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Woods JH, Katz JL, Winger G. Benzodiazepines: use, abuse, and consequences. Pharmacol Rev 44: 151-347
... Because BDZs exhibit several unwanted side effects (e.g. sedative-myorelaxant effects at anxiolytic doses, amnesia, dependence and tolerance risks) [7], it is interesting to search for safer compounds. The development of selective BDZ-R type I ligands (e.g. ...
Flavonoids are naturally occurring molecules present in the human diet. We demonstrate that some flavonoids possess central nervous system effects, acting through the central benzodiazepine receptors. The pharmacological characterization of chrysin (5,7-dihydroxyflavone) and apigenin (5,7,4′-trihydroxyflavone), isolated from Passiflora coerulea and Matricaria recutita, respectively, showed their anxiolytic, but not myorelaxant or amnesic effects. Cirsiliol (5,3′,4′-trihydroxy-6,7-dimethoxyflavone), however, isolated from Salvia guaranitica, had sedative-depressant properties. We were able to increase the biochemical and pharmacological potency of the natural flavonoids by means of the addition of halo and/or nitro groups to the flavone nucleus. Some flavonoids are partial agonists of the benzodiazepine receptors and may become new therapeutic drugs, devoid of the unwanted side effects of classical benzodiazepines.
Most medications with major potential for abuse and addiction belong to the sedative-hypnotic class. This encompasses benzodiazepines, barbiturates, and the opiates (including natural and synthetic derivations of opium) (Jaffe, 1990; Jaffe & Martin, 1990; Rall, 1990). This chapter is devoted to the sedative-hypnotic class, featuring benzodiazepines and including other sedative-hypnotic medications. In 1826 bromides were the first sedatives after alcohol to be marketed specifically for the sedative-hypnotic effects. Next, barbituric acid was introduced in 1903 followed by chloral hydrate (“Mickey Finn”) in 1932 and meprobamate in 1955. Morphine was discovered in 1806, followed by codeine in 1832, then development of the synthetic derivatives of opiates in the mid 1900s.
Background - Benzodiazepines have been used with opiates to give better pain relief than opiates alone. However, the interaction between the two groups of drugs is controversial. The aim of this study was to investigate whether midazolam potentiated the antinociceptive effect of morphine. Methods - Male albino mice were used in this study. Antinociception was measured using the tail-flick test. Results - Midazolam and morphine caused dose-dependent antinociceptive effects in mice. The combination of midazolam and morphine showed an increase in analgesia. The benzodiazepine receptor antagonist, flumazenil, decreased the response induced by midazolam or midazolam plus morphine but not that of morphine alone. However, the opioid receptor antagonist naloxone, reduced the antinociception induced by morphine, midazolam, or a combination of the two drugs. Methysergide or propranolol increased the analgesic effect of midazolam; ketanserin, phenoxybenzamine and atropine did not. Conclusion - Midazolam induced antinociception through both benzodiazepine and opioid receptors.
Book published by the Swedish National Board of Forensic Medicine (Rättsmedicinalverket) in 2010.
The allostatic load model explains the additive effects of multiple biological processes that accelerate pathophysiology related to stress, particularly in the central nervous system. Stress-related mental conditions such as anxiety disorders and neuroticism (a well-known stress vulnerability factor), have been linked to disturbances of hypothalamo-pituitary-adrenal with cognitive implications. Nevertheless, there are controversial results in the literature and there is a need to determine the impact of the psychopharmacological treatment on allostatic load parameters and in cognitive functions. Gador study of Estres Modulation by Alprazolam, aims to determine the impact of medication on neurobiochemical variables related to chronic stress, metabolic syndrome, neurocognition and quality of life in patients with anxiety, allostatic load and neuroticism.
In this observational prospective phase IV study, highly sympthomatic patients with anxiety disorders (six or more points in the Hamilton-A scale), neuroticism (more than 18 points in the Neo five personality factor inventory (NEO-FFI) scale), an allostatic load (three positive clinical or biochemical items at Crimmins and Seeman criteria) will be included. Clinical variables of anxiety, neuroticism, allostatic load, neurobiochemical studies, neurocognition and quality of life will be determined prior and periodically (1, 2, 4, 8, and 12 weeks) after treatment (on demand of alprazolam from 0.75 mg/day to 3.0 mg/day). A sample of n=55/182 patients will be considered enough to detect variables higher than 25% (pretreatment vs post-treatment or significant correlations) with a 1-ß power of 0-80. t Test and/or non-parametric test, and Pearson's test for correlation analysis will be determined.
This study protocol was approved by an Independent Ethics Committee of FEFyM (Foundation for Pharmacological Studies and Drugs, Buenos Aires) and by regulatory authorities of Argentina (ANMAT, Dossier # 61 409-8 of 20 April 2009), following the law of Habeas Data and psychotherapeutic drug control.
GEMA 20811.
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Beginning with nitrazepam in the early 1960s, the class of drugs acting as benzodiazepine (BZ) receptor agonists has become the principal therapeutic option for the pharmacologic treatment of insomnia. With the development of analytic techniques to measure plasma drug concentrations, along with the more general application of pharmacokinetic methodologies, understanding of the pharmacokinetic determinants of hypnotic drug action has progressed along with the development and clinic use of a series of BZ agonist hypnotics. Absorption rate is a key determinant of the onset of drug action and the effectiveness of a hypnotic in shortening sleep latency. Rapid absorption implies high maximum plasma concentrations and short times to reach the maximum, thereby increasing the probability of rapid-onset effects. Elimination half-life is a determinant of the duration of action and a hypnotic drug’s efficacy in prolonging sleep duration and reducing early morning awakening. However, half-life may not directly predict duration of action, since some rapidly absorbed drugs may have action terminated by distribution rather than elimination. In any case, attaining a duration of action that is long enough to sustain sleep but not so long as to produce residual daytime sedation is a difficult objective. Dosage is a major determinant of pharmacodynamics that is often overlooked. Higher doses produce effects of more rapid onset, greater intensity, and longer duration. During multiple dosage with hypnotics, drug accumulation will occur if the drug’s elimination half-life exceeds the dosage interval (24h). This may lead to cumulative daytime sedative effects. In contemporary practice, short half-life BZ agonist hypnotics are most commonly prescribed. These have a low risk of daytime sedation and accumulation, but they must be tapered at the end of treatment to avoid rebound and other discontinuation effects. Ongoing pharmaceutical research has the objective of developing drug delivery innovations that can optimize hypnotic drug action by regulation of release and systemic exposure to short half-life BZ agonists.
Disturbances of sleep are commonly seen in many of the DSM-IV Axis I psychiatric disorders. Furthermore, psychiatric symptoms are commonly experienced in association with sleep disorders. This chapter reviews some basic physiology of sleep-wake regulation as well as the most common sleep disorders of importance to the practicing psychiatrist. Included are insomnia, restless legs syndrome, obstructive sleep apnea, narcolepsy, idiopathic and other hypersomnias, and parasomnias such as sleepwalking/sleep terrors and rapid eye movement (REM) sleep behavior disorder. In each case, diagnostic criteria are described, based both on the American Psychiatric Association Diagnostic and Statistical Manual, 4th edition, text revision (DSM-IV-TR) and the International Classification of Sleep Disorders, 2nd edition (ICSD-2). Discussions of epidemiology, clinical features, typical case examples, laboratory findings, course, differential diagnosis, etiology, and treatment considerations will enable the reader to recognize these disorders in their patients and to facilitate their treatment.
Behavioural toxicity is relatively common among medicinal drug users and evidence shows that drugs frequently produce adverse effects that prevent their users from performing everyday operations in a normal manner. Epidemiological research generally indicates that the use of sedative drugs is associated with an increased risk of becoming involved in injurious accidents. Empirical studies have also demonstrated adverse effects of sedative drugs on the performance of healthy volunteers and patients in laboratory tests designed to measure psycho-motor and cognitive function, and in real life-tests measuring on-the-road driving performance. Empirical studies also indicate that behavioural toxicity can vary widely between individual drugs depending on differences in dose, dosing regimen, duration of treatment, pharmacokinetics or mechanisms of actions. Besides sedation, other CNS adverse effects such as aggression, paranoia, social withdrawal or lack of motivation may disrupt or prevent the initiation of normal performance, thus imposing a burden on the ability of the patients to function in a normal manner. Emotional disturbances are rare as indicated by the small number of case reports that mention their existence. Yet theses disturbances sometimes involve severe reactions that are more debilitating than sedation. Behavioural toxicity can be minimised by avoidance of pharmacodynamic and pharmacokinetic drug interactions, adjustment of dosage regimens to a patient’s individual response to a drug, nocturnal administration of drugs that are expected to produce sedation and patient education on the potential risks of the drugs they receive. Much of this information can be gained from experimental literature comparing the effect of individual drugs on performance. Unfortunately this is presently incomplete, since most research on behavioural toxicity has been confined to psychiatric drugs. Yet, in the interest of the patient, it should be the responsibility of drug manufacturers and regulators to always identify problematic drugs.
Accidental epidemiology.in childhood: 293-301, Hum. GUEST, childhood
- Volans General
General VOLANS, G. N.: Accidental epidemiology.in childhood: 293-301, Hum. GUEST, childhood. V.S. G., survey. Toxicol. in In A. A. ANDVOLANS