When was Zopiclone first introduced?
Zopiclone
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.
Gepirone
Gepirone is an antidepressant and anxiolytic drug of the azapirone group that was synthesized by Bristol-Myers Squibb in 1986 and has been under development for the treatment of depression but has yet to be marketed. It has been under development in the U.S. in an extended release form (referred to as gepirone ER), but despite completing phase III clinical trials and demonstrating efficacy, it has been rejected multiple times by the Food and Drug Administration (FDA) during the drug approval process. However, in March 2016, the FDA reversed course and ruled favorably on the efficacy of gepirone, clearing the way for its eventual approval. As of January 2018, the drug is still in pre-registration.
Noscapine
Noscapine was first isolated and characterized in chemical breakdown and properties in 1817 under the denomination of "Narcotine" by Pierre Robiquet, a French chemist in Paris. Robiquet conducted over 20 years between 1815 and 1835 a series of studies in the enhancement of methods for the isolation of morphine, and also isolated in 1832 another very important component of raw opium, that he called codeine, currently a widely used opium-derived compound.
Zotepine
Zotepine's primary use is as a treatment for schizophrenia although clinical trials have been conducted (with positive results) into its efficacy as an antimanic agent in patients with acute bipolar mania. In a 2013 study in a comparison of 15 antipsychotic drugs in effectivity in treating schizophrenic symptoms, zotepine demonstrated medium-strong effectivity. Less effective than clozapine, slightly less effective than olanzapine and risperidone, approximately as effective as paliperidone, and slightly more effective than haloperidol, quetiapine, and aripiprazole.
Bupropion
Bupropion was invented by Nariman Mehta of Burroughs Wellcome (now GlaxoSmithKline) in 1969, and the US patent for it was granted in 1974. It was approved by the United States Food and Drug Administration (FDA) as an antidepressant on 30 December 1985, and marketed under the name Wellbutrin. However, a significant incidence of epileptic seizures at the originally recommended dosage caused the withdrawal of the drug in 1986. Subsequently, the risk of seizures was found to be highly dose-dependent, and bupropion was re-introduced to the market in 1989 with a lower maximum recommended daily dose.
Buspirone
Buspirone was first synthesized, by a team at Mead Johnson, in 1968, but was not patented until 1975. It was initially developed as an antipsychotic drug acting on the D receptor, but was found to be ineffective in the treatment of psychosis and was repurposed as an anxiolytic. In 1986, Bristol-Myers Squibb gained FDA approval for buspirone in the treatment of GAD. The patent placed on buspirone expired in 2001 and it is now available as a generic drug.
Morphine
Morphine is a pain medication of the opiate family which is found naturally in a number of plants and animals. It acts directly on the central nervous system (CNS) to decrease the feeling of pain. It can be taken for both acute pain and chronic pain. It is frequently used for pain from myocardial infarction and during labor. It can be given by mouth, by injection into a muscle, by injection under the skin, intravenously, injection into the space around the spinal cord, or rectally. Maximum effect is reached after about 20 minutes when given intravenously and after 60 minutes when given by mouth, while duration of effect is 3–7 hours. Long-acting formulations also exist.
Potentially serious side effects include decreased respiratory effort and low blood pressure. Morphine is addictive and prone to abuse. If the dose is reduced after long-term use, opioid withdrawal symptoms may occur. Common side effects include drowsiness, vomiting, and constipation. Caution is advised when used during pregnancy or breast feeding, as morphine may affect the baby.
Morphine was first isolated between 1803 and 1805 by Friedrich Sertürner. This is generally believed to be the first isolation of an active ingredient from a plant. Merck began marketing it commercially in 1827. Morphine was more widely used after the invention of the hypodermic syringe in 18531855. Sertürner originally named the substance "morphium" after the Greek god of dreams, Morpheus, as it has a tendency to cause sleep.
The primary source of morphine is isolation from poppy straw of the opium poppy. In 2013, approximately 523 tons of morphine were produced. Approximately 45 tons were used directly for pain, a four-fold increase over the last twenty years. Most use for this purpose was in the developed world. About 70 percent of morphine is used to make other opioids such as hydromorphone, oxymorphone, and heroin. It is a Schedule II drug in the United States, Class A in the United Kingdom, and Schedule I in Canada. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. Morphine is sold under many trade names.
Morphine is used primarily to treat both acute and chronic severe pain. It is also used for pain due to myocardial infarction and for labor pains. Its duration of analgesia is about three to seven hours.
Dimethisterone
Dimethisterone was developed by the British pharmaceutical company British Drug Houses (which subsequently merged with Merck KGaA) and was first reported in the medical literature in 1959, with introduction for medical use under the brand name Secrosteron following in the same year. It was introduced in the United States as an oral contraceptive in combination with high doses of ethinylestradiol under the brand name Oracon (25 mg dimethisterone, 100 μg ethinylestradiol) in 1965. Due to the fact that it contains a weak progestogen in combination with a large dose of a potent estrogen, this preparation was eventually found to be associated with a substantially increased risk of endometrial cancer in women, and is now no longer marketed.
Dimethylaminopivalophenone
Dimethylaminopivalophenone is an opioid analgesic. with a potency ½ that of morphine. It was initially discovered by Russian scientists in 1954 and subsequently rediscovered in the US in 1969. Its LD in mice is 83 mg/kg. It has never been marketed commercially, likely due to its low potency and lack of benefits compared to existing agents.
Zopiclone
Zopiclone is indicated for the short-term treatment of insomnia where sleep initiation or sleep maintenance are prominent symptoms. Long-term use is not recommended, as tolerance, dependence, and addiction can occur with prolonged use. One low quality study found that zopiclone is ineffective in improving sleep quality or increasing sleep time in shift workers - more research in this area has been recommended.
Primidone
By the year 2000, primidone was something that was prescribed in the event that the patient had tried all other anticonvulsants and was not a candidate for surgery in the United States. In April 2001, Élan decided to concentrate its efforts towards Zanaflex, Zonegran, Skelaxin, Abelcet, Azactam, Maxipime, Myobloc, and Cutivate. Mysoline was along with many other products that did not meet "certain commercial criteria." Yamanouchi Pharma Technologies, a Palo Alto-based subsidiary of Yamanouchi Pharmaceutical Co., Ltd, manufactured the actual drug. By 2003, most of the people taking primidone for epilepsy were elderly people who had been taking the drug for many years. In July 2004, Acorus Therapeutics Ltd. took over the manufacture and distribution of Mysoline from AstraZeneca February 3, 2005: almost four years after acquiring it from Elan, Xcel was acquired by Valeant Pharmaceuticals International. On April 1, 2005, Yamanouchi merged with Fujisawa Pharmaceutical Co., Ltd to form Astellas Pharma. As of 2005, it is widely used in the treatment of many forms of epilepsy in developing countries.
Acetylpropionylmorphine
Acetylpropionylmorphine is an opiate analogue that is a derivative of morphine. It was developed in the early 1900s after first being synthesised in Great Britain in 1875 but shelved along with heroin and various other esters of morphine, but was never used medically, instead being widely sold as one of the first "designer drugs" for around five years following the introduction of the first international restrictions on the sale of heroin in 1925. It is described as being virtually identical to heroin and morphine in its effects, and consequently was itself banned internationally in 1930 by the Health Committee of the League of Nations, in order to prevent its sale as an unscheduled alternative to heroin.
Zipeprol
Zipeprol is a centrally acting cough suppressant developed in France in the 1970s. It is not an morphinan derivative (in contrast to codeine and dextromethorphan). Zipeprol acts as a local anaesthetic and has mucolytic, antihistamine and anticholinergic properties.It is sold with several brand names such as Zinolta and Respilene. It is not available in the United States or Canada and has been discontinued in Europe. It is still available in some countries in Asia and South America.
Zopiclone
The therapeutic pharmacological properties of zopiclone include hypnotic, anxiolytic, anticonvulsant, and myorelaxant properties. Zopiclone and benzodiazepines bind to the same sites on GABA-containing receptors, causing an enhancement of the actions of GABA to produce the therapeutic and adverse effects of zopiclone. The metabolite of zopiclone called desmethylzopiclone is also pharmacologically active, although it has predominately anxiolytic properties. One study found some slight selectivity for zopiclone on α1 and α5 subunits, although it is regarded as being unselective in its binding to α1, α2, α3, and α5 GABA benzodiazepine receptor complexes. Desmethylzopiclone has been found to have partial agonist properties, unlike the parent drug zopiclone, which is a full agonist. The mechanism of action of zopiclone is similar to benzodiazepines, with similar effects on locomotor activity and on dopamine and serotonin turnover.
A meta-analysis of randomised controlled clinical trials that compared benzodiazepines to zopiclone or other Z drugs such as zolpidem and zaleplon has found few clear and consistent differences between zopiclone and the benzodiazepines in sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia, and daytime alertness.
Zopiclone is in the cyclopyrrolone family of drugs. Other cyclopyrrolone drugs include suriclone. Zopiclone, although molecularly different from benzodiazepines, shares an almost identical pharmacological profile as benzodiazepines, including anxiolytic properties. Its mechanism of action is by binding to the benzodiazepine site and acting as a full agonist, which in turn positively modulates benzodiazepine-sensitive GABA receptors and enhances GABA binding at the GABA receptors to produce zopiclone's pharmacological properties. In addition to zopiclone's benzodiazepine pharmacological properties, it also has some barbiturate-like properties.
Arvid Carlsson
Carlson collaborated with the drug company Astra AB (now AstraZeneca) during the 1970s and the 1980s. He and his colleagues were able to derive the first marketed selective serotonin reuptake inhibitor (SSRI), zimelidine, from brompheniramine. Zimelidine was later withdrawn from the market due to rare cases of Guillain–Barré syndrome, but Carlson's research paved the way for fluoxetine (Prozac), one of the most widely used prescription medicines in the world.
Zopiclone
The pharmacokinetics of zopiclone are altered by aging and are influenced by renal and hepatic functions. In severe chronic renal failure, the area under the curve value for zopiclone was larger and the half-life associated with the elimination rate constant longer, but these changes were not considered to be clinically significant. Sex and race have not been found to interact with pharmacokinetics of zopiclone.
Protriptyline
Protriptyline was developed by Merck. It was patented in 1962 and first appeared in the literature in 1964. The drug was first introduced for the treatment of depression in 1966.
Primidone
By 1980, primidone was seen as not worth mentioning as an option for childhood temporal lobe epilepsy by doctors in the United Kingdom. In January 1981, Dr. O'Brien and colleagues reported that primidone had a positive effect on the essential tremor of one of their patients. This led them to initiate a twenty-person prospective study. Twelve of the participants responded well. By 1984, valproic acid was the drug of choice for juvenile myoclonic epilepsy and not the equally effective primidone. However, as late as 1985, primidone was still one of the most widely used anticonvulsants. At the close of the 1980s, primidone was still the preferred anticonvulsant for complex partial seizures in Germany. In 1989, Dainippon Pharmaceutical launched Exegran (zonisamide), the first new, chemically unique, non-benzodiazepine anticonvulsant in decades.
Pempidine
Pempidine is a ganglion-blocking drug, first reported in 1958 by two research groups working independently, and introduced as an oral treatment for hypertension.
Sertraline
Sertraline, sold under the trade name Zoloft among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is primarily used for major depressive disorder, obsessive–compulsive disorder, panic disorder, and social anxiety disorder. Effectiveness is similar to other antidepressants. Sertraline is taken by mouth.
Common side effects include diarrhea, sexual dysfunction, and troubles with sleep. Serious side effects include an increased risk of suicide in those less than 25 years old and serotonin syndrome. It is unclear whether use during pregnancy or breastfeeding is safe. It should not be used together with MAO inhibitor medication. Sertraline is believed to work by increasing serotonin effects in the brain.
Sertraline was approved for medical use in the United States in 1991 and initially sold by Pfizer. It is currently available as a generic medication. In the United States the wholesale cost is about 1.50 USD per month as of 2018. In 2016, it was the most prescribed psychiatric medication in the United States, with over 37 million prescriptions.
Sertraline is used for a number of conditions, including major depressive disorder (MDD), obsessive–compulsive disorder (OCD), body dysmorphic disorder (BDD), posttraumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), panic disorder, and social anxiety disorder (SAD). It has also been used for premature ejaculation and vascular headaches but evidence of the effectiveness in treating those conditions is not robust. Sertraline is not approved for use in children except for those with OCD.
Opium
Heroin, the first semi-synthetic opioid, was first synthesized in 1874, but was not pursued until its rediscovery in 1897 by Felix Hoffmann at the Bayer pharmaceutical company in Elberfeld, Germany. From 1898 to 1910 heroin was marketed as a non-addictive morphine substitute and cough medicine for children. Because the lethal dose of heroin was viewed as a hundred times greater than its effective dose, heroin was advertised as a safer alternative to other opioids. By 1902, sales made up 5 percent of the company's profits, and "heroinism" had attracted media attention. Oxycodone, a thebaine derivative similar to codeine, was introduced by Bayer in 1916 and promoted as a less-addictive analgesic. Preparations of the drug such as oxycodone with paracetamol and extended release oxycodone remain popular to this day.
Suproclone
Suproclone is a sedative and anxiolytic drug in the cyclopyrrolone family of drugs, developed by the French pharmaceutical company Rhône-Poulenc. Other cyclopyrrolone drugs include zopiclone, pagoclone and suriclone.
Apomorphine
The use of apomorphine to treat "the shakes" was first suggested by Weil in France in 1884, although seemingly not pursued until 1951. Its clinical use was first reported in 1970 by Cotzias et al., although its emetic properties and short half-life made oral use impractical. A later study found that combining the drug with the antiemetic domperidone improved results significantly. The commercialization of apomorphine for Parkinson's disease followed its successful use in patients with refractory motor fluctuations using intermittent rescue injections and continuous infusions.
Norepinephrine
Early in the twentieth century Walter Cannon, who had popularized the idea of a sympathoadrenal system preparing the body for fight and flight, and his colleague Arturo Rosenblueth developed a theory of two "sympathins", "sympathin E" (excitatory) and "sympathin I" (inhibitory), responsible for these actions. The Belgian pharmacologist Zénon Bacq as well as Canadian and US-American pharmacologists between 1934 and 1938 suggested that noradrenaline might be a sympathetic transmitter. In 1939, Hermann Blaschko and Peter Holtz independently identified the biosynthetic mechanism for norepinephrine in the vertebrate body. In 1945 Ulf von Euler published the first of a series of papers that established the role of norepinephrine as a neurotransmitter. He demonstrated the presence of norepinephrine in sympathetically innervated tissues and brain, and adduced evidence that it is the "sympathin" of Cannon and Rosenblueth.
Tropinone
The first synthesis of tropinone was by Richard Willstätter in 1901. It started from the seemingly related cycloheptanone, but required many steps to introduce the nitrogen bridge; the overall yield for the synthesis path is only 0.75%. Willstätter had previously synthesized cocaine from tropinone, in what was the first synthesis and elucidation of the structure of cocaine.
Morphine
Morphine became a controlled substance in the US under the Harrison Narcotics Tax Act of 1914, and possession without a prescription in the US is a criminal offense.
Morphine was the most commonly abused narcotic analgesic in the world until heroin was synthesized and came into use. In general, until the synthesis of dihydromorphine (ca. 1900), the dihydromorphinone class of opioids (1920s), and oxycodone (1916) and similar drugs, there were no other drugs in the same efficacy range as opium, morphine, and heroin, with synthetics still several years away (pethidine was invented in Germany in 1937) and opioid agonists among the semi-synthetics were analogues and derivatives of codeine such as dihydrocodeine (Paracodin), ethylmorphine (Dionine), and benzylmorphine (Peronine). Even today, morphine is the most sought after prescription narcotic by heroin addicts when heroin is scarce, all other things being equal; local conditions and user preference may cause hydromorphone, oxymorphone, high-dose oxycodone, or methadone as well as dextromoramide in specific instances such as 1970s Australia, to top that particular list. The stop-gap drugs used by the largest absolute number of heroin addicts is probably codeine, with significant use also of dihydrocodeine, poppy straw derivatives like poppy pod and poppy seed tea, propoxyphene, and tramadol.
Cosmoline
Cosmoline was developed by Houghton International in the late 1800's as a pharmaceutical product. The original Cosmoline was an ointment and was used for many different cosmetic and medical purposes. It was kept in homes to disinfect wounds and was used by veterinarians to treat cuts, abrasions, bruises and sprains. Cosmoline could even be found on the farms where it was used to relieve swelling in cow's udders. Cosmoline became an everyday name when it received a government specification as a rust preventive and began being used by the military to protect its equipment from rust and corrosion. Cosmoline could be found on military equipment in the Spanish-American War, World War I, World War II, the Korean and Vietnam Wars. Cosmoline conforms to MIL-SPEC (MIL-C-11796C, Class 3) for Preservative and Sealing Compounds.
Azepindole
Azepindole (McN-2453) is a tricyclic compound with antidepressant and antihypertensive effects that was developed in the late 1960s but was never marketed.
Tibolone
Tibolone was developed in the 1960s. It was first introduced in the Netherlands in 1988, and was subsequently introduced in the United Kingdom in 1991.
Zopiclone
Zopiclone has the potential for misuse and dosage escalation, drug abuse, and drug dependence. It is abused orally and sometimes intravenously, and often combined with alcohol to achieve a combined sedative hypnotic—alcohol euphoria. Patients abusing the drug are also at risk of dependence. Withdrawal symptoms can be seen after long-term use of normal doses even after a gradual reduction regimen. The Compendium of Pharmaceuticals and Specialties recommends zopiclone prescriptions not exceed 7 to 10 days, owing to concerns of addiction, tolerance, and physical dependence. Two types of drug misuse can occur: either recreational misuse, wherein the drug is taken to achieve a high, or when the drug is continued long-term against medical advice. Zopiclone may be more addictive than benzodiazepines. Those with a history of substance misuse or mental health disorders may be at an increased risk of high-dose zopiclone misuse. High dose misuse of zopiclone and increasing popularity amongst drug abusers who have been prescribed with zopiclone The symptoms of zopiclone addiction can include depression, dysphoria, hopelessness, slow thoughts, social isolation, worrying, sexual anhedonia, and nervousness.
Trimipramine
Trimipramine was developed by Rhône-Poulenc. It was patented in 1959 and first appeared in the literature in 1961. The drug was first introduced for medical use in 1966, in Europe. It was not introduced in the United States until later in 1979 or 1980.
Opioid
Several semi-synthetic opioids were developed in Germany in the 1910s. The first, oxymorphone, was synthesized from thebaine, an opioid alkaloid in opium poppies, in 1914.
Next, Martin Freund and Edmund Speyer developed oxycodone, also from thebaine, at the University of Frankfurt in 1916.
In 1920, hydrocodone was prepared by Carl Mannich and Helene Löwenheim, deriving it from codeine. In 1924, hydromorphone was synthesized by adding hydrogen to morphine. Etorphine was synthesized in 1960, from the oripavine in opium poppy straw. Buprenorphine was discovered in 1972.
Azathioprine
Azathioprine was synthesized by George Herbert Hitchings and Gertrude Elion in 1957 (named "BW 57-322") to produce 6-mercaptopurine (6-MP) in a metabolically active but masked form, and at first used as a chemotherapy drug.
Metenolone acetate
Metenolone acetate was first introduced for medical use in West Germany in 1961 under the brand name Primobolan and in the United States in 1962.
Morphine
The drug was first marketed to the general public by Sertürner and Company in 1817 as a pain medication, and also as a treatment for opium and alcohol addiction. It was first used as a poison in 1822 when Dr. Edme Castaing of France was convicted of murdering a patient. Commercial production began in Darmstadt, Germany in 1827 by the pharmacy that became the pharmaceutical company Merck, with morphine sales being a large part of their early growth. In the 1850s, Alexander Wood reported that he had injected morphine into his wife Rebecca as an experiment; the myth goes that this killed her because of respiratory depression, but she outlived her husband by ten years.
Amitriptyline
Amitriptyline was first synthesized in 1960 and was introduced for medical use in United States in 1961 and in the United Kingdom in 1962, in both countries under the brand name Elavil. It was the second TCA to be introduced, following the introduction of imipramine in 1957.
Drug injection
In or shortly after 1851, the drugs which had been discovered and extracted from their plants of origin and refined into pure crystalline salts soluble in water included morphine (1804 or late 1803), codeine (1832), narcotine/noscapine (1803-1805?), papaverine (1814), cocaine (1855), caffeine (1819), quinine (1820), atropine (1831), scopolamine (aka hyoscine, aka laevo-duboisine) (1833?), hyoscyamine or laevo-atropine (1831), opium salts mixtures (c. 1840s), chloral derivatives (1831 et seq.), ephedrine (1836?), nicotine (1828), and many others of all types, psychoactive and not. Morphine in particular was used much more widely after the invention of the hypodermic syringe, and the practise of local anaesthesia by infiltration was another step forward in medicine resulting from the hypodermic needle, discovered at around the same time that it was determined that cocaine produced useful numbing of the mucous membranes and eye.
Obstetric anesthesiology
The isolation of morphine in the early 1800s was yet another milestone in obstetric anesthesia. However, the drug would not be widely used until the invention of the hypodermic needle in the 1850s. The first to use a hypodermic syringe in the United States was Fordyce Barker, who actually received the syringe from H.J Simpson as a gift during a visit to Edinburgh. Eventually, the use of morphine for pain control during labor lost favor due to its effects of respiratory depression in the newborn and was replaced largely by meperidine, a synthetic narcotic, first made in Germany in 1939, that had less of an effect on respiratory depression. Meperidine is still popular in obstetrics today.
Indalpine
While citalopram and zimelidine were developed in the early 1970s, it was Pharmuka's indalpine that was first to reach the market. Baron Shopsin was recruited as consultant to Pharmuka throughout a research and development process that resulted in the marketing of indalpine in France and then worldwide, in 1982. With FDA approval of Pharmuka's IND submission to conduct clinical studies with indalpine and viqueline, Shopsin carried out and published the first clinical trials with these drugs in depressed outpatients in the U.S. Astra's SSRI zimelidine was marketed within a year (1983), but the next crop of SSRIs didn't become commercially available until the 1986 marketing of fluvoxamine in Belgium by Duphar, followed by approval in the United States later that year. Lilly's fluoxetine (Prozac) was approved in the US in 1987.
Meanwhile, zimelidine had been withdrawn soon after its marketing in 1983 due to the emergence of Guillain–Barré syndrome, a serious neurological disease. With lingering concerns among some Common Market countries and activist groups about the potential of SSRIs to induce adverse effects, and the reported association between indalpine and hematological effects, which emerged in the aftermath of Pharmuka's take over by Rhône Poulenc, indalpine was abruptly taken off the market by Rhône Poulenc. Irish psychiatrist David Healy characterized indalpine as being "born at the wrong time" during a period when "indalpine and psychiatry was under siege" by different interest groups in some of the Common Market countries. In line with indalpine's fate, research and development was halted relating to the 2 other 4-alkyl-piperidine derivatives developed by Pharmuka, viqualine (a serotonin releasing agent) and pipequaline (a GABA receptor positive allosteric modulator), both in different stages of development at the time.
Index of oncology articles
ZD 1839
– ZD0473
– ZD6474
– ziconotide
– zidovudine
– zileuton
– zoledronate
– Zollinger-Ellison syndrome
– Zoloft
– zolpidem
– zosuquidar trihydrochloride
Zopiclone
Zopiclone also interacts with trimipramine and caffeine.
Zopiclone
An extensive review of the medical literature regarding the management of insomnia and the elderly found that considerable evidence of the effectiveness and lasting benefits of nondrug treatments for insomnia exist. Compared with the benzodiazepines, the nonbenzodiazepine sedative-hypnotics, such as zopiclone, offer few if any advantages in efficacy or tolerability in elderly persons. Newer agents such as the melatonin receptor agonists may be more suitable and effective for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and is discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of nonbenzodiazepine hypnotic drugs remains to be determined.
Adenosine diphosphate receptor inhibitor
When ticlopidine and clopidogrel were first brought to the market, ticlodipine in 1978 and clopidogrel in 1998, the mechanism of action of these two major antithrombotic drugs was not fully understood. What had been shown was that they were potent inhibitors of ADP-induced platelet aggregation, but the P2Y receptor had not been identified. Furthermore, it was clear that ticlopidine and clopidogrel were prodrugs which means they are inactive in-vitro and therefore need metabolism to be activated in-vivo. It wasn't until the year 2000 when the active metabolites of these drugs were isolated and characterized. About one year later the P2Y platelet receptor for ADP was identified. Following these discoveries the active metabolites and the enzymes responsible for their formation were progressively identified. Thus it was more than 30 years later after the discovery of ticlopidine, and more than 10 years later after the discovery of clopidogrel the mechanism of action of these two drugs was explained.
Zopiclone
Zopiclone is in the top ten medications obtained using a false prescription in France.
Allopurinol
Allopurinol has been marketed in the United States since August 19, 1966, when it was first approved by FDA under the trade name Zyloprim. Allopurinol was marketed at the time by Burroughs-Wellcome. Allopurinol is now a generic drug sold under a variety of brand names, including Allohexal, Allosig, Milurit, Alloril, Progout, Ürikoliz, Zyloprim, Zyloric, Zyrik, and Aluron.
Azathioprine
Robert Schwartz investigated the effect of 6-MP on the immune response in 1958 and discovered that it profoundly suppresses the formation of antibodies when given to rabbits together with antigens. Following the work done by Sir Peter Medawar and Gertrude Elion in discovering the immunological basis of rejection of transplanted tissues and organs, and Schwartz's researches on 6-MP, Sir Roy Calne, the British pioneer in transplantation, introduced 6-MP as an experimental immunosuppressant for kidney and heart transplants. When Calne asked Elion for related compounds to investigate, she suggested azathioprine, which was subsequently found out to be superior (as effective and less toxic to the bone marrow) by Calne. On 5 April 1962, with regimens consisting of azathioprine and prednisone, the transplantation of kidneys to unrelated recipients (allotransplantation) was successful for the first time. For many years, this kind of dual therapy with azathioprine and glucocorticoids was the standard antirejection regimen, until ciclosporin was introduced into clinical practice (by Calne as well) in 1978.
Methadone
Methadone, sold under the brand name Dolophine among others, is an opioid used for opioid maintenance therapy in opioid dependence, and for pain. Detoxification using methadone can either be done relatively rapidly in less than a month or gradually over as long as six months. While a single dose has a rapid effect, maximum effect can take five days of use. The pain relieving effects last about six hours after a single dose, similar to morphine's. After long term use, in people with normal liver function, effects last 8 to 36 hours. Methadone is usually taken by mouth and rarely by injection into a muscle or vein.
Side effects are similar to those of other opioids. Commonly these include dizziness, sleepiness, vomiting, and sweating. Serious risks include opioid abuse and a decreased effort to breathe. Abnormal heart rhythms may also occur due to a prolonged QT interval. The number of deaths in the United States involving methadone poisoning declined from 4,418 in 2011 to 3,300 in 2015. Risks are greater with higher doses. Methadone is made by chemical synthesis and acts on opioid receptors.
Methadone was developed in Germany around 1937 to 1939 by Gustav Ehrhart and Max Bockmühl. It was approved for use in the United States in 1947. Methadone is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. Globally in 2013, about 41,400 kilograms were manufactured. It is regulated similarly to other narcotic drugs. It is not particularly expensive in the United States.
Methadone is used for the treatment of opioid use disorder. It may be used as a maintenance therapy or in shorter periods for detoxification to manage opioid withdrawal symptoms.
Zuclopenthixol
Zuclopenthixol (brand names Cisordinol, Clopixol-Acuphase), also known as zuclopentixol, is a medication used to treat schizophrenia and other psychoses. It is classed, pharmacologically, as a typical antipsychotic. Chemically it is a thioxanthene. It is the "cis"-isomer of clopenthixol (Sordinol, Ciatyl). Clopenthixol was introduced in 1961, while zuclopenthixol was introduced in 1978.
Zopiclone
In the United States, zopiclone is not commercially available, although its active stereoisomer, eszopiclone, is sold under the name Lunesta. Zopiclone is a controlled substance in the United States, Japan, Brazil, and some European countries, and may be illegal to possess without a prescription. However, it is readily available in other countries where it is marketed under the brand name Imovane, and is not a controlled substance in its available 10 mg, 7.5 mg, 5 mg, and 3.75 mg oral tablet formulations.
Zopiclone
Similarly to other sedative hypnotic drugs, zopiclone causes a decrease in the core body temperature and is effective in decreasing sleep latency. It causes similar alterations on EEG readings and sleep architecture as benzodiazepines and causes disturbances in sleep architecture on withdrawal as part of its rebound effect. Zopiclone reduces both delta waves and the number of high-amplitude delta waves whilst increasing low-amplitude waves. Zopiclone reduces the total amount of time spent in REM sleep as well as delaying its onset. Cognitive behavioral therapy has been found to be superior to zopiclone in the treatment of insomnia and has been found to have lasting effects on sleep quality for at least a year after therapy.
Indalpine
Indalpine (INN, BAN; brand name Upstène; developmental code name LM-5008) is a selective serotonin reuptake inhibitor (SSRI) class drug that was briefly marketed. It was discovered in 1977 by the pharmacologists Le Fur and Uzan at Pharmuka, a small French pharmaceutical firm, who credit Baron Shopsin and his colleagues at NYU-Bellevue/NYU School of Medicine in New York with providing the basis for their work. They were particularly influenced by the series of "synthesis inhibitor studies" carried out by Shopsin's team during the early to mid 1970s, and in particular, the clinical report by Shopsin et al. (1976) relating to PCPA's rapid reversal of antidepressant response to tranylcypromine in depressed patients. This led to an understanding of the role of the monoamine neurotransmitter serotonin (5-hydroxytryptamine, or 5HT) in the therapeutic effects of the available tricyclic and MAOI class antidepressants. The studies led to widespread recognition of a serotonin hypothesis of depression, contradicting theories that promoted the role of norepinephrine.
Hypnotic
Examples include zopiclone (Imovane, Zimovane), eszopiclone (Lunesta), zaleplon (Sonata), and zolpidem (Ambien, Stilnox, Stilnoct).
3,4-Methylenedioxyamphetamine
MDA was first synthesized by C. Mannich and W. Jacobsohn in 1910. It was first ingested in July 1930 by Gordon Alles who later licensed the drug to Smith, Kline & French. MDA was first used in animal tests in 1939, and human trials began in 1941 in the exploration of possible therapies for Parkinson's disease. From 1949 to 1957, more than 500 human subjects were given MDA in an investigation of its potential use as an antidepressant and/or anorectic by Smith, Kline & French. The United States Army also experimented with the drug, code named EA-1298, while working to develop a truth drug or incapacitating agent. Harold Blauer died in January 1953 after being intravenously injected, without his knowledge nor consent, with 450 mg of the drug as part of Project MKUltra. MDA was patented as a cough suppressant by H. D. Brown in 1958, as an ataractic by Smith, Kline & French in 1960, and as an anorectic under the trade name "Amphedoxamine" in 1961. MDA began to appear on the recreational drug scene around 1963 to 1964. It was then inexpensive and readily available as a research chemical from several scientific supply houses. Several researchers, including Claudio Naranjo and Richard Yensen, have explored MDA in the field of psychotherapy.
Zopiclone
Death certificates show the number of zopiclone-related deaths is on the rise. When taken alone, it usually is not fatal, but when mixed with alcohol or other drugs such as opioids, or in patients with respiratory, or hepatic disorders, the risk of a serious and fatal overdose increases.
Estradiol cypionate
Estradiol cypionate was patented by Upjohn in 1952, with a priority date of 1951. It was first introduced for medical use by Upjohn in 1952 under the brand name Depo-Estradiol in the United States. Subsequently, it was also marketed in other countries such as European countries and Japan. The first clinical reports of estradiol cypionate were published in 1952 and thereafter. It was initially known as "estradiol cyclopentylpropionate" ("ECP"), and did not become known as "estradiol cypionate" until over a decade later in the mid-to-late 1960s. Along with estradiol valerate (1954) and estradiol benzoate (1936), estradiol cypionate has become one of the most commonly used esters of estradiol.
Doxepin
Doxepin was discovered in Germany in 1963 and was introduced in the United States as an antidepressant in 1969. It was subsequently approved at very low doses in the United States for the treatment of insomnia in 2010.
Zopiclone
Zopiclone (brand names Imovane, Zimovane, and Dopareel) is a nonbenzodiazepine hypnotic agent used in the treatment of insomnia. Zopiclone is molecularly distinct from benzodiazepine drugs and is classed as a cyclopyrrolone. However, zopiclone increases the normal transmission of the neurotransmitter gamma-aminobutyric acid in the central nervous system, via modulating benzodiazepine receptors in the same way that benzodiazepine drugs do.
Cinoxacin
Cinoxacin is one of the original quinolone drugs, which were introduced in the 1970s. Commonly referred to as the first generation quinolones. This first generation also included other quinolone drugs such as pipemidic acid, and oxolinic acid, but this first generation proved to be only marginal improvements over nalidixic acid. Cinoxacin is similar chemically (and in antimicrobial activity) to oxolonic acid and nalidixic acid. Relative to nalidixic acid, cinoxacin was found to have a slightly greater inhibitory and bactericidal activity. Cinoxacin was patented in 1972 and assigned to Eli Lilly. Eli Lilly obtained approval from the FDA to market cinoxacin in the United States as Cinobac on June 13, 1980. Prior to this cinobac was marketed in the U.K. and Switzerland in 1979.
Acedapsone
Acedapsone, or 1399 F, is a diacetyl compound, derived from dapsone. It was synthesized and developed in 1937 by Ernest Fourneau and his team in the pharmaceutical chemistry laboratory of Pasteur Institute, and it was marketed as Rodilone by the Rhône-Poulenc company.
Naltrexone
Naltrexone was first synthesized in 1963 by Metossian at Endo Laboratories, a small pharmaceutical company in New York City. It was characterized by Blumberg, Dayton, and Wolf in 1965 and was found to be an orally active, long-acting, and very potent opioid antagonist. The drug showed advantages over earlier opioid antagonists such as cyclazocine, nalorphine, and naloxone, including its oral activity, a long duration of action allowing for once-daily administration, and a lack of dysphoria, and was selected for further development. It was patented by Endo Laboratories in 1967 under the developmental code name EN-1639A and Endo Laboratories was acquired by DuPont in 1969. Clinical trials for opioid dependence began in 1973, and a developmental collaboration of DuPont with the National Institute on Drug Abuse for this indication started the next year in 1974. The drug was approved by the FDA for the oral treatment of opioid dependence in 1984, with the brand name Trexan, and for the oral treatment of alcohol dependence in 1995, when the brand name was changed by DuPont to ReVia. A depot formulation for intramuscular injection was approved by the FDA under the brand name Vivitrol for alcohol dependence in 2006 and opioid dependence in 2010.
Pozanicline
Pozanicline (INN, codenamed ABT-089) is a drug developed by Abbott, that has nootropic and neuroprotective effects. Animal studies suggested it useful for the treatment of ADHD and subsequent human trials have shown ABT-089 to be effective for this application. It binds with high affinity subtype-selective to the αβ nicotinic acetylcholine receptors and has partial agonism to the αβ subtype, but not the α and αβ subtypes familiar to nicotine. It has particularly low tendency to cause side effects compared to other drugs in the class, making it an exciting candidate for clinical development.
Perospirone
Perospirone (Lullan) is an atypical antipsychotic of the azapirone family. It was introduced in Japan by Dainippon Sumitomo Pharma in 2001 for the treatment of schizophrenia and acute cases of bipolar mania.
Dopamine
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.
Pipamperone
Pipamperone (INN, USAN, BAN), also known as carpiperone and floropipamide or fluoropipamide, and as floropipamide hydrochloride (JAN), is a typical antipsychotic of the butyrophenone family used in the treatment of schizophrenia. It is or has been marketed under brand names including Dipiperon, Dipiperal, Piperonil, Piperonyl, and Propitan. Pipamperone was discovered at Janssen Pharmaceutica in 1961, and entered clinical trials in the United States in 1963.
Ticlopidine
Ticlopidine was brought to market in the US by Syntex, which got the drug approved in 1991. Syntex was acquired by the Roche group in 1994. The first generic ticlopidine hydrochloride was FDA approved in 1999. As of April 2015, Roche, Caraco, Sandoz, Par, Major, Apotex, and Teva had discontinued generic ticlopidine and no ticlopidine preparations were available in the US.
Azaperone
Azaperone (under the brand name Stresnil) was approved for use in pigs in the USA in 1983, under NADA 115-732.
Azapirone
Azapirones are poorly but nonetheless appreciably absorbed and have a rapid onset of action, but have only very short half-lives ranging from 1–3 hours. As a result, they must be administered 2-3 times a day. The only exception to this rule is umespirone, which has a very long duration with a single dose lasting as long as 23 hours. Unfortunately, umespirone has not been commercialized. Although never commercially produced, Bristol-Myers Squibb applied for a patent on Oct 28, 1993 and received the patent on Jul 11, 1995 for an extended release formulation of buspirone. An extended release formulation of gepirone is currently under development and if approved, should help to improve this issue.
Adrafinil
Adrafinil was discovered in 1974 by two chemists working for the French pharmaceutical company Laboratoires Lafon who were screening compounds in search of analgesics. Pharmacological studies of adrafinil instead revealed psychostimulant-like effects such as hyperactivity and wakefulness in animals. The substance was first tested in humans, specifically for the treatment of narcolepsy, in 1977–1978. Introduced by Lafon (now Cephalon), it reached the market in France in 1984, and for the treatment of narcolepsy in 1985.
Gertrude B. Elion
Gertrude Belle Elion (January 23, 1918 – February 21, 1999) was an American biochemist and pharmacologist, who shared the 1988 Nobel Prize in Physiology or Medicine with George H. Hitchings and Sir James Black. Working alone as well as with Hitchings and Black, Elion developed a multitude of new drugs, using innovative research methods that would later lead to the development of the AIDS drug AZT. She developed the first immunosuppressive drug, azathioprine, used for organ transplants. She also developed the first successful antiviral drug, acyclovir (ACV), for the treatment of Herpes infection.
Lofepramine
Lofepramine was developed by . It first appeared in the literature in 1969 and was patented in 1970. The drug was first introduced for the treatment of depression in either 1980 or 1983.
Theophylline
Theophylline was first extracted from tea leaves and chemically identified around 1888 by the German biologist Albrecht Kossel. Seven years later, a chemical synthesis starting with 1,3-dimethyluric acid was described by Emil Fischer and Lorenz Ach. The Traube purine synthesis, an alternative method to synthesize theophylline, was introduced in 1900 by another German scientist, Wilhelm Traube. Theophylline's first clinical use came in 1902 as a diuretic. It took an additional 20 years until it was first reported as an asthma treatment. The drug was prescribed in a syrup up to the 1970s as Theostat 20 and Theostat 80, and by the early 1980s in a tablet form called Quibron.
Ampicillin
Ampicillin is an antibiotic used to prevent and treat a number of bacterial infections, such as respiratory tract infections, urinary tract infections, meningitis, salmonellosis, and endocarditis. It may also be used to prevent group B streptococcal infection in newborns. It is used by mouth, by injection into a muscle, or intravenously. Like all antibiotics, it is not useful for the treatment of viral infections.
Common side effects include rash, nausea, and diarrhea. It should not be used in people who are allergic to penicillin. Serious side effects may include "Clostridium difficile" colitis or anaphylaxis. While usable in those with kidney problems, the dose may need to be decreased. Its use during pregnancy and breastfeeding appears to be generally safe.
Ampicillin was discovered in 1958 and came into commercial use in 1961. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. Its wholesale cost in the developing world is between US$0.13 and 1.20 for a vial of the intravenous solution as of 2014. In the United States, it is available as a generic medication and 10 days of treatment cost about $13.Ampicillin used to also be used to treat gonorrhea, but there are now too many strains resistant to penicillins.
Ethoheptazine
Ethoheptazine (trade name Zactane) is an opioid analgesic from the phenazepane family. It was invented in the 1950s and is related to other drugs such as proheptazine and pethidine.
Zopiclone
Alcohol has an additive effect when combined with zopiclone, enhancing the adverse effects including the overdose potential of zopiclone significantly. Due to these risks and the increased risk for dependence, alcohol should be avoided when using zopiclone.
Aripiprazole/sertraline
Aripiprazole/sertraline (developmental code name ASC-01) is a combination formulation of sertraline (Zoloft), a selective serotonin reuptake inhibitor (SSRI), and aripiprazole (Abilify), an atypical antipsychotic, which is under development by Otsuka Pharmaceutical for the treatment of major depressive disorder (MDD). The drug combines serotonin reuptake inhibition and modulation of dopamine and serotonin receptors. As of July 2017, it is in preregistration in Japan for the treatment of MDD.
Mizoribine
Mizoribine (INN, trade name Bredinin) is an immunosuppressive drug. The compound was first observed in Tokyo, Japan, in 1971. First isolated from the fungus "Penicillium brefeldianum". Mizoribine (MZB) is an imidazole nucleoside that has been used in renal transplantation, and in steroid-resistant nephrotic syndrome, IgA nephropathy, lupus, as well as for adults with rheumatoid arthritis, lupus nephritis and other rheumatic diseases. MZB exerts its activity through selective inhibition of inosine monophosphate synthetase and guanosine monophosphate synthetase, resulting in the complete inhibition of guanine nucleotide synthesis without incorporation into nucleotides. It arrests DNA synthesis in the S phase of cellular division. Thus, MZB has less toxicity than azathioprine, another immunosuppressant used for some of the same diseases.
Oxymetholone
Oxymetholone, sold under the brand names Anadrol and Anapolon among others, is an androgen and anabolic steroid (AAS) medication which is used primarily in the treatment of anemia. It is also used to treat osteoporosis, HIV/AIDS wasting syndrome, and to promote weight gain and muscle growth in certain situations. It is taken by mouth.
Side effects of oxymetholone include increased sexual desire as well as symptoms of masculinization like acne, increased hair growth, and voice changes. It can also cause liver damage. The drug is a synthetic androgen and anabolic steroid and hence is an agonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). It has strong anabolic effects and weak androgenic effects.
Oxymetholone was first described in 1959 and was introduced for medical use by 1961. It is used mostly in the United States. In addition to its medical use, oxymetholone is used to improve physique and performance. The drug is a controlled substance in many countries and so non-medical use is generally illicit.
Aceperone
Aceperone is a neuroleptic drug of the butyrophenone class. It is an α-noradrenergic blocking drug developed by Janssen Pharmaceutica in the 1960s.
Oxandrolone
Oxandrolone was first made by Raphael Pappo and Christopher J. Jung while at Searle Laboratories (now part of Pfizer). The researchers first described the drug in 1962. They were immediately interested in oxandrolone's very weak androgenic effects relative to its anabolic effects. It was introduced as a pharmaceutical drug in the United States in 1964.
Pagoclone
Pagoclone is an anxiolytic agent from the cyclopyrrolone family, related to better-known drugs such as the sleeping medication zopiclone. It was synthesized by a French team working for Rhone-Poulenc & Rorer S.A. Pagoclone belongs to the class of nonbenzodiazepines, which have similar effects to the older benzodiazepine group, but with quite different chemical structures. It was never commercialised.
Besipirdine
Besipirdine was first considered for the treatment of obsessive-compulsive disorder (OCD). Hoechst-Roussel Pharmaceuticals, Inc. (Hoecst AG) filed a patent in July 1993 protecting the use of N-(pyridinyl)-1H-indol-1-amines, including besipirdine, for the treatment of OCD, supported by preliminary data gathered from rat studies . In 1995, Hoechst AG filed a patent protecting the production of besipirdine, this time describing its memory-enhancing, analgetic and antidepressant qualities . With increasing research on besipirdine uncovering its effects on the cholinergic system, Hoechst AG filed a patent in the following year to protect substituted n-(pyrrol-1-yl)pyridinamines as anticonvulsant agents
. In the midst of Phase II clinical studies of besipirdine in Alzheimer's disease, Hoechst AG merged with Rhône-Poulenc S.A. to form Aventis Pharma Limited. Under the new company Aventis, besipirdine ultimately failed in Phase III clinical trials due to severe cardiovascular side effects observed in a few patients in separate studies. In January 2004, UroGene acquired exclusive development and commercialization rights to besipirdine from Aventis in order to study its application in urology
. In February 2007, UroGene filed its own patent protecting the crystal form of besipirdine chlorhydrate, its production process, and its applications in the pharmaceutical field. The drug is currently undergoing Phase III development for treatment of Lower Urinary Tract Dysfunctions
Zopiclone
Zopiclone, as traditionally sold worldwide, is a racemic mixture of two stereoisomers, only one of which is active. In 2005, the pharmaceutical company Sepracor of Marlborough, Massachusetts began marketing the active stereoisomer eszopiclone under the name Lunesta in the United States. This had the consequence of placing what is a generic drug in most of the world under patent control in the United States. Generic forms of Lunesta have since become available in the United States. Zopiclone is currently available off-patent in a number of European countries, as well as Brazil, Canada, and Hong Kong. The eszopiclone/zopiclone difference is in the dosage—the strongest eszopiclone derivative dosage contains 3 mg of the therapeutic stereoisomer, whereas the highest zopiclone dosage (10 mg) contains 5 mg of the active stereoisomer. The two agents have not yet been studied in head-to-head clinical trials to determine the existence of any potential clinical differences (efficacy, side effects, developing dependence on the drug, safety, etc.).
Pemoline
Pemoline is a stimulant drug of the 4-oxazolidinone class. It was first synthesized in 1913 but its activity was not discovered until the 1930s. Under the names Betanamin, Cylert, Tradon, and Ceractiv it was used as a medication to treat attention-deficit hyperactivity disorder (ADHD) and narcolepsy. Under the Convention on Psychotropic Substances, it is a Schedule IV drug. It is no longer generally available in the United States as a result of the FDA withdrawing approval of pemoline as an indicated treatment for ADHD, due to its implication in liver failures among children who were receiving the medication. An FDA Alert warned against prescribing pemoline for ADHD. This spurred Abbott Laboratories, the patent owner of Cylert, to cease manufacturing Cylert. Manufacturers of the generic equivalents followed suit.
Opioid epidemic
Oxycodone was first made available in the United States in 1939. In the 1970s, the FDA classified oxycodone as a Schedule II drug, indicating a high potential for abuse and addiction. In 1996, Purdue Pharma introduced OxyContin, a controlled release formulation of oxycodone. The FDA approved relabeling the reformulated version as abuse-resistant. However, drug users quickly learned how to simply crush the controlled release tablet to swallow, inhale, or inject the high-strength opioid for a powerful morphine-like high. In fact, Purdue's private testing conducted in 1995 determined that 68% of the oxycodone could be extracted from an OxyContin tablet when crushed.
Zopiclone
Zopiclone causes impaired driving skills similar to those of benzodiazepines. Long-term users of hypnotic drugs for sleep disorders develop only partial tolerance to adverse effects on driving with users of hypnotic drugs even after 1 year of use still showing an increased motor vehicle accident rate. Patients who drive motor vehicles should not take zopiclone unless they stop driving due to a significant increased risk of accidents in zopiclone users. Zopiclone induces impairment of psychomotor function. Driving or operating machinery should be avoided after taking zopiclone as effects can carry over to the next day, including impaired hand eye coordination.
Medicinal plants
The place of plants in medicine was radically altered in the 19th century by the application of chemical analysis. Alkaloids were isolated from a succession of medicinal plants, starting with morphine from the poppy in 1806, and soon followed by ipecacuanha and strychnos in 1817, quinine from the cinchona tree, and then many others. As chemistry progressed, additional classes of pharmacologically active substances were discovered in medicinal plants. Commercial extraction of purified alkaloids including morphine from medicinal plants began at Merck in 1826. Synthesis of a substance first discovered in a medicinal plant began with salicylic acid in 1853. Around the end of the 19th century, the mood of pharmacy turned against medicinal plants, as enzymes often modified the active ingredients when whole plants were dried, and alkaloids and glycosides purified from plant material started to be preferred. Drug discovery from plants continued to be important through the 20th century and into the 21st, with important anti-cancer drugs from yew and Madagascar periwinkle.
Cinchophen
Cinchophen (trade names Atophan, Quinophan, and Phenaquin) is an analgesic drug that was first produced by Doebner & Gieskel in 1887, it was commercially introduced in 1908 as a treatment for gout. This drug is still used, in combination with Prednisolone, by veterinarians to treat arthritis in animals. It can be prepared starting from anilin, benzaldehyde and pyruvic acid in absolute ethanol. Use of this drug in humans ceased in the 1930s due to the discovery that cinchophen can cause serious liver damage. There is some evidence that it stimulates C-Fos.
Zopiclone
The pharmacokinetics of zopiclone in humans are stereoselective. After oral administration of the racemic mixture, C (time to maximum plasma concentration), area under the plasma time-concentration curve (AUC) and terminal elimination half-life values are higher for the dextrorotatory enantiomers, owing to the slower total clearance and smaller volume of distribution (corrected by the bioavailability), compared with the levorotatory enantiomer. In urine, the concentrations of the dextrorotatory enantiomers of the "N"-demethyl and "N"-oxide metabolites are higher than those of the respective antipodes.
Imipramine
The parent compound of imipramine, 10,11-dihydro-5"H"-dibenz[b,f]azepine (dibenzazepine), was first synthesized in 1899, but no pharmacological assessment of this compound or any substituted derivatives was undertaken until the late 1940s. Imipramine was first synthesized in 1951, as an antihistamine. The antipsychotic effects of chlorpromazine were discovered in 1952, and imipramine was then developed and studied as an antipsychotic for use in patients with schizophrenia. The medication was tested in several hundred patients with psychosis, but showed little effectiveness. However, imipramine was serendipitously found to possess antidepressant effects in the mid-1950s following a case report of symptom improvement in a woman with severe depression who had been treated with it. This was followed by similar observations in other patients and further clinical research. Subsequently, imipramine was introduced for the treatment of depression in Europe in 1958 and in the United States in 1959. Along with the discovery and introduction of the monoamine oxidase inhibitor iproniazid as an antidepressant around the same time, imipramine resulted in the establishment of monoaminergic drugs as antidepressants.
Zopyrus (physician)
Zopyrus (; 1st-century BCE) was a surgeon at Alexandria, and the tutor of Apollonius of Citium and Posidonius. He invented an antidote, which he recommended to Mithridates VI of Pontus, and wrote a letter to that king, begging to be allowed to test its efficacy on a criminal. Another somewhat similar composition he prepared for one of the Ptolemies. Some of his medical formulae are quoted and mentioned by various ancient authors, viz. Caelius Aurelianus, Oribasius, Aetius, Paul of Aegina, Marcellus Empiricus, and Nicolaus Myrepsus. Pliny and Dioscorides mention that a certain plant was called "zopyron", perhaps after his name. Nicarchus satirizes a physician named Zopyrus in one of his epigrams. Not to be confused with Zopyron.
Zafuleptine
Zafuleptine (INN) (proposed brand name Thymeon) is an antidepressant developed in the mid-1970s which, despite apparently having a chosen brand name, was never marketed.
Ondansetron
Ondansetron (marketed under the brand name Zofran) was developed in the mid-1980s by GlaxoSmithKline in London. It was granted US patent protection in September 1987, received a use patent June 1988, and was approved by the US FDA in January 1991. It was granted another divisional patent in November 1996. Finally, owing to GlaxoSmithKline's research on pediatric use, ondansetron's patent protection was extended until December 2006. By this final year of its patent (2006), Zofran had become the 20th highest-selling brand-name drug in the United States, with sales of US$1.3 billion in the first 9 months of 2006 (80% from the US). The first generic versions were approved by the US FDA in December 2006, with marketing approval granted to Teva Pharmaceuticals USA and SICOR Pharmaceuticals.
Opioid
Codeine was discovered in 1832 by Pierre Jean Robiquet. Robiquet was reviewing a method for morphine extraction, described by Scottish chemist William Gregory (1803-1838). Processing the residue left from Gregory's procedure, Robiquet isolated a crystalline substance from the other active components of opium. He wrote of his discovery: "Here is a new substance found in opium ... We know that morphine, which so far has been thought to be the only active principle of opium, does not account for all the effects and for a long time the physiologists are claiming that there is a gap that has to be filled." His discovery of the alkaloid led to the developmemt of a generation of antitussive and antidiarrheal medicines based on codeine.
Zopiclone
Zopiclone is sometimes used as a method of suicide. It has a similar fatality index to that of benzodiazepine drugs, apart from temazepam, which is particularly toxic in overdose. Deaths have occurred from zopiclone overdose, alone or in combination with other drugs. Overdose of zopiclone may present with excessive sedation and depressed respiratory function that may progress to coma and possibly death. Zopiclone combined with alcohol, opiates, or other central nervous system depressants may be even more likely to lead to fatal overdoses. Zopiclone overdosage can be treated with the benzodiazepine receptor antagonist flumazenil, which displaces zopiclone from its binding site on the benzodiazepine receptor, thereby rapidly reversing its effects. Serious effects on the heart may also occur from a zopiclone overdose when combined with piperazine.
Adrafinil
In 1976, two years after the discovery of adrafinil, modafinil, its active metabolite, was discovered. Modafinil appeared to be more potent than adrafinil in animal studies, and was selected for further clinical development, with both adrafinil and modafinil eventually reaching the market. Modafinil was first approved in France in 1994, and then in the United States in 1998. Lafon was acquired by Cephalon in 2001. As of September 2011, Cephalon has discontinued Olmifon, its adrafinil product, while modafinil continues to be marketed.
Morphine
Diacetylmorphine (better known as heroin) was synthesized from morphine in 1874 and brought to market by Bayer in 1898. Heroin is approximately 1.5 to 2 times more potent than morphine weight for weight. Due to the lipid solubility of diacetylmorphine, it can cross the blood–brain barrier faster than morphine, subsequently increasing the reinforcing component of addiction. Using a variety of subjective and objective measures, one study estimated the relative potency of heroin to morphine administered intravenously to post-addicts to be 1.80–2.66 mg of morphine sulfate to 1 mg of diamorphine hydrochloride (heroin).
Moprolol
Moprolol was first patented by SIMS in 1987 under US patent number 4647590. In this patent SIMS states that moprolol can be used to treat glaucoma when administered locally as well as arterial hypertension. Then it goes into the studies conducted that proved the effectiveness of moprolol to treat these conditions without having the side effects of treatments on the market. This led to many other patents over the years, a few of which are listed in the table below:
Zotepine
Zotepine is an atypical antipsychotic drug indicated for acute and chronic schizophrenia. It has been used in Germany since 1990 (although it has been discontinued in Germany) and Japan since 1982.
Dizocilpine
Dizocilpine, along with other NMDA antagonists, induce the formation of brain lesions first discovered by John W. Olney in 1989. Dizocilpine leads to the development of neuronal vacuolization in the posterior cingulate/retrosplenial cortex. Other neurons in the area expressed an abnormal amount of heat shock protein as well as increased glucose metabolism in response to NMDA antagonist exposure. Vacuoles began to form within 30 minutes of a subcutaneous dose of dizocilpine 1 mg/kg. Neurons in this area necrotized and were accompanied by a glial response involving astrocytes and microglia.
Suriclone
Suriclone (Suril) is a sedative and anxiolytic drug in the cyclopyrrolone family of drugs. Other cyclopyrrolone drugs include zopiclone and pagoclone.
Cinchophen
Cinchophen was first introduced in 1908 as 'Atophan' and used for the treatment of gout and arthritis. It was efficacious at reducing the buildup of uric acid and became a popular medicine. Further studies in 1911 and 1912 were successful in isolating metabolites of cinchophen from human urine. During the 1920s, cases of severe adverse effects such as liver damage and cirrhosis had been clinically observed; the first case of jaundice was recorded in 1923 and the first fatality occurred in 1925. Approximately half of all patients experienced toxic effects and by 1932 there were 32 drugs available that contained cinchophen or its derivatives as their active ingredients , experiments were conducted to determine the drugs pharmacology but the mechanism of drug induced liver injury remained unclear. Cinchophen was considered to be too dangerous for human use in most countries but has applications in veterinary medicine as a treatment for osteoarthritis in dogs.