Instruct: Given a question, retrieve relevant documents that answer the question.
Query: When was Zopiclone first introduced?
Zopiclone was developed and first introduced in 1986 by Rhône-Poulenc S.A., now part of Sanofi-Aventis, the main worldwide manufacturer. Initially, it was promoted as an improvement on benzodiazepines, but a recent meta-analysis found it was no better than benzodiazepines in any of the aspects assessed. On April 4, 2005, the U.S. Drug Enforcement Administration listed zopiclone under schedule IV, due to evidence that the drug has addictive properties similar to benzodiazepines.
Astemizole (marketed under the brand name Hismanal, developmental code R43512) was a second-generation antihistamine drug that has a long duration of action. Astemizole was discovered by Janssen Pharmaceutica in 1977. It has been withdrawn from the market in most countries because of rare but potentially fatal side effects (QTc interval prolongation and related arrhythmias due to hERG channel blockade).
In 2016 the American College of Physicians advised that insomnia be treated first by treating comorbid conditions, then with cognitive behavioral therapy and behavioral changes, and then with drugs; doxepin was among those recommended for short-term help maintaining sleep, on the basis of weak evidence. The 2017 American Academy of Sleep Medicine recommendations focused on treatment with drugs were similar. A 2015 AHRQ review of treatments for insomnia had similar findings.
Pharmacological treatments are used to chemically treat sleep disturbances such as insomnia or excessive daytime sleepiness. The kinds of drugs used to treat sleep disorders include: anticonvulsants, anti-narcoleptics, anti-Parkinsonian drugs, benzodiazepines, non-benzodiazepine hypnotics, and opiates as well as the hormone melatonin and melatonin receptor stimulators. Anticonvulsants, opiates, and anti-Parkinsonian drugs are often used to treat restless legs syndrome. Furthermore, melatonin, benzodiazepines hypnotics, and non-benzodiazepine hypnotics may be used to treat insomnia. Finally, anti-narcoleptics help treat narcolepsy and excessive daytime sleepiness.
While insomnia is a common symptom of depression, antidepressants are effective for treating sleep problems whether or not they are associated with depression. While all antidepressants help regulate sleep, some antidepressants such as amitriptyline, doxepin, mirtazapine, and trazodone can have an immediate sedative effect, and are prescribed to treat insomnia. Amitriptyline and doxepin both have antihistaminergic, anticholinergic, and antiadrenergic properties, which contribute to both their therapeutic effects and side effect profiles, while mirtazapine's side effects are primarily antihistaminergic, and trazodone's side-effects are primarily antiadrenergic. Mirtazapine is known to decrease sleep latency (i.e., the time it takes to fall asleep), promoting sleep efficiency and increasing the total amount of sleeping time in people with both depression and insomnia.
Middle-of-the-night insomnia is often treated with medication, although currently Intermezzo (zolpidem tartrate sublingual tablets) is the only Food and Drug Administration-approved medication specifically for treating MOTN awakening. Because most medications usually require 6–8 hours of sleep to avoid lingering effects the next day, these are often used every night at bedtime to prevent awakenings. Medication may not be prescribed in some cases, especially if the cause turns out to be the patient ingesting too much fluid during the day or just before they go to sleep.
Wilson Therapeutics' lead product, Decuprate, is the proprietary bis-choline salt of tetrathiomolybdate. Decuprate is initially being developed as a novel treatment for Wilson's disease, a rare genetic disease that affects approximately 1 in 30,000, causing copper overload in the liver, brain and other tissues and resulting in organ damage and dysfunction. Decuprate has been granted orphan drug designation for the treatment of Wilson's disease in both Europe and the United States.. Wilson Therapeutics presented during the 10th Kempen & Co Life Sciences Conference 2017 and showed the world the result with the drug Decuprate. The company also presented during the international investmentconference Bioequity Europe in Paris, France, on May 23rd 2017 and showed some promising result.
However, Sterling Products did not market "Panadol" in the United States or other countries where "Bayer Aspirin" still dominated the aspirin market. Other firms began selling acetaminophen drugs, most significantly, McNeil Laboratories with liquid "Tylenol" in 1955, and "Tylenol" pills in 1958. By 1967, "Tylenol" was available without a prescription. Because it did not cause gastric irritation, acetaminophen rapidly displaced much of aspirin's sales. Another analgesic, anti-inflammatory drug was introduced in 1962: ibuprofen (sold as "Brufen" in the U.K. and "Motrin" in the U.S.). By the 1970s, aspirin had a relatively small portion of the pain reliever market, and in the 1980s sales decreased even more when ibuprofen became available without prescription.
A "qui tam" suit filed under the False Claims Act led AstraZeneca to make a massive $520 million settlement to resolve all civil and criminal liability with respect to illegal promotion of the anti-psychotic drug Seroquel. Approved by the FDA in 1997 to treat manifestations of psychotic disorders, in 2000 the FDA subsequently approved Seroquel for short-term treatment of schizophrenia, bipolar disorder, and bipolar depression. Between January 2001 through December 2006, AstraZeneca promoted Seroquel to psychiatrists and other physicians for certain uses that were not approved by the FDA, including aggression, Alzheimer’s disease, anger management, anxiety, attention deficit hyperactivity disorder, bipolar maintenance, dementia, depression, mood disorder, post-traumatic stress disorder, and sleeplessness. Federal health programs do not reimburse for prescriptions prescribed for indications not approved by the FDA.
Before the discovery of SSRI drugs the treatment for mood disorders were relatively limited. Now, however there are dozens of antidepressants on the market for the treatment of depression. Monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) were the first drugs to be developed for the treatment of depression, dating back to the early 1950s. Because of their undesirable adverse-effect profile and high potential for toxicity, due to their non-selective pharmacological effects, strict regiments were for taking the drugs which limited their use. Because of this, researchers looked for other alternatives with similar effectiveness but fewer adverse effects e.g. drugs that did not cause cardiac conduction abnormalities in overdoses or had the tendency to cause seizures, which led to the discovery of the SSRI drugs. The SSRIs are the most significant class of antidepressants marketed in recent years and make one of the major medicinal discoveries of the last few decades. SSRIs were the first drugs to establish beyond doubt a pathophysiological role for 5-HT in affective illnesses and in the broad spectrum of anxiety disorders. Likewise, they were the first to confirm the inhibition of neurotransmitter re-uptake as an important therapeutic principle.
The SSRIs are the first rationally designed class of psychotropic medications. The strategy behind rational drug design is to develop a new drug that is capable of affecting a specific biological target, or in this case a special neural site of action (uptake pumps, receptors), while trying to avoid effects on other site of actions. The goal in such development is to produce pharmacological agents that are more efficacious, safer and better tolerated than older medications. An initial success was achieved when medicinal chemists set out in search of the ideal SSRI with the chemical synthesis of zimelidine (figure 1) from the antihistamine drug brompheniramine, which exhibited selective inhibition of 5-HT re-uptake with minimal inhibition of norepinephrine (NE) re-uptake. Most importantly, zimelidine did not come with the adverse effect profile as the TCAs and therefore it became the template for the second generation SSRIs. Zimelidine was the first SSRI to be marketed, but several cases of Guillain–Barré syndrome were associated with the use of the drug which led to withdrawal from the market in 1983. Subsequently, several non-tricyclic SSRIs were discovered and marketed. Fluoxetine, which was FDA approved in 1987 and is usually thought to be the first SSRI to be marketed, paved the way for the next generation of SSRIs and was thought to be some kind of prototype. Introduction of fluoxetine to the market is hailed as a miracle drug for the treatment of depression because it had fewer adverse effects, simpler dosing strategies and greater margin of safety when overdoses were consumed and thus it had better adherence, compared to the older antidepressants (TCAs and MAOIs). Since then the number of drugs in the SSRI class has become bigger and they are now six (fluoxetine, paroxetine, citalopram, escitalopram, sertraline and fluvoxamine), as demonstrated in table 1.
Corticosteroids (cortisone), accutane (isotretinoin) and other vitamin A derivatives, barbiturates, certain antibiotics, propofol, volatile anesthetics, non-depolarizing muscle relaxants, some local anesthetics, statins, fibrates, glitazones, beta blockers, biguanides, amiodarone, some chemotherapies, some neuroleptics, nucleoside reverse transcriptase inhibitors and various other drugs.
Currently most people who use an antihistamine to treat allergies use a second generation drug.
The brand was introduced in 1955 by McNeil Laboratories, a family owned pharmaceutical manufacturer. Two brothers took over the company from their father that year, and that year one of them learned about paracetamol, which was not on the US market at that time. To avoid competing with aspirin, they marketed it as a product to reduce fever in children, packaging it like a red fire truck with the slogan, "for little hotheads". The name "Tylenol" and the generic name "acetaminophen" were generated by McNeil from the chemical name of the drug. Johnson & Johnson bought McNeil in 1959, and one year later the drug was made available over the counter.
Antidepressants which have been shown to be effective in treating OCD include fluvoxamine (trade name Luvox), fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), citalopram (Celexa), and clomipramine (Anafranil). Although SSRIs are known to be effective for OCD in general, there have been fewer studies on their effectiveness for intrusive thoughts. A retrospective chart review of patients with sexual symptoms treated with SSRIs showed the greatest improvement was in those with intrusive sexual obsessions typical of OCD. A study of ten patients with religious or blasphemous obsessions found that most patients responded to treatment with fluoxetine or clomipramine. Women with postpartum depression often have anxiety as well, and may need lower starting doses of SSRIs; they may not respond fully to the medication, and may benefit from adding cognitive behavioral or response prevention therapy.
Stimulants are the most commonly prescribed medications for ADHD. The stimulant medications indicated to treat ADHD are methylphenidate (Ritalin, Concerta), dexmethylphenidate (Focalin), mixed amphetamine salts (Adderall), dextroamphetamine (Dexedrine), lisdexamfetamine (Vyvanse), and in rare cases methamphetamine (Desoxyn). Controlled-release pharmaceuticals may allow once daily administration of medication in the morning. This is especially helpful for children who do not like taking their medication in the middle of the school day. Several controlled-release methods are used.
Dopamine was first synthesized in 1910 by George Barger and James Ewens at Wellcome Laboratories in London, England and first identified in the human brain by Kathleen Montagu in 1957. It was named dopamine because it is a monoamine whose precursor in the Barger-Ewens synthesis is 3,4-dihydroxyphenylalanine (levodopa or L-DOPA). Dopamine's function as a neurotransmitter was first recognized in 1958 by Arvid Carlsson and Nils-Åke Hillarp at the Laboratory for Chemical Pharmacology of the National Heart Institute of Sweden. Carlsson was awarded the 2000 Nobel Prize in Physiology or Medicine for showing that dopamine is not only a precursor of norepinephrine (noradrenaline) and epinephrine (adrenaline), but is also itself a neurotransmitter.
Beginning in the 1980s, a series of lawsuits were filed based on the perceived harmful side effects of Ritalin. John Coale, who had participated in one of these lawsuits, joined what became an ever larger contingent of lawyers involved in what was then a growing series of Ritalin class action lawsuits. In the late 90's, there was a significant increase in production of Ritalin. A minority but vocal group of critics perceived that a crisis was on hand. Coale also expressed alarm, "They were giving this stuff away like candy”. The Church of Scientology advocacy organization, Citizens Commission on Human Rights, and anti-psychiatry critics believed Ritalin to be highly dangerous and completely unnecessary. Coale seemed to share these beliefs as he stated the purpose of the lawsuit to be; “...to put [Ritalin] off the market." The "St. Petersburg Times" wrote at that time that Coale, like his wife Greta Van Susteren, was a practicing Scientologist. Richard Scruggs, like John Coale, and a few other lawyers who participated in the Ritalin class action lawsuits, had previously helped win a landmark settlement from the asbestos and tobacco industries, Ritalin was to be the next major battleground. Scruggs would lead and also become a spokesman for the plaintiffs. He asserted the Ritalin defendants, "manufactured a disease"...and "it has been grossly over-prescribed. It is a huge risk." Peter Breggin who is a noted anti-psychiatry critic, was hired as a medical consultant by the firm and was also involved as a consultant in the other lawsuits.
In April 2000, Celgene reached an agreement with Novartis Pharma AG to license d-MPH, Celgene's chirally pure version of RITALIN. The FDA subsequently granted approval to market d-MPH, or Focalin, in November 2001.
Dexmethylphenidate has a 4–6 hour duration of effect (a long-acting formulation, Focalin XR, which spans 12 hours is also available and has been shown to be as effective as -TMP (threo-methylphenidate) XR (extended release) (Concerta, Ritalin LA), with flexible dosing and good tolerability.) It has also been demonstrated to reduce ADHD symptoms in both children and adults. d-MPH has a similar side-effect profile to MPH and can be administered without regard to food intake.
GSK was fined for promoting Paxil/Seroxat (paroxetine) for treating depression in the under-18s, although the drug had not been approved for pediatric use.
Paxil had $4.97 billion worldwide sales in 2003. The company conducted nine clinical trials between 1994 and 2002, none of which showed that Paxil helped children with depression. From 1998 to 2003 it promoted the drug for the under-18s, paying physicians to go on all-expenses paid trips, five-star hotels and spas. From 2004 Paxil's label, along with those of similar drugs, included an FDA-mandated boxed warning that it might increase the risk of suicidal ideation and behaviour in patients under 18.
The Ritalin class-action lawsuits were a series of federal lawsuits in 2000, filed in five separate US states. All five lawsuits were dismissed by the end of 2002. The lawsuits alleged that the makers of methylphenidate (brand name Ritalin) and the American Psychiatric Association had conspired to invent and promote the disorder ADHD to create a highly profitable market for the drug. The lawsuit also alleged that CHADD (children and adults with attention deficit/hyperactivity disorder) deliberately attempted to increase the supply of Ritalin and ease restrictions on the supply of Ritalin to help increase profits for Novartis.
On September 11, 2007, Sepracor signed a marketing deal with British pharmaceutical company GlaxoSmithKline for the rights to sell Eszopiclone (under the name Lunivia rather than Lunesta) in Europe. Sepracor was expected to receive approximately 155 million dollars if the deal went through. In 2008 Sepracor submitted an application to the EMA (the European Union's equivalent to the U.S. FDA) for authorization to market the drug in the EU, and initially received a favourable response. However, Sepracor withdrew its authorization application in 2009 after the EMA stated it would not be granting eszopiclone 'new active substance' status, as it was essentially pharmacologically and therapeutically too similar to zopiclone to be considered a new patentable product. Since zopiclone's patent has expired, this ruling would have allowed rival companies to also legally produce cheaper generic versions of eszopiclone for the European market. , Sepracor has not resubmitted its authorization application and Lunesta/Lunivia is not available in Europe. The deal with GSK fell through, and GSK instead launched a $3.3 billion deal to market Actelion's Almorexant sleeping tablet, which entered stage three medical trials before development was abandoned due to side effects.
The Ġgantija temples were listed as a UNESCO World Heritage Site in 1980. In 1992, the Committee decided to expand the listing to include five other megalithic temples situated across the islands of Malta and Gozo. The Ġgantija listing was renamed "the Megalithic Temples of Malta"
Z-drugs emerged in the last years of the 1980s and early 1990s, with zopiclone (Imovane) approved by the British National Health Service as early as 1989, quickly followed by Sanofi with zolpidem (Ambien). By 1999, King Pharmaceuticals had finalized approval with the American Food and Drug Administration (FDA) to market zaleplon (Sonata, Starnoc) across the US. In 2005, the FDA approved eszopiclone (Lunesta) the ("S")-enantiomer of zopiclone. That same year, 2005, the FDA finalized approval for Ambien CR, or extended-release zolpidem. Most recently, in 2012 the FDA approved Intermezzo, which still utilizes zolpidem as its active ingredient, but is marketed for middle-of-the-night insomnia, available in doses only half of the strength of immediate-release Ambien to avoid residual next-day sedation.
This enzyme belongs to the family of oxidoreductases, specifically those acting on paired donors, with O2 as oxidant and incorporation or reduction of oxygen. The oxygen incorporated need not be derived from O2 with 2-oxoglutarate as one donor, and incorporation of one atom o oxygen into each donor. The systematic name of this enzyme class is N6,N6,N6-trimethyl-L-lysine,2-oxoglutarate:oxygen oxidoreductase (3-hydroxylating). Other names in common use include trimethyllysine alpha-ketoglutarate dioxygenase, TML-alpha-ketoglutarate dioxygenase, TML hydroxylase, 6-N,6-N,6-N-trimethyl-L-lysine,2-oxoglutarate:oxygen oxidoreductase, and (3-hydroxylating). This enzyme participates in lysine degradation and L-carnitine biosynthesis and requires the presence of iron and ascorbate.