The Yellow Card Scheme is the United Kingdom's system for collecting information on suspected adverse drug reactions (ADRs) to medicines. The scheme allows the safety of the medicines and vaccines that are on the market to be monitored.
83-697: The scheme was founded in 1964 after the thalidomide disaster, and was developed by Bill Inman . It is run by the Medicines and Healthcare products Regulatory Agency (MHRA) and the Commission on Human Medicines . It was extended to hospital pharmacists in 1997, and to community pharmacists in 1999. The Yellow Card Centre Scotland is a joint venture between MHRA and the Scottish Government . Suspected adverse reactions are collected on all licensed medicines and vaccines, whether issued on prescription or bought over
166-641: A special prescription form : Restricted substances which easily lead to addiction like: co-codamol , tramadol , diazepam , nitrazepam and all other benzodiazepines (with the exception of temazepam and flunitrazepam ) phentermine . The Food and Drug Administration regulates drugs and medical devices in the Philippines . Prohibited. Brands and packages not actively marketed in Sri Lanka. Medicines in Switzerland are regulated by Swissmedic . The country
249-411: A 31% yield of S -thalidomide, whereas the two-step synthesis yields 85–93% product that is 99% pure. In 2023, it is reported that phthalic anhydride and L -glutamine under suitable conditions can react directly to form thalidomide. In the procedure, phthalic anhydride and L -glutamine are grounded and added into toluene solvent. The solution, along with triethylamine and acetic anhydride ,
332-501: A challenge for these people, and women in particular have experienced difficulty in locating healthcare professionals who can understand and embrace their needs. Brand names include Contergan, Thalomid, Talidex, Talizer, Neurosedyn, Distaval and many others. Research efforts have been focused on determining how thalidomide causes birth defects and its other activities in the human body, efforts to develop safer analogs, and efforts to find further uses for thalidomide. The exploration of
415-408: A consequence of thalidomide use. The severity and location of the deformities depended on how many days into the pregnancy the mother was before beginning treatment, with the time-sensitive window occurring approximately between day 20 and day 36 post-fertilisation. Thalidomide taken on the 20th day of pregnancy caused central brain damage, day 21 would damage the eyes, day 22 the ears and face, day 24
498-447: A group to look into safety of drugs on the market in 1959 prior to the crisis and was moving in the direction of address the problem of unregulated drugs entering the market. The crisis created a greater sense of emergency to establish safety and efficacy standards around the world. The UK started a temporary Committee on Safety of Drugs while they attempted to pass more comprehensive legislation. Though compliance and submission of drugs to
581-473: A patient critically ill with leprosy . The patient exhibited erythema nodosum leprosum (ENL), a painful skin condition, one of the complications of leprosy. The treatment was attempted despite the ban on thalidomide's use, and results were favourable: the patient slept for hours and was able to get out of bed without aid upon awakening. A clinical trial studying the use of thalidomide in leprosy soon followed. Thalidomide has been used by Brazilian physicians as
664-433: A pregnant woman could pass across the placental barrier and harm the developing fetus. There soon appeared reports of abnormalities in children being born to mothers using thalidomide. In late 1959, it was noticed that peripheral neuritis developed in patients who took the drug over a period of time, and it was only after this point that thalidomide ceased to be provided over the counter. While initially considered safe,
747-615: A regimen to fight two conditions. Interest turned to pomalidomide , a derivative of thalidomide marketed by Celgene . It is a very active anti-angiogenic agent and also acts as an immunomodulator . Pomalidomide was approved in February 2013 by the FDA as a treatment for relapsed and refractory multiple myeloma . It received a similar approval from the European Commission in August 2013, and
830-770: A sense of unwellness. There are no expected pharmacokinetic interactions between thalidomide and other medicines due to its neutral effects on P-glycoprotein and the cytochrome P450 family. It may interact with sedatives due to its sedative action and bradycardic agents, like beta-blockers, due to its bradycardia-inducing effects. Risk of peripheral neuropathy may be increased by concomitant treatment of thalidomide with other agents known to cause peripheral neuropathy. The risk of venous thromboembolisms with thalidomide seems to be increased when patients are treated with oral contraceptives or other cytotoxic agents (including doxorubicin and melphalan ) concurrently. Thalidomide may interfere with various contraceptives, and hence it
913-418: Is racemic ; while S -thalidomide is the bioactive form of the molecule, the individual enantiomers can racemize to each other due to the acidic hydrogen at the chiral centre , which is the carbon of the glutarimide ring bonded to the phthalimide substituent . The racemization process can occur in vivo . The process of conversion of one enantiomer to its mirror-image version with no other change in
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#1732855503083996-401: Is a known human teratogen and carries an extremely high risk of severe, life-threatening birth defects if administered or taken during pregnancy. It causes skeletal deformities such as amelia (absence of legs and/or arms), absence of bones, and phocomelia (malformation of the limbs). A single dose of thalidomide, regardless of dosage, is enough to cause teratogenic effects. Thalidomide
1079-419: Is advised that women of reproductive age use at least two different means of contraception to ensure that no child will be conceived while they are taking thalidomide. As of 2013, eighteen cases of overdoses had been reported with doses of up to 14.4 grams, none of them fatal. No specific antidote for overdose exists and treatment is purely supportive . The precise mechanism of action for thalidomide
1162-558: Is based on a network of around 50 regulatory authorities from the 31 EEA countries (28 EU Member States plus Iceland, Liechtenstein and Norway), the European Commission and European Medicines Agency (EMA). EMA and the Member States cooperate and share expertise in the assessment of new medicines and of new safety information. They also rely on each other for exchange of information in the regulation of medicine, for example regarding
1245-491: Is designed mainly to protect the health and safety of the population. Regulation is aimed at ensuring the safety, quality, and efficacy of the therapeutic goods which are covered under the scope of the regulation. In most jurisdictions, therapeutic goods must be registered before they are allowed to be sold. There is usually some degree of restriction on the availability of certain therapeutic goods, depending on their risk to consumers. Modern drug regulation has historical roots in
1328-456: Is estimated at over 10,000, possibly 20,000, of whom about 40% died around the time of birth. Those who survived had limb, eye, urinary tract, and heart problems. Its initial entry into the US market was prevented by Frances Kelsey , a reviewer at the FDA. The birth defects caused by thalidomide led to the development of greater drug regulation and monitoring in many countries. It was approved in
1411-649: Is expected to be marketed in Europe under the brand name Imnovid . Drug regulation The regulation of therapeutic goods , defined as drugs and therapeutic devices , varies by jurisdiction. In some countries, such as the United States, they are regulated at the national level by a single agency. In other jurisdictions they are regulated at the state level, or at both state and national levels by various bodies, as in Australia. The role of therapeutic goods regulation
1494-532: Is not part of the European Union , and is regarded by many as one of the easiest places to conduct clinical trials on new drug compounds. There are five categories from A to E to cover different types of delivery category: Medicines for Human Use in the United Kingdom are regulated by the Medicines and Healthcare products Regulatory Agency (MHRA). The availability of drugs is regulated by classification by
1577-486: Is refluxed at ~110°C for 9 hours; after that the solution goes though a simple vacuum filtration procedure to obtain the product. In 1952, thalidomide was synthesised by Chemical Industry Basel , but was found "to have no effect on animals" and was discarded on that basis. In 1957, it was acquired by Chemie Grünenthal in Germany. The German company had been established as a soap maker after World War II ended, to address
1660-747: Is regulated by the separation of substances into various schedules according to the Therapeutic Goods (Poisons Standard) Instrument, the Poisons Standard may also be cited as the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP). The Poisons Standard organises substances into 10 schedules (and unscheduled substances), therapeutic goods are generally organised only into schedules 2, 3, 4 and 8: Therapeutic goods in Brazil are regulated by
1743-410: Is related to leprosy . Thalidomide may be helpful in some cases where standard TB drugs and corticosteroids are not sufficient to resolve severe inflammation in the brain. It is used as a second-line treatment to manage graft-versus-host disease and aphthous stomatitis in children and has been prescribed for other conditions in children, including actinic prurigo and epidermolysis bullosa ;
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#17328555030831826-773: The Drug and Pharmacies Regulation Act governs "any substance that is used in the diagnosis, treatment, mitigation or prevention of a disease...in humans, animals or fowl." The regulation of drugs in China is governed by the National Medical Products Administration (NMPA) which replaced the former China Food and Drug Administration . The regulation of drugs in Egypt is governed by the Egyptian Drug Authority (EDA) The European Union (EU) medicines regulatory system
1909-668: The Medicines Act 1968 (UK). In the United States, the new regulations strengthened the FDA, among other ways, by requiring applicants to prove efficacy and to disclose all side effects encountered in testing. The FDA subsequently initiated the Drug Efficacy Study Implementation to reclassify drugs already on the market. In 1977 the US Federal Drug Administration published a clinical trial guideline that excluded women of "childbearing potential" from
1992-578: The Ministry of Health of Brazil , through its Brazilian Health Regulatory Agency (Anvisa), equivalent to the US Food and Drug Administration . There are six main categories: Biological medications are complex molecules of high molecular weight obtained from a biological source or biotechnological procedures and are divided by Anvisa into the following categories: The regulatory status of vaccines, which determines their marketing and distribution, may be one of
2075-751: The Misuse of Drugs Regulations 1988 . Controlled drugs (CDs) are divided into five categories based on their potential for misuse and therapeutic effectiveness. The regulation of drugs in Burma is governed by the Food and Drug Administration (Burma) and Food and Drug Board of Authority . Medicines in Norway are regulated by the Norwegian Medical Products Agency . Drugs are divided into five groups: Narcotics, sedative-hypnotics, and amphetamines in this class require
2158-595: The U.S. Food and Drug Administration (FDA), which makes some drugs available over the counter (OTC) at retail outlets and others by prescription only . The prescription or possession of some substances is controlled or prohibited by the Controlled Substances Act , under the FDA and the Drug Enforcement Administration (DEA). Some US states apply more stringent limits on the prescription of certain controlled substances C-V and BTC (behind
2241-455: The androgen receptor and hence is a nonsteroidal antiandrogen of some capacity. In accordance, it can produce gynecomastia and sexual dysfunction as side effects in men. Thalidomide is provided as a racemic mixture of two enantiomers ; while there are reports that only one of the enantiomers may cause birth defects, the body converts each enantiomer into the other through mechanisms that are not well understood. The (R)-enantiomer has
2324-415: The antiangiogenic and immunomodulatory activities of thalidomide has led to the study and creation of thalidomide analogs . Celgene has sponsored numerous clinical trials with analogues to thalidomide, such as lenalidomide , that are substantially more powerful and have fewer side effects — except for greater myelosuppression . In 2005, Celgene received FDA approval for lenalidomide (Revlimid) as
2407-447: The 'Apothecary Wares, Drugs and Stuffs' Act (also sometimes referred to as the 'Pharmacy Wares, Drugs and Stuffs' Act) was passed in 1540 by Henry VIII and set the foundation for others. Through this act, he encouraged physicians in his College of Physicians (founded by him in 1518) to appoint four people dedicated to consistently inspecting what was being sold in apothecary shops. In conjunction with this first piece of legislation, there
2490-660: The 1960s had thalidomide embryopathy (TE). Of these babies born with TE, "about 40% of them died before their first birthday". The surviving individuals are now middle-aged and they report experiencing challenges (physical, psychological, and socioeconomic) related to TE. Individuals born with TE frequently experience a wide variety of health problems secondary to their TE. These health conditions include both physical and psychological conditions. When compared to individuals of similar demographic profiles, those born with TE report less satisfaction with their quality of life and their overall health. Access to health care services can also be
2573-715: The 1960s, despite greater preclinical and clinical standards. In 1989, the International Conference of Drug Regulatory Authorities organized by the WHO, officials from around the world discussed the necessity for streamlined processes for global drug approval. Therapeutic goods in Australia are regulated by the Therapeutic Goods Administration (TGA), which is a regulatory body of the Commonwealth Department of Health. Access to medicines and poisons
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2656-418: The 1990s. Judah Folkman pioneered studies into the role of angiogenesis (the proliferation and growth of blood vessels) in the development of cancer, and in the early 1970s had shown that solid tumors could not expand without it. In 1993 he surprised the scientific world by hypothesizing the same was true of blood cancers , and the next year he published work showing that a biomarker of angiogenesis
2739-602: The Committee on Safety of Drugs was not mandatory immediately after, the pharmaceutical industry later complied due to the thalidomide situation. The European Economic Commission also passed a directive in 1965 in order to impose greater efficacy standards before marketing a drug. Drug legislation in both the EU and US were passed in order to assure drug safety and efficacy. Of note, increased regulations and standards for testing actually led to greater innovation in pharmaceutical research in
2822-560: The MHRA as part of marketing authorisation of a product. The United Kingdom has a three-tiered classification system: Within POM, certain agents with a high abuse/addiction liability are also separately scheduled under the Misuse of Drugs Act 1971 (amended with the Misuse of Drugs Regulations 2001); and are commonly known as Controlled Drugs (CD). Therapeutic goods in the United States are regulated by
2905-631: The MHRA's website, or a smartphone app which is available for iOS and Android devices. The app can also provide news and alerts to users. Yellow Cards are available from pharmacies and a few are presented near the back of the BNF as tear-off pages; copies may also be obtained by telephoning +44 (0) 808 100 3352. The scheme provides forms that allow members of the public to report suspected side effects, as well as health professionals. NHS Digital publishes an information standard DCB1582 for electronic submission of adverse reactions by IT systems (until 2014, this
2988-484: The National Institute of Health policy that women should, when beneficial, be included in clinical trials. In the 1960s, thalidomide was successfully marketed as a safer alternative to barbiturates . Due to a successful marketing campaign, thalidomide was widely used by pregnant women during the first trimester of pregnancy. However, thalidomide is a teratogenic substance, and a proportion of children born during
3071-467: The UK, Australia and New Zealand, under the brand name Distaval, as a remedy for morning sickness . Their advertisement claimed that "Distaval can be given with complete safety to pregnant women and nursing mothers without adverse effect on mother or child ... Outstandingly safe Distaval has been prescribed for nearly three years in this country." Globally, more pharmaceutical companies started to produce and market
3154-506: The US drug industry. A 1911 Supreme Court decision, United States vs. Johnson , established that misleading statements were not covered under the FFDA. This directly led to Congress passing the Sherley Amendment which established a clearer definition of 'drug marketing requirements'. More catalysts for advances in drug regulation in the US were certain catastrophes that served as calls to
3237-469: The US government to step in and impose regulations that would prevent repeats of those instances. One such instance occurred in 1937 when more than a hundred people died from using sulfanilamide elixir which had not gone through any safety testing. This directly led to the passing of the Federal, Food, Drug, and Cosmetic Act in 1938. One other major catastrophe occurred in the late 1950s when Thalidomide, which
3320-553: The US. The US FDA refused to approve thalidomide for marketing and distribution. However, the drug was distributed in large quantities for testing purposes, after the American distributor and manufacturer Richardson-Merrell had applied for its approval in September 1960. The official in charge of the FDA review, Frances Oldham Kelsey , did not rely on information from the company, which did not include any test results. Richardson-Merrell
3403-616: The US. She was also inducted into the National Women's Hall of Fame in 2000. Canada's Food and Drug Directorate approved the sale of thalidomide by prescription in November, 1960. There were many different forms sold: Kevadon, produced by the William S. Merrell Company seeking approval for its thalidomide product, was released on the market in April 1961, and the most common variant (Horner's Talimol)
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3486-532: The United States in 1998 for use as a treatment for cancer. It is on the World Health Organization's List of Essential Medicines . It is available as a generic medication . Thalidomide is used as a first-line treatment for multiple myeloma in combination with dexamethasone or with melphalan and prednisone to treat acute episodes of erythema nodosum leprosum , as well as for maintenance therapy. The bacterium that causes tuberculosis (TB)
3569-489: The archives of the FDA, shows that in 1956–57, as part of its in-licensing approach, Smith, Kline and French conducted animal tests and ran a clinical trial of the drug in the US involving 875 people, including pregnant women. In 1956, researchers involved in clinical trials at SKF noted that, even when used in very high doses, thalidomide could not induce sleep in mice. When administered at doses 50 to 650 times larger than that claimed by Chemie Grünenthal to be "sleep inducing",
3652-522: The arms, and leg damage would occur if taken up to day 28. It is not known exactly how many worldwide victims of the drug there have been, although estimates range from 10,000 to 20,000. Despite the side effects, thalidomide was sold in pharmacies in Canada until 1962. The disaster prompted many countries to introduce tougher rules for the testing and licensing of drugs, such as the 1962 Kefauver Harris Amendment (US), 1965 Directive 65/65/EEC1 (EU), and
3735-1476: The authorisation and monitoring of medicines. Within the EU, EudraLex maintains the collection of rules and regulations governing medicinal products in the European Union, and the European Medicines Agency acts to regulate many of these rules and regulations. Amongst these rules and regulations are: German law classifies drugs into Medicines in Iceland are regulated by the Icelandic Medicines Control Agency . Medicines in India are regulated by Central Drugs Standard Control Organization (CDSCO) Under Ministry of Health and Family Welfare . Headed by Directorate General of Health Services(India).CDSCO regulates pharmaceutical products through Drugs Controller General of India (DCGI) at chair. Drugs are classified under five headings. Under retail and distribution: Under manufacturing practice: Medicines in Indonesia are regulated by National Agency of Drug and Food Control of Indonesia . Drugs in Indonesia are classified into: Medicines in Ireland are regulated according to
3818-424: The concept of 'risk management planning' within the field of regulation by introducing the need to understand how various safety concerns would be managed. Various cases over recent years have demonstrated the need for regulation to keep up with scientific advances that have implications for people's health. In the United States, regulation of drugs was originally a state right, as opposed to federal right. But with
3901-453: The controls. In 1998, the FDA approved the drug's use in the treatment of ENL. Because of thalidomide's potential for causing birth defects, the drug may be distributed only under tightly controlled conditions. The FDA required that Celgene Corporation , which planned to market thalidomide under the brand name Thalomid , establish a system for thalidomide education and prescribing safety (STEPS) oversight program. The conditions required under
3984-405: The counter from a pharmacist or supermarket. The scheme also includes all herbal preparations and unlicensed medicines. Adverse reactions can be reported by anyone; this is usually done by healthcare professionals – including doctors, pharmacists and nurses – but patients and carers can also make reports. The types of adverse reactions that should be reported are: Reports can be entered through
4067-466: The desired sedative effect while the (S)-enantiomer harbors embryo-toxic and teratogenic effect. Attempting to extract solely R -thalidomide does not remove the risk of birth defects, as it was demonstrated that the "safe" R -thalidomide undergoes an in vivo chiral inversion to the "teratogenic" S -thalidomide. Under biological conditions, the enantiomers interconvert ( bidirectional chiral inversion – (R)- to (S)- and vice versa). Thalidomide
4150-408: The development of government involvement and regulation. Additionally, the creation of these concoctions took on ritualistic form and were often created in public and the process was observed and recorded. It was believed that if the concoction proved unsuccessful, it was due to the apothecaries' process of making them and they could be held accountable because of the public nature of the creation. In
4233-438: The difficulty of adequately controlling its use, and due to the availability of clofazimine . Shortly after the teratogenic properties of thalidomide were recognized in the mid-1960s, its anti-cancer potential was explored and two clinical trials were conducted in people with advanced cancer, including some people with multiple myeloma; the trials were inconclusive. Little further work was done with thalidomide in cancer until
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#17328555030834316-1460: The drug can be transmitted in semen . There is a high risk that thalidomide can cause excessive blood clots . There is also a high risk that thalidomide can interfere with production of several types of new blood cells, creating a risk of infection via neutropenia , leukopenia , and lymphopenia , and risks that blood will not clot via thrombocytopenia . There is also a risk of anemia via lack of red blood cells. The drug can also damage nerves, causing potentially irreversible peripheral neuropathy . Thalidomide has several adverse cardiovascular effects, including risk of heart attacks , pulmonary hypertension , and changes in heart rhythm, such as syncope , bradycardia , and atrioventricular block . Thalidomide can cause liver damage and severe skin reactions like Stevens–Johnson syndrome . It tends to make people sleepy, which creates risk when driving and operating other machinery. As it kills cancer cells, it can cause tumor lysis syndrome . Thalidomide can prevent menstruation . In addition, very common (reported in more than 10% of people) adverse effects include tremor , dizziness, tingling, numbness, constipation, and peripheral edema . Common adverse effects (reported by 1–10% of people) include confusion, depressed mood, reduced coordination, heart failure, difficulty breathing, interstitial lung disease, lung inflammation, vomiting, dry mouth, rashes, dry skin, fever, weakness, and
4399-686: The drug of choice for the treatment of severe ENL since 1965, and by 1996, at least 33 cases of thalidomide embryopathy were recorded in people born in Brazil after 1965. Since 1994, the production, dispensing, and prescription of thalidomide have been strictly controlled, requiring women to use two forms of birth control and submit to regular pregnancy tests. Despite this, cases of thalidomide embryopathy continue, with at least 100 cases identified in Brazil between 2005 and 2010. 5.8 million thalidomide pills were distributed throughout Brazil in this time period, largely to poor Brazilians in areas with little access to healthcare, and these cases have occurred despite
4482-458: The drug under license from Chemie Grünenthal. By the mid-1950s, 14 pharmaceutical companies were marketing thalidomide in 46 countries under at least 37 different trade names. In the US, representatives from Chemie Grünenthal approached Smith, Kline & French (SKF), now GlaxoSmithKline , with a request to market and distribute the drug in North America. A memorandum, rediscovered in 2010 in
4565-634: The drug was responsible for teratogenic deformities in children born after their mothers used it during pregnancies, prior to the third trimester. In November 1961, thalidomide was taken off the market due to massive pressure from the press and public. Experts estimate that thalidomide led to the death of approximately 2,000 children and serious birth defects in more than 10,000 children, with over half of them in West Germany. The regulatory authorities in East Germany never approved thalidomide. One reason for
4648-487: The early phases of most clinical trials, which in practice led to their exclusion from later trial phases as well. This 1977 FDA guideline was implemented in response to a protectionist climate caused by the thalidomide tragedy. In the 1980s, a US task force on women's health concluded that a lack of women's health research (in part due to the FDA guideline) had compromised the amount and quality of information available about diseases and treatments affecting women. This led to
4731-405: The evidence for these uses is weak. It is recommended only as a third line treatment in graft-versus-host-disease in adults because of lack of efficacy and side effects observed in clinical trials. Prescriptions of thalidomide are accompanied by strict measures to avoid any possibility of use during pregnancy, and thalidomide should be avoided in women wanting to conceive. In the United States,
4814-483: The first commercially useful derivative. Revlimid is available only in a restricted distribution setting to avoid its use during pregnancy. Further studies are being conducted to find safer compounds with useful qualities. Another more potent analog, pomalidomide , is now FDA approved. Additionally, apremilast was approved by the FDA in March 2014. These thalidomide analogs can be used to treat different diseases, or used in
4897-502: The following established by Anvisa: Vaccines can only be administered in public health centers or authorized private vaccination services. In Canada, regulation of therapeutic goods is done by Health Canada and governed by the Food and Drug Act and associated regulations. In addition, the Controlled Drugs and Substances Act specifies additional regulatory requirements for controlled drugs and drug precursors. In Ontario ,
4980-412: The importance of drug and medicine regulation keeping up with scientific advances. In 2006, the challenges associated with TGN 1412 highlighted the shortcomings of animal models and paved the way for further advances in regulation and development for biological products. Rofecoxib represents a drug that was on the market that had not clearly represent the risks associated with the use drug which led to
5063-508: The increase in fraudulent practices due to private incentives to maximize profits and poor enforcement of state laws, the need for stronger federal regulation increased. In 1906 President Roosevelt signed the Federal Food and Drug Act (FFDA) which both established stricter national standards for drug manufacture and sales, and also established the Federal government as the regulating authority over
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#17328555030835146-484: The initially unobserved side effects of the drug and the subsequent approval in West Germany was that at that time drugs did not have to be tested for teratogenic effects. They were tested for toxicity on rodents only, as was usual at the time. In the UK, the British pharmaceutical company The Distillers Company (Biochemicals) Ltd, a subsidiary of Distillers Co. Ltd (now part of Diageo plc ), marketed thalidomide throughout
5229-443: The lead compound into a suitable drug: the result was thalidomide. The toxicity was examined in several animals, and the drug was introduced in 1956 as a sedative, but it was never tested on pregnant women. Researchers at Chemie Grünenthal found that thalidomide was a particularly effective antiemetic that had an inhibitory effect on morning sickness . On 1 October 1957, the company launched thalidomide and began marketing it under
5312-543: The molecule is called chiral inversion. Celgene Corporation originally synthesized thalidomide using a three-step sequence starting with L -glutamic acid treatment, but this has since been reformed by the use of L -glutamine . As shown in the image below, N -carbethoxyphthalimide (1) can react with L -glutamine to yield N -phthaloyl- L -glutamine (2). Cyclization of N -phthaloyl- L -glutamine occurs using carbonyldiimidazole , which then yields thalidomide (3). Celgene Corporation's original method resulted in
5395-489: The ninth century, many Muslim countries established an office of the hisba , which in addition to regulating compliance to Islamic principles and values took on the role of regulating other aspects of social and economic life, including the regulation of medicines. Inspectors were appointed to employ oversight on those who were involved in the process of medicine creation and were given a lot of leeway to ensure compliance and punishments were stringent. The first official 'act',
5478-588: The patient's doctor to try thalidomide, and that doctor conducted a clinical trial of thalidomide for people with multiple myeloma in which about a third of the subjects responded to the treatment. The results of that trial were published in the New England Journal of Medicine in 1999. After further work was done by Celgene and others, in 2006 the US ;Food and Drug Administration granted accelerated approval for thalidomide in combination with dexamethasone for
5561-468: The prescribing doctor is required to ensure that contraception is being used, and that regular pregnancy tests are taken. Thalidomide causes birth defects . The U.S. Food and Drug Administration (FDA) and other regulatory agencies have approved marketing of the drug only with an auditable risk evaluation and mitigation strategy that ensures that people using the drug are aware of the risks and avoid pregnancy; this applies to both men and women, as
5644-425: The program include limiting prescription and dispensing rights to authorized prescribers and pharmacies only, keeping a registry of all patients prescribed thalidomide, providing extensive patient education about the risks associated with the drug, and providing periodic pregnancy tests for women who take the drug. In 2010, the World Health Organization stated that it did not recommend thalidomide for leprosy due to
5727-401: The reporting of side effects of medicines, the oversight of clinical trials, and the conduct of inspections of medicines' manufacturers and compliance with good clinical practice (GCP), good manufacturing practice (GMP), good distribution practice (GDP), and good pharmacovigilance practice (GVP). EU legislation requires that each Member State operates to the same rules and requirements regarding
5810-468: The researchers could still not achieve the hypnotic effect in animals that it had on humans. After completion of the trial, and based on reasons kept hidden for decades, SKF declined to commercialize the drug. In 1958, Chemie Grünenthal reached an agreement with the William S. Merrell Company in Cincinnati, Ohio ( later Richardson-Merrell , now part of Sanofi ), to market and distribute thalidomide throughout
5893-514: The response to the proliferation of universal antidotes which appeared in the wake of Mithridates ' death. Mithridates had brought together physicians, scientists, and shamans to concoct a potion that would make him immune to poisons. Following his death, the Romans became keen on further developing the Mithridates potion's recipe. Mithridatium re-entered western society through multiple means. The first
5976-424: The trade name Contergan. It was proclaimed a "wonder drug" for insomnia , coughs, colds and headaches. During that period, the use of medications during pregnancy was not strictly controlled, and drugs were not thoroughly tested for potential harm to the fetus . Thousands of pregnant women took the drug to relieve their symptoms. At the time of the drug's development, scientists did not believe any drug taken by
6059-405: The treatment of newly diagnosed multiple myeloma patients. It was also evaluated whether thalidomide can be combined with melphalan and prednisone for patients with multiple myeloma. This combination of drugs probably results in an increase of the overall survival. In the late 1950s and early 1960s, more than 10,000 children in 46 countries were born with deformities, such as phocomelia , as
6142-473: The urgent market need for antibiotics. Heinrich Mückter was appointed to head the discovery program based on his experience working with the German army's antiviral research. While preparing reagents for the work, Mueckter's assistant Wilhelm Kunz isolated a by-product that was recognized by pharmacologist Herbert Keller as an analog of glutethimide , a sedative . The medicinal chemistry work turned to improving
6225-997: Was ISB 1582 from the Information Standards Board). The specification is based on the ICH E2B (R2) international standard format. Thalidomide Thalidomide , sold under the brand names Contergan and Thalomid among others, is an oral medication used to treat a number of cancers (e.g., multiple myeloma ), graft-versus-host disease , and many skin disorders (e.g., complications of leprosy such as skin lesions ). Thalidomide has been used to treat conditions associated with HIV : aphthous ulcers , HIV-associated wasting syndrome , diarrhea, and Kaposi's sarcoma , but increases in HIV viral load have been reported. Common side effects include sleepiness , rash , and dizziness . Severe side effects include tumor lysis syndrome , blood clots , and peripheral neuropathy . Thalidomide
6308-668: Was an emergence of standard formulas for the creation of certain 'drugs' and 'antidotes' through Pharmacopoeias which first appeared in the form of a decree from Frederick II of Sicily in 1240 to use consistent and standard formulas. The first modern pharmacopoeias were the Florence Pharmacopoeia published in 1498, the Spanish Pharmacopoeia published in 1581 and the London Pharmacopoeia published in 1618. Various other events throughout history have demonstrated
6391-461: Was called on to perform tests and report the results. The company demanded approval six times, and was refused each time. The distribution for "testing" resulted in 17 children born in the US with thalidomide-induced malformations. Oldham Kelsey was awarded the President's Award for Distinguished Federal Civilian Service by President Kennedy in 1962 for not allowing thalidomide to be approved for sale in
6474-446: Was first marketed in 1957 in West Germany, where it was available over-the-counter . When first released, thalidomide was promoted for anxiety , trouble sleeping , "tension", and morning sickness . While it was initially thought to be safe in pregnancy, concerns regarding birth defects arose, resulting in its removal from the market in Europe in 1961. The total number of infants severely harmed by thalidomide use during pregnancy
6557-531: Was higher in all people with cancer, but especially high in people with blood cancers, and other evidence emerged as well. Meanwhile, a member of his lab, Robert D'Amato, who was looking for angiogenesis inhibitors , discovered in 1994 that thalidomide inhibited angiogenesis and was effective in suppressing tumor growth in rabbits. Around that time, the wife of a man who was dying of multiple myeloma and whom standard treatments had failed, called Folkman asking him about his anti-angiogenesis ideas. Folkman persuaded
6640-445: Was not known until the twenty-first century, although efforts to identify thalidomide's teratogenic action generated more than 2,000 research papers and the proposal of 15 or 16 plausible mechanisms by 2000. The primary mechanism of action of thalidomide and its analogs in both their anti-cancer and teratogenic effects is now known to be as cereblon E3 ligase modulators. Thalidomide also binds to and acts as an antagonist of
6723-582: Was originally sold in Germany (introduced into a virtually unregulated market) and eventually sold around the world, led to approximately 100,000 babies being born with various deformities. In 1962 the United States Congress passed the Drug Amendments Act of 1962 . The Drug Amendments Act required the FDA to ensure that new drugs being introduced to the market had passed certain tests and standards. The UK's Chief Medical Officer had established
6806-479: Was put on the market on October 23 of the same year. Two months after Talimol went on sale, pharmaceutical companies sent physicians letters warning about the risk of birth defects. It was not until March 1962 that both drugs were banned from the Canadian market by the directorate, and soon afterward physicians were warned to destroy their supplies. In 1964, Israeli physician Jacob Sheskin administered thalidomide to
6889-549: Was through the Leechbook of the Bald ( Bald's Leechbook ), written somewhere between 900 and 950, which contained a formula for various remedies, including for a theriac. Additionally, theriac became a commercial good traded throughout Europe based on the works of Greek and Roman physicians. The resulting proliferation of various recipes needed to be curtailed in order to ensure that people were not passing off fake antidotes, which led to
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