Benzodiazepines typically used to treat anxiety or depression include alprazolam (Xanax), chlordiazepoxide (Librium), diazepam (Valium) and lorazepam (Ativan).
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Xanax—a benzodiazepine under the same class as Klonopin (clonazepam), Valium (diazepam) and Librium (chlordiazepoxide)—is used to treat panic disorders, insomnia, seizures, alcohol withdrawal, and anxiety.
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The patient also experienced paranoid ideation (believing she was being poisoned and persecuted by co-employees), accompanied by sensory hallucinations. Symptoms developed after abrupt withdrawal of chlordiazepoxide and persisted for 14 months. Various psychiatric medications were trialed which were unsuccessful in alleviating the symptomatology. Symptoms were completely relieved by recommending chlordiazepoxide for irritable bowel syndrome 14 months later.
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Common benzodiazepines are chlordiazepoxide and lorazepam. It has been shown that management has been effective with a combination of abstinence from alcohol and the use of neuroleptics. It is also possible to treat withdrawal before major symptoms start to happen in the body. Diazepam and chlordiazepoxide have proven to be effective in treating alcohol withdrawal symptoms such as alcoholic hallucinosis.
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DemoxepamUS Patent 3136815 is a drug which is a benzodiazepine derivative. It is a metabolite of chlordiazepoxide and has anticonvulsant properties and presumably other characteristic benzodiazepine properties.
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Used in fixed combination with chlordiazepoxide in the treatment of acute enterocolitis. However, antimuscarinics should be used with extreme caution in patients with diarrhea or ulcerative colitis.
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Dibudinic acid, or dibudinate, is an organic compound. It is found in some salts of pharmaceutical drugs like chlordiazepoxide dibudinate, desipramine dibudinate, levopropoxyphene dibudinate, and propranolol dibudinate.
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Monkey studies looking at the dependence liability of several sedative drugs showed that benzoctamine was a dependence- free drug, while pentobarbital, alcohol, chloroform, meprobamate, diazepam, chlordiazepoxide, and oxazolam were not.
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In a rat study looking at the effects of benzoctamine and chlordiazepoxide on serotonin turnover, rats treated with drug were found to have elevated levels of [14C]-5HT, indicating a decrease in serotonin turnover.
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The benzodiazepines chlordiazepoxide (Librium) and oxazepam (Serax) have largely replaced phenobarbital for detoxification. While phenobarbital has been used for insomnia, such use is not recommended due to the risk of addiction and other side affects.
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This syndrome may be hard to recognize, as it starts several days after delivery, for example, as late as 21 days for chlordiazepoxide. The symptoms include tremors, hypertonia, hyperreflexia, hyperactivity, and vomiting and may last for up to three to six months. Tapering down the dose during pregnancy may lessen its severity. If used in pregnancy, those benzodiazepines with a better and longer safety record, such as diazepam or chlordiazepoxide, are recommended over potentially more harmful benzodiazepines, such as temazepamTemazepam-Rxlist Pregnancy Category@ or triazolam.
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The molecular structure of chlordiazepoxide, the first benzodiazepine. It was marketed by Hoffmann–La Roche from 1960 branded as Librium. The first benzodiazepine, chlordiazepoxide (Librium), was synthesized in 1955 by Leo Sternbach while working at Hoffmann–La Roche on the development of tranquilizers. The pharmacological properties of the compounds prepared initially were disappointing, and Sternbach abandoned the project. Two years later, in April 1957, co-worker Earl Reeder noticed a "nicely crystalline" compound left over from the discontinued project while spring-cleaning in the lab.
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The typical treatment of alcohol withdrawal is with benzodiazepines such as chlordiazepoxide or diazepam. Often the amounts given are based on a person's symptoms. Thiamine is recommended routinely. Electrolyte problems and low blood sugar should also be treated.
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Delirium tremens due to alcohol withdrawal can be treated with benzodiazepines. High doses may be necessary to prevent death. Amounts given are based on the symptoms. Typically the person is kept sedated with benzodiazepines, such as diazepam, lorazepam, chlordiazepoxide, or oxazepam.
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Moreover, the crayfish calmed down when they were injected with the benzodiazepine anxiolytic, chlordiazepoxide, used to treat anxiety in humans, and they entered the dark as normal. The authors of the study concluded "...stress-induced avoidance behavior in crayfish exhibits striking homologies with vertebrate anxiety." A follow-up study using the same species confirmed the anxiolytic effect of chlordiazepoxide, but moreover, the intensity of the anxiety-like behaviour was dependent on the intensity of the electric shock until reaching a plateau. Such a quantitative relationship between stress and anxiety is also a very common feature of human and vertebrate anxiety.
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Clidinium bromide (INN) is an anticholinergic (specifically a muscarinic antagonist) drug. It may help symptoms of cramping and abdominal/stomach pain by decreasing stomach acid, and slowing the intestines. It is commonly prescribed in combination with chlordiazepoxide (a benzodiazepine derivative) using the brand name Librax.
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Treatment in a quiet intensive care unit with sufficient light is often recommended. Benzodiazepines are the medication of choice with diazepam, lorazepam, chlordiazepoxide, and oxazepam all commonly used. They should be given until a person is lightly sleeping. The antipsychotic haloperidol may also be used.
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In tests in pentobarbital trained rhesus monkeys benzodiazepines produced effects similar to barbiturates. In a 1991 study, triazolam had the highest self-administration rate in cocaine trained baboons, among the five benzodiazepines examined: alprazolam, bromazepam, chlordiazepoxide, lorazepam, triazolam. A 1985 study found that triazolam and temazepam maintained higher rates of self-injection in both human and animal subjects compared to a variety of other benzodiazepines (others examined: diazepam, lorazepam, oxazepam, flurazepam, alprazolam, chlordiazepoxide, clonazepam, nitrazepam, flunitrazepam, bromazepam, and clorazepate). A 1991 study indicated that diazepam, in particular, had a greater abuse liability among people who were drug abusers than did many of the other benzodiazepines.
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Chlordiazepoxide/clidinium bromide is indicated to control emotional and somatic factors in gastrointestinal disorders. It may also be used as adjunctive therapy in the treatment of peptic ulcer and in the treatment of the irritable bowel syndrome (irritable colon, spastic colon, mucous colitis) and acute enterocolitis.
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Used in fixed combination with chlordiazepoxide in the treatment of functional GI motility disturbances (e.g., irritable bowel syndrome). Has limited efficacy in treatment of GI motility disturbance and should only be used if other measures (e.g., diet, sedation, counseling, amelioration of environmental factors) have been of little or no benefit.
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This compound, later named chlordiazepoxide, had not been tested in 1955 because of Sternbach's focus on other issues. Expecting pharmacology results to be negative, and hoping to publish the chemistry-related findings, researchers submitted it for a standard battery of animal tests. The compound showed very strong sedative, anticonvulsant, and muscle relaxant effects.
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Tolerance to the anticonvulsant effects of clonazepam occurs in both animals and humans. In humans, tolerance to the anticonvulsant effects of clonazepam occurs frequently. Chronic use of benzodiazepines can lead to the development of tolerance with a decrease of benzodiazepine binding sites. The degree of tolerance is more pronounced with clonazepam than with chlordiazepoxide.
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5 mg Valium Roche packaging Australia Diazepam is a long-acting "classical" benzodiazepine. Other classical benzodiazepines include chlordiazepoxide, clonazepam, lorazepam, oxazepam, nitrazepam, temazepam, flurazepam, bromazepam, and clorazepate. Diazepam has anticonvulsant properties. Benzodiazepines act via micromolar benzodiazepine binding sites as calcium channel blockers and significantly inhibit depolarization-sensitive calcium uptake in rat nerve cell preparations.
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The structure that the first benzodiazepine is based on was discovered by Leo H. Sternbach. He thought the compound had a heptoxdiazine structure (Figure 7) but it was later determined to be a quinazoline-3-oxide. Possible drug candidates were then synthesized from that compound and screened for activity. One of these compounds was active, chlordiazepoxide.
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Used in fixed combination with chlordiazepoxide as adjunctive therapy in the treatment of peptic ulcer disease; however, no conclusive data that antimuscarinics aid in the healing, decrease the rate of recurrence, or prevent complications of peptic ulcers. With the advent of more effective therapies for the treatment of peptic ulcer disease, antimuscarinics have only limited usefulness in this condition.
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Clorazepate is a "classical" benzodiazepine. Other classical benzodiazepines include chlordiazepoxide, diazepam, clonazepam, oxazepam, lorazepam, nitrazepam, bromazepam and flurazepam. Clorazepate is a long-acting benzodiazepine drug. Clorazepate produces the active metabolite desmethyl-diazepam, which is a partial agonist of the GABAA receptor and has a half life of 20 – 179 hours; a small amount of desmethyldiazepam is further metabolised into oxazepam.
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Nordazepam (INN; marketed under brand names Nordaz, Stilny, Madar, Vegesan, and Calmday; also known as nordiazepam, desoxydemoxepam, and desmethyldiazepam) is a 1,4-benzodiazepine derivative. Like other benzodiazepine derivatives, it has amnesic, anticonvulsant, anxiolytic, muscle relaxant, and sedative properties. However, it is used primarily in the treatment of anxiety disorders. It is an active metabolite of diazepam, chlordiazepoxide, clorazepate, prazepam, pinazepam, and medazepam.
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Benzodiazepine derivatives are the pivotal structural elements of breakthrough CNS Drugs, such as Librium (chlordiazepoxide) and Valium (diazepam). Pyridine derivatives are found in both well-known Diquat and Chlorpyrifos herbicides, and in modern nicotinoid insecticides, such as Imidacloprid. Even modern pigments, such as diphenylpyrazolopyrazoles, quinacridones, and engineering plastics, such as polybenzimidazoles, polyimides, and triazine resins, exhibit an N-heterocyclic structure.
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Benzodiazepines with a half-life of more than 24 hours include chlordiazepoxide, diazepam, clobazam, clonazepam, chlorazepinic acid, ketazolam, medazepam, nordazepam, and prazepam. Benzodiazepines with a half-life of less than 24 hours include alprazolam, bromazepam, brotizolam, flunitrazepam, loprazolam, lorazepam, lormetazepam, midazolam, nitrazepam, oxazepam, and temazepam. The resultant equivalent dose is then gradually reduced. The consensus is to reduce dosage gradually over several weeks, e.g.
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Chlordiazepoxide, 5 mg capsules, are sometimes used as an alternative to diazepam for benzodiazepine withdrawal. Like diazepam, it has a long elimination half-life and long-acting active metabolites. Management of benzodiazepine dependence involves considering the person's age, comorbidity and the pharmacological pathways of benzodiazepines. Psychological interventions may provide a small but significant additional benefit over gradual dose reduction alone at post- cessation and at follow-up.
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A 1995 study found that temazepam is more rapidly absorbed and oxazepam is more slowly absorbed than most other benzodiazepines. A 1985 study found that temazepam and triazolam maintained significantly higher rates of self-injection than a variety of other benzodiazepines. The study tested and compared the abuse liability of temazepam, triazolam, diazepam, lorazepam, oxazepam, flurazepam, alprazolam, chlordiazepoxide, clonazepam, nitrazepam, flunitrazepam, bromazepam, and clorazepate.
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Demoxepam is also an intermediate in the synthesis of oxazepam; it is also used in one of the syntheses of medazepam. It can be considered directly analogous/synonoymous with the synthesis of chlordiazepoxide, with the exception that instead of methylamine, hydroxide ion is the choice of base; here acid is not used for the cyclodehydration step though. Demoxepam synthesis: Reeder Earl, Sternbach Leo Henryk, (1959 to Hoffmann La Roche).
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As of September 2018, amitriptyline was marketed under many brand names worldwide alone and as a combination drug with each of chlordiazepoxide, perphenazine, and medazepam. Brands include Adepril, ADT, Ambival, Amicon, Amilavil, Amilin, Amiline, Amineurin, Amiplin, Amirol, Amit, Amitin, Amitone, Amitrac, Amitrip, Amitriptilina, Amitriptilino, Amitriptilins, Amitriptine, Amitriptylin, Amitriptyline, Amitriptylinhydrochlorid, Amitriptylini, Amitriptylinum, Amitryp, Amotrip, Amyline, Amypres, Amytril, Amyzol, Anapsique, Arpidox, Deprelio, Elatrol, Elatrolet, Elavil, Endep, Fiorda, Laroxyl, Latilin, Levate, Maxitrip, Maxivalet, Mitryp, Modup, Normaln, Odep, Pinsaun, Polytanol, Protanol, Qualitriptine, Redomex, Saroten, Sarotex, Stelminal, Syneudon, Teperin, Trepiline, Triamyl, Trilin, Trip, Tripta, Triptiline, Triptizol, Triptric, Triptyl, Triptyline, Tripyline, Trynol, Tryptalgin, Tryptanol, Tryptin, Tryptizol, Tryptomer, and Vanatrip. Brands as of that date for the combination with chlordiazepoxide included Amicon Forte, Amitrac-CZ, Amypres-C, Antalin, Antalin Forte, Arpidox-CP, Axeptyl, Diapatol, Diaztric-A, Emotrip, Klotriptyl, Libotryp, Limbatril, Limbitrol, Limbitryl, Limbival, Limbritol, Maxitrip-CZ, Mitryp Forte, Morelin, Ristryl, and Sedans. Brands as of that date for the combination with perphenazine included Levazine, Minitran, Mutabase, Mutabon, Pertriptyl, Triavil, and Triptafen.
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Title page of the Canadian Medical Association Journal including Le Vann's article, Chlordiazepoxide, a tranquillizer with anticonvulsant properties Canadian Medical Association Journal, 86, 123-125. During the years that Le Vann Worked at the school, he published a number of documents ranging over many topics. The majority of his work, however, was focused on the antipsychotic drugs.Le Vann, L. J. (1953). Controlling unpleasant odors among mental patients Hospitals, 27(2), 93-94.
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Finally, Le Vann illustrates that cultures with strong father figures are less likely to resort to alcohol and to lead a life of alcoholism. Le Vann also researched the effectiveness of drugs such as chlordiazepoxide, chlorpromazine, haperidol, trifluperidol, and trifluoperazine dihyrochloride. In his 1959 article Trifluoperazine Dihyrochloride: an effective tranquillizing agent for behavioural abnormalities in defective children, Le Vann treated 33 patients. These consisted of "14 idiots, 14 imbeciles and two morons".
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According to the British National Formulary, it is better to withdraw too slowly rather than too quickly from benzodiazepines. The rate of dosage reduction is best carried out so as to minimize the symptoms' intensity and severity. Anecdotally, a slow rate of reduction may reduce the risk of developing a severe protracted syndrome. Long half-life benzodiazepines like diazepam or chlordiazepoxide are preferred to minimize rebound effects and are available in low dose forms.
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A further benefit is that it is available in liquid form, which allows for even smaller reductions. Chlordiazepoxide, which also has a long half-life and long-acting active metabolites, can be used as an alternative. Nonbenzodiazepines are contraindicated during benzodiazepine withdrawal as they are cross tolerant with benzodiazepines and can induce dependence. Alcohol is also cross tolerant with benzodiazepines and more toxic and thus caution is needed to avoid replacing one dependence with another.
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On August 13, 2007, Adams was found unconscious by his wife at their Tampa, Florida home. The medical examiner concluded that the cause of death was a result of mixing the painkiller buprenorphine with the muscle relaxant carisoprodol and the sedatives chlordiazepoxide and alprazolam. The coroner determined the drugs in his system were individually at therapeutic levels, but their combination impeded his respiratory system enough to kill him. He was 43 years old.
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50 Pills of Lexotanil (containing 6 mg of Bromezepam apiece) as sold by Hoffmann-La Roche in Germany Bromazepam is a "classical" benzodiazepine; other classical benzodiazepines include: diazepam, clonazepam, oxazepam, lorazepam, chlordiazepoxide, nitrazepam, flurazepam, and clorazepate. Its molecular structure is composed of a diazepine connected to a benzene ring and a pyridine ring, the benzene ring having a single nitrogen atom that replaces one of the carbon atoms in the ring structure.Bromazepam Eutimia.com - Salud Mental.
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Shorter-acting benzodiazepines are often preferred for insomnia due to their lesser hangover effect. It is fairly important to note that elimination half-life of diazepam and chlordiazepoxide, as well as other long half-life benzodiazepines, is twice as long in the elderly compared to younger individuals. Individuals with an impaired liver also metabolize benzodiazepines more slowly. Many doctors make the mistake of not adjusting benzodiazepine dosage according to age in elderly patients.
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Iclazepam (Clazepam) is a drug which is a benzodiazepine derivative. It has sedative and anxiolytic effects similar to those produced by other benzodiazepine derivatives, and is around the same potency as chlordiazepoxide. Iclazepam is a derivative of nordazepam substituted with a cyclopropylmethoxyethyl group on the N1 nitrogen. Once in the body, iclazepam is quickly metabolised to nordazepam and its N-(2-hydroxyethyl) derivative, which are thought to be mainly responsible for its effects.
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The Central Narcotics Bureau of Singapore seized 94,200 nimetazepam tablets in 2003. This is the largest nimetazepam seizure recorded since nimetazepam became a controlled drug under the Misuse of Drugs Act in 1992. In Singapore nimetazepam is a Class C controlled drug. In Hong Kong abuse of prescription medicinal preparations continued in 2006 and seizures of midazolam (120,611 tablets), nimetazepam/nitrazepam (17,457 tablets), triazolam (1,071 tablets), diazepam (48,923 tablets) and chlordiazepoxide (5,853 tablets) were made.
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It can be too difficult to withdraw from short- or intermediate-acting benzodiazepines because of the intensity of the rebound symptoms felt between doses. Moreover, short-acting benzodiazepines appear to produce a more intense withdrawal syndrome. For this reason, discontinuation is sometimes carried out by first substituting an equivalent dose of a short-acting benzodiazepine with a longer-acting one like diazepam or chlordiazepoxide. Failure to use the correct equivalent amount can precipitate a severe withdrawal reaction.
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Chlordiazepoxide 5 mg capsules, which are sometimes used as an alternative to diazepam for benzodiazepine withdrawal. Like diazepam it has a long elimination half-life and long-acting active metabolites. Discontinuation of benzodiazepines or abrupt reduction of the dose, even after a relatively short course of treatment (two to four weeks), may result in two groups of symptoms—rebound and withdrawal. Rebound symptoms are the return of the symptoms for which the patient was treated but worse than before.
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The possibility of using lofexidine to treat alcohol withdrawal symptoms has been investigated, and has not yet been shown to be an effective treatment.Keaney F, Strang J, Gossop M, Marshall EJ, Farrell M, Welch S, Hahn B, Gonzalez A. A double-blind randomized placebo-controlled trial of lofexidine in alcohol withdrawal: lofexidine is not a useful adjunct to chlordiazepoxide. Alcohol Alcohol (2001) 36:426–30. It is also used in treatment of cases suffering from postmenopausal hot flashes.
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Therefore, gradual reduction is recommended, titrated against withdrawal symptoms. For withdrawal purposes, stabilisation with a long-acting agent such as diazepam is recommended before commencing withdrawal. Chlordiazepoxide (Librium), a long-acting benzodiazepine, is gaining attention as an alternative to diazepam in substance abusers dependent on benzodiazepines due to its decreased abuse potential. In individuals dependent on benzodiazepines who have been using benzodiazepines long-term, taper regimens of 6–12 months have been recommended and found to be more successful.
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Benzodiazepines are the most commonly used medication for the treatment of alcohol withdrawal and are generally safe and effective in suppressing symptoms of alcohol withdrawal. This class of medication is generally effective in symptoms control, but need to be used carefully. Although benzodiazepines have a long history of successfully treating and preventing withdrawal, there is no consensus on the ideal one to use. The most commonly used agents are long-acting benzodiazepines, such as chlordiazepoxide and diazepam.
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Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of psychoactive drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. The first such drug, chlordiazepoxide (Librium), was discovered accidentally by Leo Sternbach in 1955, and made available in 1960 by Hoffmann–La Roche, which, since 1963, has also marketed the benzodiazepine diazepam (Valium). In 1977 benzodiazepines were globally the most prescribed medications. They are in the family of drugs commonly known as minor tranquilizers.
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Diazepam was the second benzodiazepine invented by Leo Sternbach of Hoffmann-La Roche at the company's Nutley, New Jersey, facility following chlordiazepoxide (Librium), which was approved for use in 1960. Released in 1963 as an improved version of Librium, diazepam became incredibly popular, helping Roche to become a pharmaceutical industry giant. It is 2.5 times more potent than its predecessor, which it quickly surpassed in terms of sales. After this initial success, other pharmaceutical companies began to introduce other benzodiazepine derivatives.
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Abrupt withdrawal from therapeutic doses of temazepam after long-term use may result in a severe benzodiazepine withdrawal syndrome. Gradual and careful reduction of the dosage, preferably with a long-acting benzodiazepine with long half-life active metabolites, such as chlordiazepoxide or diazepam, are recommended to prevent severe withdrawal syndromes from developing. Other hypnotic benzodiazepines are not recommended. A study in rats found temazepam is cross tolerant with barbiturates and is able to effectively substitute for barbiturates and suppress barbiturate withdrawal signs.
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Some of the available data also suggested that lorazepam and alprazolam are more diazepam-like in having relatively high abuse liability, while oxazepam, halazepam, and possibly chlordiazepoxide, are relatively low in this regard. A 1991–1993 British study found that the hypnotics flurazepam and temazepam were more toxic than average benzodiazepines in overdose. A 1995 study found that temazepam is more rapidly absorbed and oxazepam is more slowly absorbed than most other benzodiazepines. Benzodiazepines have been abused both orally and intravenously.
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The safety profile of clonazepam during pregnancy is less clear than that of other benzodiazepines, and if benzodiazepines are indicated during pregnancy, chlordiazepoxide and diazepam may be a safer choice. The use of clonazepam during pregnancy should only occur if the clinical benefits are believed to outweigh the clinical risks to the fetus. Caution is also required if clonazepam is used during breastfeeding. Possible adverse effects of use of benzodiazepines such as clonazepam during pregnancy include: miscarriage, malformation, intrauterine growth retardation, functional deficits, carcinogenesis, and mutagenesis.
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In a study in rats, cross-tolerance between the benzodiazepine drug chlordiazepoxide and bretazenil has been demonstrated. In a primate study bretazenil was found to be able to replace the full agonist diazepam in diazepam dependent primates without precipitating withdrawal effects, demonstrating cross tolerance between bretazenil and benzodiazepine agonists, whereas other partial agonists precipitated a withdrawal syndrome. The differences are likely due to differences in instrinsic properties between different benzodiazepine partial agonists. Cross-tolerance has also been shown between bretazenil and full agonist benzodiazepines in rats.
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While working for Hoffmann- La Roche in Nutley, New Jersey, Sternbach did significant work on new drugs. He is credited with the discovery of chlordiazepoxide (Librium), diazepam (Valium), flurazepam (Dalmane), nitrazepam (Mogadon), flunitrazepam (Rohypnol), clonazepam (Klonopin), and trimethaphan (Arfonad). Librium, based on the R0 6-690 compound discovered by Sternbach in 1956, was approved for use in 1960. In 1963, its improved version, Valium, was released and became astonishingly popular: between 1969 and 1982, it was the most prescribed drug in America, with over 2.3 billion doses sold in its peak year of 1978.
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Variation in potency of certain effects may exist amongst individual benzodiazepines. Some benzodiazepines produce active metabolites. Active metabolites are produced when a person's body metabolizes the drug into compounds that share a similar pharmacological profile to the parent compound and thus are relevant when calculating how long the pharmacological effects of a drug will last. Long- acting benzodiazepines with long-acting active metabolites, such as diazepam and chlordiazepoxide, are often prescribed for benzodiazepine or alcohol withdrawal as well as for anxiety if constant dose levels are required throughout the day.
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Part of the success was attributed to the placebo method used for part of the trial which broke the psychological dependence on benzodiazepines when the elderly patients realised they had completed their gradual reduction several weeks previously, and had only been taking placebo tablets. This helped reassure them they could sleep without their pills. The authors also warned of the similarities in pharmacology and mechanism of action of the newer nonbenzodiazepine Z drugs. The elimination half-life of diazepam and chlordiazepoxide, as well as other long half-life benzodiazepines, is twice as long in the elderly compared to younger individuals.
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Chlordiazepoxide is the most commonly used benzodiazepine for alcohol detoxification, but diazepam may be used as an alternative. Both are used in the detoxification of individuals who are motivated to stop drinking, and are prescribed for a short period of time to reduce the risks of developing tolerance and dependence to the benzodiazepine medication itself. The benzodiazepines with a longer half-life make detoxification more tolerable, and dangerous (and potentially lethal) alcohol withdrawal effects are less likely to occur. On the other hand, short-acting benzodiazepines may lead to breakthrough seizures, and are, therefore, not recommended for detoxification in an outpatient setting.
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Direct intraspinal injection of the catecholamines epinephrine and norepinephrine, and the α-adrenergic agents dexmedetomidine and clonidine, produce a dose-dependent elevation of pain thresholds in the Northern leopard frog (Rana pipiens). This analgesia occurs without accompanying motor or sedative effects. A range of non-opioid drugs administered through the dorsal lymph sac of Northern leopard frogs has demonstrable analgesic effects, established by using the acetic acid test. Chlorpromazine and haloperidol (antipsychotics), chlordiazepoxide (a benzodiazepine) and diphenhydramine (a histamine antagonist) produced moderate to strong analgesic effects, whereas indomethacin and ketorolac (NSAIDs), and pentobarbital (a barbiturate) produced weaker analgesic effects.
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The risk factors for benzodiazepine dependence are long-term use beyond four weeks, use of high doses, use of potent short-acting benzodiazepines, dependent personalities, and proclivity for drug abuse. Use of short-acting benzodiazepines leads to repeated withdrawal effects that are alleviated by the next dose, which reinforce in the individual the dependence. A physical dependence develops more quickly with higher potency benzodiazepines such as alprazolam (Xanax) than with lower potency benzodiazepines such as chlordiazepoxide (Librium). Symptom severity is worse with the use of high doses, or with benzodiazepines of high potency or short half-life.
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Cases of intentional suicide by overdose using etizolam in combination with GABA agonists have been reported. Although etizolam has a lower LD50 than certain benzodiazepines, the LD50 is still far beyond the prescribed or recommended dose. Flumazenil, a GABA antagonist agent used to reverse benzodiazepine overdoses, inhibits the effect of etizolam as well as classical benzodiazepines such as diazepam and chlordiazepoxide. Etizolam overdose deaths are rising - for instance, the National Records of Scotland report on drug-related deaths, implicated 548 deaths from 'street' Etizolam in 2018, almost double the number from 2017 (299) and only six years from the first recorded death (in 2012).
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4 or more weeks for diazepam doses over 30 mg/day, with the rate determined by the person's ability to tolerate symptoms. cited The recommended reduction rates range from 50% of the initial dose every week or so, cited to 10-25% of the daily dose every 2 weeks. For example, the reduction rate used in the Heather Ashton protocol calls for eliminating 10% of the remaining dose every two to four weeks, depending on the severity and response to reductions with the final dose at 0.5 mg dose of diazepam or 2.5 mg dose of chlordiazepoxide. For most people, discontinuation over 4-6 weeks or 4-8 weeks is suitable.
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These impressive clinical findings led to its speedy introduction throughout the world in 1960 under the brand name Librium. Following chlordiazepoxide, diazepam marketed by Hoffmann–La Roche under the brand name Valium in 1963, and for a while the two were the most commercially successful drugs. The introduction of benzodiazepines led to a decrease in the prescription of barbiturates, and by the 1970s they had largely replaced the older drugs for sedative and hypnotic uses. The new group of drugs was initially greeted with optimism by the medical profession, but gradually concerns arose; in particular, the risk of dependence became evident in the 1980s.
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NS-2710 (LS-193,970) is an anxiolytic drug with a novel chemical structure, developed by the small pharmaceutical company NeuroSearch. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic. NS-2710 is a potent but non- selective partial agonist at GABAA receptors, although with little efficacy at the α1 subtype and more at α2 and α3. It has anxiolytic effects comparable to chlordiazepoxide, and while it is a less potent anticonvulsant than the related drug NS-2664, it has a much longer duration of action, and similarly to other α2/α3-preferring partial agonists produces little sedative effects or physical dependence.
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This gives it selective anxiolytic effects, which are mediated mainly by α2 and α3 subtypes, but with little sedative or amnestic effects as these effects are mediated by α1. Some sedation might still be expected due to its activity at the α5 subtype, which can also cause sedation, however no sedative effects were seen in animal studies even at high doses, suggesting that L-838,417 is primarily acting at α2 and α3 subtypes with the α5 subtype of lesser importance. As might be predicted from its binding profile, L-838,417 substitutes for the anxiolytic benzodiazepine chlordiazepoxide in animals, but not for the hypnotic imidazopyridine drug zolpidem.
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SL651498 is a subtype-selective GABAA agonist, which acts as a full agonist at α2 and α3 subtypes, and as a partial agonist at α1 and α5 (although its action at α5 subtypes is much weaker than at the others). In animal studies, it has primarily anxiolytic effects, although some sedation, ataxia and muscle relaxant effects are observed at higher doses. It substitutes fully for the anxiolytic benzodiazepine chlordiazepoxide, but only partially substituted for the imidazopyridine hypnotic drug zolpidem and the benzodiazepine hypnotic triazolam. When given repeatedly it failed to produce tolerance or dependence, probably due to its low affinity and efficacy at the α5 subtype.
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Nonbenzodiazepines should not be discontinued abruptly if taken for more than a few weeks due to the risk of rebound withdrawal effects and acute withdrawal reactions, which may resemble those seen during benzodiazepine withdrawal. Treatment usually entails gradually reducing the dosage over a period of weeks or several months depending on the individual, dosage, and length of time the drug has been taken. If this approach fails, a crossover to a benzodiazepine equivalent dose of a long-acting benzodiazepine (such as chlordiazepoxide or more preferably diazepam) can be tried followed by a gradual reduction in dosage. In extreme cases and, in particular, where severe addiction and/or abuse is manifested, an inpatient detoxification may be required, with flumazenil as a possible detoxification tool.
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Very limited evidence indicates that topiramate or pregabalin may be useful in the treatment of alcohol withdrawal syndrome. Limited evidence supports the use of gabapentin or carbamazepine for the treatment of mild or moderate alcohol withdrawal as the sole treatment or as combination therapy with other medications; however, gabapentin does not appear to be effective for treatment of severe alcohol withdrawal and is therefore not recommended for use in this setting. A 2010 Cochrane review similarly reported that the evidence to support the role of anticonvulsants over benzodiazepines in the treatment of alcohol withdrawal is not supported. Paraldehyde combined with chloral hydrate showed superiority over chlordiazepoxide with regard to life-threatening side effects and carbamazepine may have advantages for certain symptoms.
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In 1965, Monroe and Wise reported using primidone along with a phenothiazine derivative antipsychotic and chlordiazepoxide in treatment-resistant psychosis. What is known is that ten years later, Monroe went on to publish the results of a meta-analysis of two controlled clinical trials on people displaying out-of-character and situationally inappropriate aggression, who had abnormal EEG readings, and who responded poorly to antipsychotics; one of the studies was specifically mentioned as involving psychosis patients. When they were given various anticonvulsants not only did their EEGs improve, but so did the aggression. In March 1993, S.G. Hayes of the University of Southern California School of Medicine reported that nine out of twenty-seven people (33%) with either treatment-resistant depression or treatment-resistant bipolar disorder had a permanent positive response to primidone.
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Failing that, an alternative method may be necessary for some people, such as a switch to a benzodiazepine equivalent dose of a longer-acting benzodiazepine drug, as for diazepam or chlordiazepoxide, followed by a gradual reduction in dose of the long-acting benzodiazepine. In people who are difficult to treat, an inpatient flumazenil administration allows for rapid competitive binding of flumazenil to GABAA–receptor as an antagonist, thus stopping (a effectively detoxifying) zolpidem from being able to bind as an agonist on GABAA–receptor; slowly drug dependence or addiction to zolpidem will wane. Alcohol has cross tolerance with GABAA receptor positive allosteric modulators, such as the benzodiazepines and the nonbenzodiazepine drugs. For this reason, alcoholics or recovering alcoholics may be at increased risk of physical dependency or abuse of zolpidem.
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An example in case is F.I.S., Italy, which partnered with Roche, Switzerland for custom manufacturing precursors of the benzodiazepine class of tranquilizers, such as Librium (chlordiazepoxide HCl) and Valium (diazepam). The growing complexity and potency of new pharmaceuticals and agrochemicals requiring production in multipurpose, instead of dedicated plants and, more recently, the advent of biopharmaceuticals had a major impact on the demand for fine chemicals and the evolution of the fine chemical industry as a distinct entity. For many years, however, the life science industry continued considering captive production of the active ingredients of their drugs and agrochemicals as a core competency. Outsourcing was recurred to only in exceptional cases, such as capacity shortfalls, processes requiring hazardous chemistry or new products, where uncertainties existed about the chance of a successful launch.
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Xanax (alprazolam) 2 mg tri-score tablets A benzodiazepine (sometimes colloquially "benzo"; often abbreviated "BZD") is a drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring. The first such drug, chlordiazepoxide (Librium), was discovered accidentally by Leo Sternbach in 1955, and made available in 1960 by Hoffmann–La Roche, which has also marketed the benzodiazepine diazepam (Valium) since 1963. Benzodiazepines enhance the effect of the neurotransmitter gamma-aminobutyric acid (GABA) at the GABAA receptor, resulting in sedative, hypnotic (sleep-inducing), anxiolytic (anti-anxiety), anticonvulsant, and muscle relaxant properties; also seen in the applied pharmacology of high doses of many shorter-acting benzodiazepines are amnesic- dissociative actions. These properties make benzodiazepines useful in treating anxiety, insomnia, agitation, seizures, muscle spasms, alcohol withdrawal and as a premedication for medical or dental procedures.
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