under the Tiger Balm brand, [ 10 ]  in over 100 countries. [ 11 ]  Tiger Balm generated  S$ 152 million ( US$ 110.56 million) in revenues in 2015. [ 12 ]  Haw Par's revenues from Tiger Balm sales in India were  ₹ 85 crore  (US$12.43 million) in 2018. [ 13 ]  The product sold in India is manufactured in  Hyderabad  by Makson [ 14 ]  and marketed by  Alkem Laboratories . [ 15 ]  Between 1993 and 2011, it had been manufactured and marketed by  Elder Pharmaceuticals . [ 16 ]


The remainder is a  petroleum jelly  and  paraffin  base.  The packaging label states that the active ingredients are menthol and camphor.


The Camphor concentration varies by country of sale; as of Nov 2023 Tiger Balm Red and Tiger Balm White both contain 25% Camphor in Singapore and Cambodia, but only 11% in Australia as an example.  This is likely due to different regulatory requirements. [ citation needed ]


A new product named  Tiger Balm White HR  uses eucalyptus oil instead of cajuput oil. [ citation needed ]


Venalex  is a micronized purified  flavenoid  fraction (MPFF). It is a  vegan ,  gluten-free  nutritional supplement. [ 1 ]


Venalex is used to treat chronic functional or structural  venous insufficiency  of the lower limbs. [ 2 ]


No results of clinical trials have been published. [ citation needed ]  Venalex is not currently approved by the FDA. [ 3 ]


Venalex is made with a 9-1 ratio of  diosmin  and  hesperidin . [ 2 ]


Hydroxypropol methylcellulose ,  magnesium stearate .


Zam-Buk  is a  patent medicine  which was produced by the Zam-Buk Company of  Leeds , England, founded by Charles Edward Fulford. It was first sold by his  Bile Beans  company in 1902, [ 1 ]  as a herbal balm and antiseptic ointment; the use of a complementary Zam-Buk soap was recommended to augment the treatment. The ointment was advertised as being effective against a wide range of conditions, including cuts, bruises, sprains, ulcers, bleeding  piles  and even colds and toothache. It could also be used as an  embrocation  by rubbing it into the muscles of the back, legs or feet. [ 2 ]


The source of the name is uncertain, but a link to South Africa has been suggested.  It remains very widely popular in South Africa. [ 3 ]  The brand name was at one time used to refer to ambulance-men and first aiders at rugby league matches in Australia and New Zealand. [ 4 ]


The product is still manufactured today, often by  Bayer , who now owns the trade mark [ 5 ]  in some, but not all, countries. It is available in Southern Africa, Malaysia, Indonesia and Thailand.


In the early 20th century, it was reported that the formulation comprised 66%  paraffin wax , 20% pale resin ( colophony ), and 14%  eucalyptus oil , with small amounts of other ingredients. [ 2 ]  More recently, the composition eucalyptus oil, 1.8%  camphor , 0.5%  thyme oil , and 0.65%  sassafras oil . The English and Thai varieties do not contain sassafras oil. [ 6 ]  A 1908 report published in  The British Medical Journal  estimated that the cost of ingredients for a standard 0.6-ounce (17 g) box was one  farthing , yet its retail price was 1 s  1½  d . [ 2 ]


Widely used in earlier times as an all-round antiseptic and healing ointment, particularly with rugby players worldwide. [ 7 ]


When  Radio Luxembourg  started  longwave   commercial radio  broadcasts in English in 1933, its first advertisers were Fulford's Zam-Buk and  Bile Beans . [ 8 ]


The Zam-Buk brand and trademark were eventually acquired by  Fisons , but production ceased in 1994 after the business was sold to  Rhone-Poulenc ; the product was revived in the United Kingdom by Rose & Co. in 1996. [ 9 ]  After the original trademarks expired, Rose & Co successfully resisted a new application by a third party to register Zam-Buk as a trademark in 2008. [ 10 ]  As of 2015, the trademark for Zam-Buk is registered to  Bayer Consumer Care AG  in Australia, Canada and the United States. [ 11 ] [ 12 ] [ 13 ] . Zam Buk is manufactured for Bayer in Thailand by Interthai Pharmaceutical Manufacturing and is distributed in Malaysia, Thailand, Singapore, Indonesia and South Africa.


In Leeds, the tin boxes used for Zam-buk were printed in Hunslet by Charles Lightowler, at their Hunslet Printing Sheds on Jack Lane.  They also printed the Peps and Bile Beans tins, which were delivered by horse and cart to the Fulford's factory on Carlton Hill, off Woodhouse Lane. [ 14 ]


The  Bencao gangmu , known in English as the  Compendium of Materia Medica  or  Great Pharmacopoeia , [ 1 ]  is an encyclopedic gathering of medicine, natural history, and  Chinese herbology  compiled and edited by  Li Shizhen  and published in the late 16th century, during the  Ming dynasty . Its first draft was completed in 1578 and printed in  Nanjing  in 1596. The  Compendium  lists the  materia medica  of  traditional Chinese medicine  known at the time, including plants, animals, and minerals that were believed to have medicinal properties.


Li compiled his entries not only from hundreds of earlier works in the  bencao  medical tradition, but from literary and historical texts. He reasoned that a poem might have better value than a medical work and that a  tale of the strange  could illustrate a drug's effects. [ 2 ]  The Ming dynasty emperors did not pay too much attention to his work, and it was ignored. [ 3 ]


Li's work contained errors and mistakes due to his limited scientific knowledge at the time. For example, Li claimed that all otters were male [ 4 ]  and that  quicksilver  (mercury) was not toxic. [ 5 ] [ 6 ]


The title, translated as " Materia Medica , Arranged according to Drug Descriptions and Technical Aspects", [ 7 ]  uses two  Chinese   compound words .  Bencao  ( Pen-ts'ao ; "roots and herbs; based on herbs, pharmacopeia,  materia medica ") combines  ben  ( 本  'origin, basis') and  cao  ( 草  'grass, plant, herb').  Gangmu  ( Kang-mu ; 'detailed outline; table of contents') combines  gang  ( kang ;  綱  'main rope, hawser; main threads, essential principles') and  mu  ( 目  'eye, look; category, division').


The characters  綱  and  目  were later used as ' class ' and ' order ', respectively, in  biological classification .


Li Shizhen  travelled widely for field study, combed through more than 800 works of literature, and compiled material from the copious historical  bencao  literature. He modelled his work on a  Song dynasty  compilation, especially its use of non-medical texts. He worked for more than three decades, with the help of his son, Li Jianyuan, who drew the illustrations. He finished a draft of the text in 1578, the printer began to carve the blocks in 1593, but it was not published until 1596, three years after Li died. Li Jianyuan presented a copy to the  Ming dynasty  emperor, who saw it but did not pay much attention. Further editions were then published in 1603, 1606, 1640, and then in many editions, with increasing numbers of illustrations, down to the 21st century. [ 3 ]


The text consists of 1,892 entries, each entry with its own name called a  gang . The  mu  in the title refers to the synonyms of each name. [ 8 ]


The  Compendium  has 53 volumes in total:


The text is written in almost 2 million  Chinese characters , classified into 16 divisions and 60 orders.  For every herb there are entries on their names, a detailed description of their appearance and odor, nature, medical function, side effects, recipes, etc.


The text contains information that was proven to be wrong due to Li's limited scientific and technical knowledge. For example, it is claimed that  quicksilver  (mercury) and  lead  were not  toxic . [ 5 ]  Li also claimed that  otters  are always male [ 4 ]  and that the Moupin  langur  is ten-foot (three-metre) tall, has backwards feet and can be caught when it draws its upper lip over its eyes. [ 4 ] [ 6 ]


The British historian  Joseph Needham  writes about the Compendium in his  Science and Civilisation in China . [ 9 ] [ 10 ]


The text provided classification of how traditional medicine was compiled and formatted, as well as biology classification of both plants and animals.


The text corrected some mistakes in the knowledge of herbs and diseases at the time. Several new herbs and more details from experiments were also included. It also has notes and records on general medical data and medical history.


The text includes information on pharmaceutics,  biology ,  chemistry ,  geography ,  mineralogy ,  geology ,  history , and even  mining  and  astronomy .


The  Biopharmaceutics Classification System  ( BCS ) is a system to differentiate drugs on the basis of their solubility and permeability. [ 1 ]


This system restricts the prediction using the parameters  solubility  and  intestinal permeability . The solubility classification is based on a  United States Pharmacopoeia  (USP) aperture. The intestinal permeability classification is based on a comparison to the  intravenous injection . All those factors are highly important because 85% of the most sold drugs in the  United States  and  Europe  are  orally administered . [ citation needed ]


According to the Biopharmaceutics Classification System (BCS) drug substances are classified to four classes upon their solubility and permeability: [ 1 ]


The drugs are classified in BCS on the basis of solubility and permeability.


Solubility class boundaries are based on the highest dose strength of an immediate release product. A drug is considered highly soluble when the highest dose strength is soluble in 250 ml or less of aqueous media over the pH range of 1 to 6.8. The volume estimate of 250 ml is derived from typical  bioequivalence  study protocols that prescribe administration of a drug product to fasting human volunteers with a glass of water.


Permeability class boundaries are based indirectly on the extent of absorption of a drug substance in humans and directly on the measurement of rates of mass transfer across human intestinal membrane. Alternatively non-human systems capable of predicting drug absorption in humans can be used (such as in-vitro culture methods).  A drug substance is considered highly permeable when the extent of absorption in humans is determined to be 85% or more of the administered dose based on a mass-balance determination or in comparison to an  intravenous  dose.


The  Brazilian Nonproprietary Name  or  DCB , from the Portuguese  Denominação Comum Brasileira  is the official Portuguese nomenclature for  drugs  or  active ingredients  that have been approved by the  Brazilian Health Regulatory Agency (ANVISA)  for use in  Brazil . [ 1 ] [ 2 ]  The consolidated list from October 2021 contains just over 12,300 items. [ 3 ]


Every record has a numerical  identifier  known as the  DCB Number , used in contexts such as registrations, tenders and official documentation. [ 4 ] [ 5 ]


In 1970 Andrejus Korolkovas, from the Faculty of Pharmaceutical Sciences,  University of São Paulo , was already publishing about the importance of a nomenclature to harmonize the names of drugs. [ 6 ]  In the year 1981, a list of generic names that would be mandatory for a new registration of a medicine was published in the Official Gazette of the Union, by the Ministry of Health. A standardization of nomenclature was carried out, and the introduction of numerical codes that would allow the identification of the substances. In 1983 the use of the standard nomenclature in official documents was made mandatory. [ 6 ]


The  Classification of Pharmaco-Therapeutic Referrals  ( CPR ) is a  taxonomy  focused on defining and grouping together situations requiring a  referral  from  pharmacists  to  physicians  (and vice versa) regarding the  pharmacotherapy  used by the  patients . It has been published in 2008. It is bilingual: English/Spanish ( Clasificación de Derivaciones Fármaco-terapéuticas ). [ 1 ]


It is a simple and efficient classification of pharmaco-therapeutic referrals between physicians and pharmacists permitting a common inter-professional language. [ 2 ]  It is adapted to any type of referrals among health professionals, and to increase its specificity it can be combined with  ATC codes ,  ICD-10 , and  ICPC-2 PLUS . [ citation needed ]


It is a part of the  MEDAFAR Project , whose objective is to improve, through different scientific activities, the coordination processes between physicians and pharmacists working in  primary health care . [ 3 ] [ 4 ] [ 5 ] [ 6 ]


It is structured in 4 chapters (E, I, N, S) and 38 rubrics. The terminology used follows the rules of ICPC-2. [ 7 ]


Each rubric consists in an alphanumeric code (the letter corresponds to the chapters and the number to the component) and each title of the rubric (the assigned name) is expressed and explained by:


– A series of terms  related with  the title of the rubric.


– A  definition  expressing the meaning of the rubric.


– A list of  inclusion criteria  and another list with  exclusion criteria  to select and qualify the contents corresponding to a rubric.


– Some  example  to illustrate every term.


It also includes a glossary of 51 terms defined by consensus, an alphabetical index with 350 words used in the rubrics; and a standardized model of inter-professional referral form, to facilitate referrals from community pharmacists to primary care physicians.


The  Coding Symbols for a Thesaurus of Adverse Reaction Terms  ( COSTART ) was developed by the  United States   Food and Drug Administration  (FDA) for the coding, filing and retrieving of post-marketing  adverse reaction  reports. [ 1 ]  COSTART provides a method to deal with the variation in vocabulary used by those who submit adverse event reports to the FDA. Use of this dictionary allowed for standardization of adverse reaction reporting towards the FDA in a consistent way.


COSTART was last updated in 1999. It has been replaced by the Medical Dictionary for Regulatory Activities,  MedDRA . [ 1 ]


The  national drug code  ( NDC ) is a unique product identifier used in the  United States  for drugs intended for  human  use. The Drug Listing Act of 1972 [ 1 ] [ 2 ]  requires registered drug establishments to provide the  Food and Drug Administration  (FDA) with a current list of all drugs manufactured, prepared, propagated, compounded, or processed by it for commercial distribution. Drug products are identified and reported using the NDC.


There are several alternative drug classification systems in addition to NDC that are also commonly used when analyzing drug data, such as  Generic Product Identifier (GPI) .


The national drug code is a unique 10 or 11 digit, 3-segment numeric identifier assigned to each  medication  listed under Section 510 of the US Federal  Food, Drug, and Cosmetic Act . The segments identify the labeler or  vendor , product (within the scope of the labeler), and trade  package  (of this product).


While the labeler code is assigned by the FDA, both the product and package segments are assigned by the labeler. [ 5 ]  While in the past labelers may have had the opportunity to reassign old product codes no longer used to new products, according to the new FDA validation procedures, once an NDC code is assigned to one product (defined by key properties including active ingredients, strength, and dosage form) it may not be later reassigned to a different product.


NDC codes exist in one of the following groupings of digits into segments: 4-4-2, 5-3-2, 5-4-1, 6-3-2, or 6-4-1. [ 5 ] [ 3 ]


The following NDC structure rules apply depending on the length of certain segments.  These rules include the 11 digit format.  Unless stated otherwise, search for drug codes using the 10 digit format.


The official FDA format for NDCs separates the 3 segments with dashes. This is the format in which the NDC must be submitted by labelers since mandatory electronic listing was established in June 2009. [ 6 ]


While the NDC is a 10-digit identifier, confusion exists because of a proliferation of different notations and variants.


The previous NDC directory, populated by a paper-based listing system, sometimes inserted an  asterisk  in either a product code or a package code in addition to the dashes. This format is easily transformed to the official format in effect today by deleting the asterisk (if any).


Each NDC-coded product package in the US bears a  barcode  with a  Universal Product Code  that begins with a 3 ( UPC-A ) or 03 ( EAN-13 ). [ 7 ]  The remainder of the numbers can be the 10 NDC digits, plus the  check digit , but this is not required. If the NDC is used in the UPC it is the most minimal form of the NDC code with 10 digits only. Because the NDC code has been linked with product barcodes in this way, the NDC code could contain ambiguities in this form. For example, 1234-5678-90, 12345-678-90, and 12345-6789-0 could all be entirely different products with the same barcode 1234567890. To prevent any actual ambiguity from impacting the marketplace, ambiguity checks are part of the new electronic listing process.


The pure 10-digit NDC format cannot be transformed back into the standard format with dashes without the help of the product listing database.


The  Centers for Medicare and Medicaid Services  (CMS) had created an 11-digit NDC derivative, which pads the labeler, product, or package code segments of the NDC with leading zeroes wherever they are needed to result in a fixed length 5-4-2 configuration (but always written without dashes). [ 8 ]  This format was adopted by data standards selected pursuant to  HIPAA  regulation, thus other government agencies' lists and databases (such as the  UMLS ) may contain the 11-digit derivative of the original NDC.


The 11-digit NDC format cannot be transformed back into the 10-digit standard format without the help of a product listing database.


In some applications, the fully expanded 5+4 digit labeler+product code is used as a 9-digit number to identify a product regardless of packaging.  Thus an 11-digit NDC can be transformed into a 9-digit NDC product code by removing the last two digits.  This does not work reliably for 10-digit NDCs where the packaging code might be one digit and not two.


In 2022, the FDA proposed revising the NDC regulations to require use of a uniform 12-digit NDC with the same three functional segments but with uniform segment lengths of 6, 4, and 2 digits. [ 9 ]


The  National Pharmaceutical Product Index  or  NAPPI  is a comprehensive database of  pharmaceutical codes  for  medical products classification  used in  South Africa . Each product has a unique  NAPPI code  which enables  electronic data interchange  throughout the health care delivery chain.


NAPPI is governed by the NAPPI Advisory Board (NAB), a non-profit organisation representing hospitals, medical schemes, medical scheme administrators, and medical and dental associations. MediKredit is responsible for the management and maintenance of the NAPPI Product File.


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


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


The  pregnancy category  of a medication is an assessment of the risk of  fetal  injury due to the pharmaceutical, if it is used as directed by the mother during  pregnancy . It does  not  include any  risks conferred by pharmaceutical agents or their metabolites in breast milk .


Every drug has specific information listed in its product literature. The  British National Formulary  used to provide a table of drugs to be avoided or used with caution in pregnancy, and did so using a limited number of key phrases, but now Appendix 4 (which was the Pregnancy table) has been removed. Appendix 4 is now titled "Intravenous Additives". [ 1 ]  However, information that was previously available in the former Appendix 4 (pregnancy) and Appendix 5 (breastfeeding) is now available in the individual drug monographs. [ 2 ]


American law requires that certain drugs and biological products must be labelled very specifically.  Title 21, Part 201.57 (9)(i)  of the  Code of Federal Regulations  lists specific requirements regarding the labeling of drugs with respect to their effects on pregnant populations, including a definition of a "pregnancy category". These rules are enforced by the  Food and Drug Administration .


To supplement this information, the  FDA  publishes additional rules regarding pregnancy and lactation labeling. [ 3 ]


The FDA does not regulate labeling for all hazardous and non-hazardous substances. Many substances, including  alcohol , are widely known to cause serious hazards to pregnant women and their fetuses, including  fetal alcohol syndrome . Many other  pollutants  and  hazardous materials  are similarly known to cause reproductive harm. However, some of these substances are not subject to drug labeling laws, and are therefore not assigned a "Pregnancy Category" per 21 CFR 201.57.


One characteristic of the FDA definitions of the pregnancy categories is that the FDA requires a relatively large amount of high-quality data on a pharmaceutical for it to be defined as Pregnancy Category A. As a result of this, many drugs that would be labelled as safe in other countries are allocated to Category C by the FDA.


On December 13, 2014, the FDA published the Pregnancy and Lactation Labeling Final Rule (PLLR), which changed the labeling requirements for the pregnancy and lactation sections for prescription drugs and biological agents. [ 3 ]  The final rule removed the pregnancy letter categories, and created descriptive subsections for pregnancy exposure and risk, lactation, and effects to reproductive potential for females and males.   Labeling changes from this rule began on June 30, 2015, with all submissions for prescription drugs and biological agents using the labeling changes immediately. Previously approved drugs from June 30, 2001, will switch to the new labeling gradually. The rule does not affect the labeling of over-the-counter drugs or of drugs approved prior to June 30, 2001.


Australia  has a slightly different pregnancy category system from the United States. The categorisation of medicines for use in pregnancy does not follow a hierarchical structure. [ 4 ]


The system, as outlined below, was developed by medical and scientific experts based on available evidence of risks associated with taking particular medicines while pregnant. Being general in nature, it is not presented as medical advice to health professionals or the public. [ 4 ]


Some prescribing guides, such as the  Australian Medicines Handbook , are shifting away from using pregnancy categories since, inherent in these categories, there is an implied assumption that the alphabetical code is one of safety when this is not always the case. Categorisation does not indicate which stages of fetal development might be affected and does not convey information about the balance between risks and benefits in a particular situation. Additionally, categories are not necessarily maintained or updated with availability of new data. [ 5 ]


The data presented is for comparative and illustrative purposes only, and may have been superseded by updated data.


The  Unique Ingredient Identifier  ( UNII ) is an alphanumeric identifier linked to a substance's  molecular structure  or descriptive information and is generated by the  Global Substance Registration System  (GSRS) of the  Food and Drug Administration  (FDA). It classifies substances as  chemical ,  protein ,  nucleic acid ,  polymer ,  structurally diverse , or  mixture [ 1 ] [ 2 ]  according to the standards outlined by the  International Organization for Standardization  in ISO 11238 [ 3 ]  and ISO DTS 19844. [ 4 ]  UNIIs are non-proprietary, unique, unambiguous, and free to generate and use. [ 2 ]  A UNII can be generated for substances at any level of complexity, being broad enough to include "any substance, from an atom to an organism." [ 1 ]


The GSRS is used to generate permanent, unique identifiers for substances in regulated products, such as ingredients in drug and biological products. The GSRS uses molecular structure, protein and nucleic sequences and descriptive information to generate the UNII. The preferred means for defining a chemical substance is by its two-dimensional molecular structure since it is pertinent to a substance's identity and information regarding a substance's  stereochemistry  is readily available. [ 5 ]  Nucleic acids are defined by their sequences and by any modifications that may be present. In the case of proteins only end-group modifications will be uniquely identified, along with any other modifications that are essential for activity. This is because of the inherently heterogenous nature of proteins. Therefore, two different protein substances can share the same UNII and yet have no biosimilarity or therapeutic equivalence. [ 5 ]  Polymers are defined by their structural repeating units and  physical properties  such as  molecular weight  or properties related to molecular weight (e.g.  viscosity ). Structurally diverse materials are inherently heterogenous preparations from natural materials such as  plant   extract  and  vaccines. [ 2 ]


The GSRS is a freely distributable software system provided through a collaboration between the FDA, the  National Center for Advancing Translational Sciences  (NCATS) and the  European Medicines Agency  (EMA). [ 1 ]  The GSRS was developed to implement the ISO 11238 standard which is one of the core ISO  Identification of Medicinal Product  (IDMP) standards. The GSRS Board which governs the GSRS includes experts from FDA, European Regulatory Agencies, and the  United States Pharmacopoeia  (USP). [ 1 ]


A  United States Adopted Name  ( USAN ) is a unique nonproprietary name assigned to a  medication  marketed in the  United States .  Each name is assigned by the USAN Council, which is co-sponsored by the  American Medical Association  (AMA), the  United States Pharmacopeial Convention  (USP), and the  American Pharmacists Association  (APhA).


The USAN Program states that its goal is to select simple, informative, and unique nonproprietary names (also called generic names) for drugs by establishing logical nomenclature classifications based on pharmacological or chemical relationships. [ 1 ]   In addition to drugs, the USAN Council names agents for  gene therapy  and cell therapy,  contact lens polymers , surgical materials, diagnostics, carriers, and substances used as an  excipient .  The USAN Council works in conjunction with the  World Health Organization  (WHO)  international nonproprietary name  (INN) Expert Committee and national nomenclature groups to standardize  drug nomenclature  and establish rules governing the classification of new substances. [ 2 ]


The USAN Council began in June 1961 after the AMA and the USP jointly formed the AMA-USP Nomenclature Committee. [ 3 ]   The American Pharmacists Association (APhA) became the third sponsoring organization in 1964, at which point the name of the committee was changed to the USAN Council, and United States Adopted Name became the official term to describe any nonproprietary name negotiated and formally adopted by the Council.  In 1967, a liaison representative from the  Food and Drug Administration  (FDA) was appointed to serve on the USAN Council. The FDA announced in 1984 that it would discontinue adding drug names to its official list and use the USAN as the established name for labeling and advertising new single-entity  drugs  marketed in the United States. [ 4 ] [ 5 ]  The AMA Council on Drugs no longer exists as a separate entity. The FDA now has a representative on the USAN Council, which has moved away from chemically derived names.


Currently, the USAN Council has five members, one from each sponsoring organization, one from the FDA, and a member-at-large.  One member is nominated to the USAN Council annually by each sponsoring organization; the FDA nominates one liaison member annually.  The member-at-large is selected by the sponsoring organizations from a list of candidates proposed by the AMA, APhA, and the USP.  The five nominees to the Council must be approved annually by the  board of trustees  of the three sponsoring organizations.


By definition, nonproprietary names are not subject to proprietary  trademark  rights but are entirely in the public domain. This distinguishes them from the trademarked names that have been registered for private use.


Assignment of a USAN takes into account practical considerations, such as the existence of  trademarks , international harmonization of drug nomenclature, the development of new classes of drugs, and the fact that the intended uses of substances for which names are being selected may change. [ 7 ] [ 8 ]


USANs assigned today reflect both present nomenclature practices and older methods used to name drug entities.  Early drug nomenclature was based on the  chemical structure .  As newer drugs became chemically more complex and numerous, nonproprietary names based on chemistry became long and difficult to spell, pronounce, or remember.  Additionally, chemically derived names provided little useful information to non-chemist health practitioners.  Considering the needs of health professionals led to a system in which USANs reflect relationships between new entities and older drugs, and avoid names that might suggest non-existent relationships.


Current nomenclature practices involve the adoption of standardized syllables called "stems" that relate new chemical entities to existing drug families. Stems may be  prefixes ,  suffixes , or  interfixes  in the nonproprietary name.  Each stem can emphasize a specific  chemical structure  type, a pharmacologic property, or a combination of these attributes. The recommended list of USAN stems is updated regularly to keep pace to accommodate drugs with new  chemical  and pharmacologic properties. [ 9 ]


As a general rule, the application for a USAN should be forwarded to the USAN Council after the  Investigational New Drug  (IND) is active and  clinical trials  have begun.


Many drug manufacturers seeking a USAN are multinational companies with  subsidiaries  in various parts of the world or contractual agreements with drug firms outside the  United States .  Therefore, it is highly desirable to the  pharmaceutical company , the various nomenclature committees, and the medical community in general that a global name be established for each new single-entity compound introduced.  Assigning a USAN and standardizing names internationally can take anywhere from several months to a few years.


Examples of drugs for which the USAN differs from the INN include: [ 10 ]


VigiBase  is a  World Health Organization 's (WHO) global Individual Case Safety Report (ICSR) database that contains ICSRs submitted by the participating member states enrolled under WHO's international drug monitoring programme. It is the single largest drug safety data repository in the world. Since 1978, the  Uppsala Monitoring Centre  (UMC; established in  Uppsala ,  Sweden ) on behalf of WHO, have been maintaining VigiBase. [ 1 ]


Vigibase is used to obtain the information about a safety profile of a medicinal product. These data are used by pharmaceutical industries, academic institutions and regulatory authorities for statistical signal detection, updating periodic reports, ICSR comparisons with company databases and studying the reporting patterns. [ 2 ]
The data (pre-dominantly post-marketing serious and non-serious cases) is collected from each of its 110 member states which currently comprises to over 10 million ICSRs (October 2014). [ 2 ]  About a hundred thousand ICSRs are added each year.


It is mandatory for all the participating countries (125 members states and 28 associate members) to submit ICSRs to UMC via its appointed national centre based in the respective member states, authorized by its  competent authority  or the  health authority  itself.
These reports are usually sent to the respective national centre by marketing authorization holders, health care professionals (HCP), consumers or any regional centre. Most of participating member have a well established system for collection of ICSRs. [ 3 ]
These submissions are in  ICH  E2B format and are reported more than once a month or at least every quarter. For some member states that lack an E2B compatible database for ICSR management, UMC in collaboration with  Swissmedic  has developed  VigiFlow , a web-based ICSR management system. VigiFlow functions as a national ICSR database management system and analysis tool, through which cases are sent to UMC. [ 4 ]


With primary objective of identify the earliest possible  pharmacovigilance  signals, the usage of VigiBase is permitted and accessed by the following authorities: [ 5 ]


VigiBase is a  relational database management system  (RDMS) which is compatible with ODBC ( open database connectivity ) and uses  SQL  for the database communication. The RDMS can be accessed through client server applications, ODBC, and Internet applications. Apart from data management, the VigiBase system includes an automated signal detection process using advanced data mining tools ( VigiMine - a Bayesian Confidence Propagation Neural Network (BCPNN) data mining tool). [ 1 ]  VigiBase further includes a WHO Drug Dictionaries (WHO-DD and -DDE), and medical terminology dictionary such as WHO Adverse Reaction Terminology (WHO-ART),  International Classification of Diseases  (ICD), and the  Medical Dictionary for Regulatory Activities  (MedDRA). [ 6 ]


Type of reports: Most preferred data includes post-marketing spontaneous serious and non-serious cases ICSRs. Case reports from studies,  clinical trials  or special monitoring and literature are sometimes included, but are flagged. [ 4 ]
Type of medicine: Database includes ICSRs on ordinary  allopathic  medicines, traditional medicines (herbals), biologics,  vaccines  and  medical devices . In addition, ICSRs on medication errors, therapeutic failure and counterfeit/substandard medicines are also considered. [ 4 ]


The  WHODrug Dictionary  is an international classification of  medicines  created by the WHO Programme for International Drug Monitoring and managed by the  Uppsala Monitoring Centre . [ 1 ]


It is used by  pharmaceutical companies ,  clinical trial  organizations and  drug regulatory  authorities for identifying drug names in spontaneous  ADR  reporting (and  pharmacovigilance ) and in clinical trials. [ 2 ]  Created in 1968 and regularly updated, since 2005 there have been major developments in the form of a WHO Drug Dictionary Enhanced (with considerably more  fields  and data entries) and a WHO Herbal Dictionary, which covers traditional and  herbal  medicines. Since 2016 all of the WHODrug products have been available in a single subscription service called WHODrug Global. [ 3 ]


Organization
WHODrug drug code consist of 11 characters (alphanumeric code). It has 3 parts: Drug Record Number(Drug Rec No), Sequence number 1(Seq1) and Sequence number 2 (Seq2). Drug Rec No consists of 6 characters. It uniquely identifies active  moieties , regardless of salt form or plant part and extract.
Seq1 is used to uniquely identify different variations (e.g. salts and esters), plant parts and extraction methods, thereby defining active substances or a combination of active substances. WHODrug records sharing the same Drug Rec No and Seq1 contain the same variation/plant part/extract variation of the same active moiety. For single-ingredient records, Seq1=01 identifies a specific active moiety. If Seq1 is higher than 01 it refers to variations of that active moiety. For multi-ingredient records, Seq1=01 identifies a combination of active moieties. If Seq1 is higher than 01 it refers to variations of one or more of the active moieties in the combination. Finally, Seq2 uniquely identifies the name of the record in WHODrug.


Example
The Drug Code for the substance  Ibuprofen  is 001092 01 001. The Drug Code for the trade name Advil infants pain & fever relief is 001092 01 A3D.


WHODrug records are classified with at least one code from  Anatomical Therapeutic Chemical Classification System  (including the HATC which stands for Herbal ATC and which is treated as part of ATC for mapping purposes). Preferably, a fourth level ATC code is assigned. ATC assignments in WHODrug are marked as 'official' or 'UMC-assigned'. Official ATC codes are classifications included in the official ATC index, while UMC-assigned ATC codes are classifications NOT included in the official ATC index.


In addition, a separate cross reference called "Cross Reference ATC 5". In this additional reference, WHODrug records are matched to fifth level ATC codes where applicable.


WHODrug is offered in Four formats (called B3 and C3). B3 format is brief while C3 format contains additional columns on top of B3 format.


WHODrug concepts can be organized into groups. Standardised Drug Groupings (SDGs) define groups of drugs. For example, diuretics, corticosteroids, drugs used in diabetes. Groups are also defined based on interaction, for example, drugs interacting with CYP2C8 or drugs interacting with UGT.
R,Lee


The  WHO Adverse Reactions Terminology  (WHOART) was a dictionary meant to serve as a basis for rational coding of  adverse reaction  terms. The system was maintained by the  Uppsala Monitoring Centre  (UMC), the  World Health Organization  Collaborating Centre for International Drug Monitoring. The system is no longer actively maintained since 2015. [ 1 ]


S -Adenosyl methionine  ( SAM ), also known under the commercial names of  SAMe ,  SAM-e , or  AdoMet , is a common  cosubstrate  involved in  methyl group  transfers, transsulfuration, and aminopropylation. Although these  anabolic  reactions occur throughout the body, most SAM is produced and consumed in the liver. [ 1 ]  More than 40 methyl transfers from SAM are known, to various substrates such as  nucleic acids ,  proteins ,  lipids  and  secondary metabolites . It is made from  adenosine triphosphate  (ATP) and  methionine  by  methionine adenosyltransferase . SAM was first discovered by  Giulio Cantoni  in 1952. [ 1 ]


In  bacteria , SAM is bound by the  SAM riboswitch , which regulates  genes  involved in methionine or  cysteine  biosynthesis. In  eukaryotic  cells, SAM serves as a regulator of a variety of processes including  DNA ,  tRNA , and  rRNA   methylation ;  immune response ; [ 2 ]  amino acid metabolism;  transsulfuration ; and more. In plants, SAM is crucial to the biosynthesis of  ethylene , an important  plant hormone  and signaling molecule. [ 3 ]


S -Adenosyl methionine consists of the adenosyl group attached to the sulfur of methionine, providing it with a positive charge. It is synthesized from ATP and methionine by  S -Adenosylmethionine synthetase enzyme  through the following reaction:


The  sulfonium  functional group present in  S -adenosyl methionine is the center of its peculiar reactivity. Depending on the enzyme,  S -adenosyl methionine can be converted into one of three  products:


The reactions that produce, consume, and regenerate SAM are called the SAM cycle. In the first step of this cycle, the SAM-dependent  methylases  (EC 2.1.1) that use SAM as a substrate produce  S -adenosyl homocysteine as a product. [ 4 ]   S -Adenosyl homocysteine is a strong negative regulator of nearly all SAM-dependent methylases despite their biological diversity. This is hydrolysed to  homocysteine  and  adenosine  by  S -adenosylhomocysteine hydrolase   EC 3.3.1.1  and the homocysteine recycled back to  methionine  through transfer of a methyl group from  5-methyltetrahydrofolate , by one of the two classes of  methionine synthases  (i.e.  cobalamin -dependent ( EC 2.1.1.13 ) or cobalamin-independent ( EC 2.1.1.14 )). This methionine can then be converted back to SAM, completing the cycle. [ 5 ]  In the rate-limiting step of the SAM cycle, MTHFR (methylenetetrahydrofolate reductase) irreversibly reduces 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. [ 6 ]


A large number of enzymes cleave SAM reductively to produce radicals:   5′-deoxyadenosyl 5′-radical , methyl radical, and others.  These enzymes are called  radical SAMs .  They all feature  iron-sulfur cluster  at their active sites. [ 7 ]  Most enzymes with this capability share a region of sequence homology that includes the motif CxxxCxxC or a close variant. This sequence provides three cysteinyl thiolate ligands that bind to three of the four metals in the 4Fe-4S cluster.  The fourth Fe binds the SAM.


The radical intermediates generated by these enzymes perform a wide variety of unusual chemical reactions. Examples of radical SAM enzymes include  spore photoproduct lyase ,  activases of  pyruvate formate lyase  and anaerobic sulfatases,  lysine 2,3-aminomutase , and various enzymes of cofactor biosynthesis, peptide modification,  metalloprotein  cluster formation,  tRNA  modification, lipid metabolism, etc. Some radical SAM enzymes use a second SAM as a methyl donor. Radical SAM enzymes are much more abundant in anaerobic bacteria than in aerobic organisms. They can be found in all domains of life and are largely unexplored. A recent bioinformatics study concluded that this family of enzymes includes at least 114,000 sequences including 65 unique reactions. [ 8 ]


Deficiencies in radical SAM enzymes have been associated with a variety of diseases including  congenital heart disease ,  amyotrophic lateral sclerosis , and increased viral susceptibility. [ 8 ]


Another major role of SAM is in  polyamine  biosynthesis. Here, SAM is decarboxylated by  adenosylmethionine decarboxylase  ( EC 4.1.1.50 ) to form  S -adenosylmethioninamine . This compound then donates its  n -propylamine group in the biosynthesis of polyamines such as  spermidine  and  spermine  from  putrescine . [ 9 ]


SAM is required for cellular growth and repair. It is also involved in the biosynthesis of several hormones and neurotransmitters that affect mood, such as  epinephrine .   Methyltransferases  are also responsible for the addition of methyl groups to the 2′ hydroxyls of the first and second  nucleotides  next to the 5′ cap in  messenger RNA . [ 10 ] [ 11 ]


As of 2012, the evidence was inconclusive as to whether SAM can mitigate the pain of  osteoarthritis ; clinical trials that had been conducted were too small from which to generalize. [ 12 ]


The SAM cycle has been closely tied to the liver since 1947 because people with  alcoholic cirrhosis  of the liver would accumulate large amounts of methionine in their blood. [ 13 ]  While multiple lines of evidence from laboratory tests on cells and  animal models  suggest that SAM might be useful to treat various  liver diseases , as of 2012 SAM had not been studied in any large randomized placebo-controlled clinical trials that would allow an assessment of its efficacy and safety. [ 14 ] [ 15 ]


A 2016 Cochrane review concluded that for  major depressive disorder , "Given the absence of high quality evidence and the inability to draw firm conclusions based on that evidence, the use of SAMe for the treatment of depression in adults should be investigated further." [ 16 ]


A 2020 systematic review found that it performed significantly better than placebo, and  had similar outcomes to other commonly used antidepressants ( imipramine  and  escitalopram ). [ 17 ]


SAM has recently been shown to play a role in  epigenetic  regulation. DNA methylation is a key regulator in epigenetic modification during mammalian cell development and differentiation. In mouse models, excess levels of SAM have been implicated in erroneous methylation patterns associated with diabetic neuropathy. SAM serves as the methyl donor in cytosine methylation, which is a key epigenetic regulatory process. [ 18 ]  Because of this impact on epigenetic regulation, SAM has been tested as an anti-cancer treatment. In many cancers, proliferation is dependent on having low levels of DNA methylation. In vitro addition in such cancers has been shown to remethylate oncogene promoter sequences and decrease the production of proto-oncogenes. [ 19 ]  In cancers such as colorectal cancer, aberrant global hypermethylation can inhibit promoter regions of tumor-suppressing genes. Contrary to the former information, colorectal cancers (CRCs) are characterized by global hypomethylation and promoter-specific DNA methylation. [ 20 ]


Oral SAM achieves peak plasma concentrations three to five hours after ingestion of an enteric-coated tablet (400–1000 mg). The half-life is about 100 minutes. [ 21 ]


In Canada, the UK, [ 22 ]  and the United States, SAM is sold as a  dietary supplement  under the marketing name SAM-e (also spelled SAME or SAMe). [ 23 ]  It was introduced in the US in 1999, after the  Dietary Supplement Health and Education Act  was passed in 1994. [ 24 ]


It was introduced as a  prescription drug  in Italy in 1979, in Spain in 1985, and in Germany in 1989. [ 24 ]  As of 2012, it was sold as a prescription drug in Russia, India, China, Italy, Germany, Vietnam, and Mexico. [ 15 ]


Gastrointestinal disorder,  dyspepsia  and  anxiety  can occur with SAM consumption. [ 21 ]  Long-term effects are unknown. SAM is a weak DNA- alkylating  agent. [ 25 ]


Another reported side effect of SAM is  insomnia ; therefore, the supplement is often taken in the morning. Other reports of mild side effects include lack of appetite, constipation, nausea, dry mouth, sweating, and anxiety/nervousness, but in placebo-controlled studies, these side effects occur at about the same incidence in the placebo groups. [ medical citation needed ]


Taking SAM at the same time as some drugs may increase the risk of  serotonin syndrome , a potentially dangerous condition caused by having too much serotonin. These drugs include, but are certainly not limited to,  dextromethorphan  (Robitussin),  meperidine  (Demerol),  pentazocine  (Talwin), and  tramadol  (Ultram). [ 26 ]


SAM can also interact with many antidepressant medications — including  tryptophan  and the herbal medicine  Hypericum perforatum  (St. John's wort) — increasing the potential for serotonin syndrome or other side effects, and may reduce the effectiveness of  levodopa  for Parkinson's disease. [ 27 ]  SAM can increase the risk of manic episodes in people who have  bipolar disorder . [ 27 ]


A 2022 study concluded that SAMe could be toxic. Jean-Michel Fustin of  Manchester University  said that the researchers found that excess SAMe breaks down into  adenine  and  methylthioadenosine  in the body, both producing the  paradoxical effect  of inhibiting methylation. This was found in  laboratory mice , causing harm to health, and in  in vitro  tests on human cells. [ 28 ] [ 22 ]


Alcohol withdrawal syndrome  ( AWS ) is a set of symptoms that can occur following a reduction in  alcohol  use after a period of excessive use. [ 1 ]  Symptoms typically include  anxiety ,  shakiness , sweating, vomiting,  fast heart rate , and a mild fever. [ 1 ]  More severe symptoms may include  seizures , and  delirium tremens  (DTs); which can be fatal in untreated patients. [ 1 ]  Symptoms start at around 6 hours after the last drink. [ 2 ]  Peak incidence of seizures occurs at 24 to 36 hours [ 5 ]  and peak incidence of  delirium tremens  is at 48 to 72 hours. [ 6 ]


Alcohol withdrawal may occur in those who are alcohol  dependent . [ 1 ]  This may occur following a planned or unplanned decrease in alcohol intake. [ 1 ]  The underlying mechanism involves a decreased responsiveness of  GABA receptors  in the brain. [ 3 ]  The withdrawal process is typically followed using the  Clinical Institute Withdrawal Assessment for Alcohol  scale (CIWA-Ar). [ 3 ]


The typical treatment of alcohol withdrawal is with  benzodiazepines  such as  chlordiazepoxide  or  diazepam . [ 2 ]  Often the amounts given are based on a person's symptoms. [ 2 ]   Thiamine  is recommended routinely. [ 2 ]   Electrolyte problems  and  low blood sugar  should also be treated. [ 2 ]  Early treatment improves outcomes. [ 2 ]


In the Western world about 15% of people have problems with  alcoholism  at some point in time. [ 3 ]  Alcohol depresses the central nervous system, slowing cerebral messaging and altering the way signals are sent and received. Progressively larger amounts of alcohol are needed to achieve the same physical and emotional results. The drinker eventually must consume alcohol just to avoid the physical cravings and withdrawal symptoms. About half of people with alcoholism will develop withdrawal symptoms upon reducing their use, with four percent developing severe symptoms. [ 3 ]  Among those with severe symptoms up to 15% die. [ 2 ]  Symptoms of alcohol withdrawal have been described at least as early as 400 BC by  Hippocrates . [ 7 ] [ 8 ]  It is not believed to have become a widespread problem until the 1700s. [ 8 ]


Signs and symptoms of alcohol withdrawal occur primarily in the central nervous system. The severity of withdrawal can vary from mild symptoms such as insomnia, trembling, and anxiety to severe and life-threatening symptoms such as  alcoholic hallucinosis ,  delirium tremens , and  autonomic instability . [ 9 ] [ 10 ]


Withdrawal usually begins 6 to 24 hours after the last drink. [ 11 ]  Symptoms are worst at 24 to 72 hours, and improve by seven days. [ 2 ] [ 3 ]  To be classified as alcohol withdrawal syndrome, patients must exhibit at least two of the following symptoms: increased hand tremor, insomnia, nausea or vomiting, transient hallucinations (auditory, visual or tactile),  psychomotor agitation , anxiety,  generalized tonic–clonic seizures , and autonomic instability. [ 12 ]


The severity of symptoms is dictated by a number of factors, the most important of which are degree of alcohol intake, length of time the individual has been using alcohol, and previous history of alcohol withdrawal. [ 12 ] [ 13 ]  Symptoms are also grouped together and classified:


Six to 12 hours after the ingestion of the last drink, withdrawal symptoms such as shaking, headache, sweating, anxiety, nausea or vomiting may occur. [ 15 ]  Twelve to 24 hours after cessation, the condition may progress to such major symptoms as confusion, hallucinations [ 15 ]  (with awareness of reality), while less severe symptoms may persist and develop including tremor, agitation, hyperactivity and insomnia. [ 13 ]


At 12 to 48 hours following the last ethanol ingestion, the possibility of  generalized tonic–clonic seizures  should be anticipated, occurring in 3–5% of cases. [ 13 ]  Meanwhile, none of the earlier withdrawal symptoms will typically have abated. Seizures carry the risk of major complications and death for individuals with an alcohol use disorder. [ 16 ] [ 13 ]


Although the person's condition usually begins to improve after 48 hours, withdrawal symptoms sometimes continue to increase in severity and advance to the most severe stage of withdrawal,  delirium tremens . This occurs in 5–20% of patients experiencing detoxification and one third of untreated cases, [ 14 ] [ 13 ]  which is characterized by hallucinations that are indistinguishable from reality, severe confusion, seizures, high blood pressure, and fever that can persist anywhere from 4 to 12 days. [ 15 ]


A protracted alcohol withdrawal syndrome occurs in many alcoholics when withdrawal symptoms continue beyond the acute withdrawal stage but usually at a subacute level of intensity and gradually decreasing with severity over time. This syndrome is sometimes referred to as the  post-acute-withdrawal syndrome . Some withdrawal symptoms can linger for at least a year after discontinuation of alcohol. Symptoms can include a craving for alcohol, inability to feel pleasure from normally pleasurable things (known as  anhedonia ), clouding of  sensorium , disorientation, nausea and vomiting or headache. [ 17 ]


Insomnia is a common  protracted withdrawal  symptom that persists after the acute withdrawal phase of alcohol. Insomnia has also been found to influence relapse rate. Studies have found that  magnesium  or  trazodone  can help treat the persisting withdrawal symptom of insomnia in recovering alcoholics. Insomnia can be difficult to treat in these individuals because many of the traditional sleep aids (e.g., benzodiazepine receptor agonists and barbiturate receptor agonists) work via a GABA A  receptor mechanism and are cross-tolerant with alcohol. However,  trazodone  is not cross-tolerant with alcohol. [ 18 ] [ 19 ] [ 20 ]  The acute phase of the alcohol withdrawal syndrome can occasionally be protracted. Protracted  delirium tremens  has been reported in the medical literature as a possible but unusual feature of alcohol withdrawal. [ 21 ]


Chronic use of  alcohol  leads to changes in brain chemistry especially in the GABAergic system. Various adaptations occur such as changes in  gene expression  and down regulation of  GABA A  receptors . During acute alcohol withdrawal, changes also occur such as upregulation of alpha4 containing GABA A  receptors and downregulation of alpha1 and alpha3 containing GABA A  receptors. Neurochemical changes occurring during alcohol withdrawal can be minimized with drugs which are used for acute detoxification. With abstinence from alcohol and cross-tolerant drugs these changes in neurochemistry may gradually return towards normal. [ 22 ] [ 23 ]  Adaptations to the  NMDA  system also occur as a result of repeated alcohol intoxication and are involved in the hyper-excitability of the central nervous system during the alcohol withdrawal syndrome.  Homocysteine  levels, which are elevated during chronic drinking, increase even further during the withdrawal state, and may result in  excitotoxicity . [ 24 ]  Alterations in  ECG  (in particular an increase in  QT interval ) and  EEG  abnormalities (including abnormal quantified EEG) may occur during early withdrawal. [ 24 ]  Dysfunction of the  hypothalamic–pituitary–adrenal axis  and increased release of  corticotropin-releasing hormone  occur during both acute as well as protracted abstinence from alcohol and contribute to both acute and protracted withdrawal symptoms.  Anhedonia / dysphoria  symptoms, which can persist as part of a  protracted withdrawal , may be due to  dopamine  underactivity. [ 25 ]


Kindling is a phenomenon where repeated alcohol detoxifications leads to an increased severity of the withdrawal syndrome. For example, binge drinkers may initially experience no withdrawal symptoms, but with each period of alcohol use followed by cessation, their withdrawal symptoms intensify in severity and may eventually result in full-blown  delirium tremens  with convulsive seizures. Alcoholics who experience seizures during detoxification are more likely to have had previous episodes of alcohol detoxification than patients who did not have seizures during withdrawal. In addition, people with previous withdrawal syndromes are more likely to have more medically complicated alcohol withdrawal symptoms. [ 26 ]