Hypnotics development

An interesting set of central nervous system properties has also been discovered and studied (Table VI-10). The work devoted to piscaine must be emphasized besides finding hypnotic properties of 2-amino-4-phenyl-thiazole on fish, the authors studied the structure of the metabolite, as well as the localization of the (radio labeled) metabolic product in various organs. Recently, thiazol-4-yl methoxyamine was shown to inhibit the development of morphine tolerance (1607). 5-Aminothiazole derivatives such as 419a were proposed as cardiovascular agents (1608, 1610). Substitution of the 5-aminothiazole radical on the cephalophosphorin structure gives a series of antibacterial products (1609). 

Barbituric acid was first pre pared in 1864 by Adolf von Baeyer (page 112) A histori cal account of his work and the later development of barbiturates as sedative-hypnotics appeared in the October 1951 issue of the Journal of Chemical Education (pp 524-526)... 

The CCK system shares one property with the opioid system, ie, the existence of selective nonpeptide antagonists. These include aspedicine, a natural benzodiazepine (136), and Devazepide (L-364,718 MK-329) (137). Selective, potent peptide antagonists for CCK, eg, Cl-988 and PD 134308, have been developed that maybe useful as anxiolytics and as dmgs which increase the analgesic effect of morphine but at the same time prevent morphine tolerance (138) (see Hypnotics, sedatives, anticonvulsants, and anxiolytics). 

Other apphcations of sodium bromide iaclude use ia the photographic iadustry both to make light-sensitive silver bromide [7785-23-1] emulsions and to lower the solubiUty of silver bromides during the developing process use as a wood (qv) preservative in conjunction with hydrogen peroxide (14) as a cocatalyst along with cobalt acetate [917-69-1] for the partial oxidation of alkyl side chains on polystyrene polymers (15) and as a sedative, hypnotic, and anticonvulsant. The FDA has, however, indicated that sodium bromide is ineffective as an over-the-counter sleeping aid for which it has been utilized (16). 

Heaven Hill hired Nick Storm, too. Mr. Storm, who spent six years as a promoter at Sony Music, is the man who developed the original strategy to introduce the Hpnotiq (pronounced hypnotic ) brand. 

Glutethimide (3-ethyl-3-phenyl-2,6-piperidinedione) is a sedative-hypnotic drug that is now rarely used therapeutically because of wide variation in gastrointestinal absorption, fast development of pharmacodynamic tolerance, a fairly severe discontinuation syndrome, and potential for abuse. Reports of... 

Tolerance to hypnotic effects develops after 2 weeks of continuous use of triazolam. Efficacy offlurazepam, quazepam, and temazepam lasts for at least 1 month of continuous nightly use. Estazolam reportedly maintains efficacy at maximum dosage (2 mg nightly) for up to 12 weeks. 

Sleep is another concern during maintenance therapy. As we noted in the discussion of acute phase treatment, sleep deprivation can destabilize mood and is often the first sign of an impending episode of illness. Therefore, it remains imperative that the patient sleeps well. It is common practice for patients to keep a small supply of a hypnotic agent such as zolpidem or a benzodiazepine to use as needed in the event of sleep disturbance. Furthermore, patients should routinely be advised to notify their physician should they have two or more consecutive nights of poor sleep so that more aggressive measures can be taken to circumvent the possible development of an illness episode. 

Like the barbiturates, the benzodiazepines make it easier to fall asleep and to stay asleep through the night. However, they also suppress REM sleep, which can lead to REM rebound when they are discontinued. Tolerance to their sleep-promoting effects often develops after chronic use. Some long-acting benzodiazepines, such as flurazepam (Dalmane), are associated with pronounced hangover effects in the morning and are therefore problematic as sedative-hypnotics. Others, with a short-to-intermediate dnration of action, are more desirable as hypnotics. 

The development of tolerance is a major drawback to the use of benzodiazepines in the long-term treatment of insomnia. Whereas tolerance to the hypnotic effects of benzodiazepines permits them to be used without excessive sedation when treating anxiety disorders, this is counterproductive when attempting to treat insomnia. Patients often find themselves requiring higher doses to obtain the same sedative-hypnotic effect initially accomplished by lower doses. For this reason, careful consideration must be given before benzodiazepines are used to treat chronic insomnia. 

Use of a hypnotic drug should not be extended beyond 4 wk, because tolerance may develop. The risk of a rebound decrease in sleep propensity after drug withdrawal may be avoided by tapering off the dose over 2 to 3 wk. 

The development of the benzodiazepine class of drugs for the treatment of a variety of neurological indications has proven to be an outstanting success story in the field of chemotherapy. However, these compounds often produce undesirable side effects when used as anti-anxiety or hypnotic agents. These side effects include sedation, physical dependence, amnesia, muscle relaxation, and ethanol potentiation. The development of a benzodiazepine receptor-based anxiolytic agent devoid of these side effects would constitute a major advance in the field and has been the focus of significant research efforts [284]. 

The sedative hypnotic ethchlorvynol has approximately the same activity and toxicity as phenobarbital however, its hypnotic effect develops and dissipates qnicker. It is nsed mnch less than benzodiazepines in treating insomnia for a nnmber of reasons. 

The second catastrophe that influenced the development of medicines regulation far more than any event in history was the thalidomide disaster. Thalidomide was a sedative and hypnotic that first went on sale in Western Germany in 1956. Between 1958 and 1960 it was introduced in 46 different countries worldwide resulting in an estimated 10,000 babies being born with phocomelia and other... 

Related hypnotics that also act at benzodiazepine receptors are the newer agents zolpidem, a imida-zopyridine, zaleplon a pyrazolopyrimidine and the cyclopyrrolone zopiclone. Zopiclone might have a role for the treatment of benzodiazepine addiction. In patients in whom zopiclone was substituted for a benzodiazepine for 1 month and then itself abmptly terminated, improved sleep was reported during the zopiclone treatment, and withdrawal effects were absent on discontinuation of zopiclone. A series of non-sedating anxiolytic drugs derived from the same structural families as the above mentioned nonbenzodiazepines, have been developed, such as alpi-dem and pagoclone. 

Buspirone is as effective as the benzodiazepines in the treatment of general anxiety. However, the full anxiolytic effect of buspirone takes several weeks to develop, whereas the anxiolytic effect of the benzodiazepines is maximal after a few days of therapy. In therapeutic doses, buspirone has little or no sedative effect and lacks the muscle relaxant and anticonvulsant properties of the benzodiazepines. In addition, buspirone does not potentiate the central nervous system depression caused by sedative-hypnotic drugs or by alcohol, and it does not prevent the symptoms associated with benzodiazepine withdrawal. 

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