Effects of chronic alprazolam treatment on plasma concentrations of glucocorticoids,thyroid hormones,and testosterone in cardiomyopathic hamsters

In the first of two experiments, young male cardiomyopathic hamsters were injected intraperitoneally twice a day for 29 days with 8 mg alprazolam/kg body weight or saline. Three hours after the same injections on day 30, they were sacrificed and plasma hormone levels were measured. Alprazolam increased cortisol, total glucocorticoid and triiodothyronine levels. It did not affect corticosterone, thyroxine or testosterone levels. The same protocol was used in a second experiment, except the controls received vehicle and a third group was treated with 48 mg diazepam/kg body weight. Alprazolam again increased cortisol and total glucocorticoid levels, but not those of corticosterone. On the other hand, diazepam increased both cortisol and corticosterone levels. These experiments suggest that chronic benzodiazepine treatment can affect adrenocortical function and perhaps some aspects of thyroid function.     

Effect of chronic administration of alprazolam and adinazolam on clonidine- or apomorphine-induced aggression in laboratory rodents

The activity of chronic (3 weeks) treatment with the triazolobenzodiazepines, alprazolam and adinazolam, on clonidine- and apomorphine-induced aggression were studied. Adinazolam, like desipramine, potentiated aggression induced by clonidine while diazepam and alprazolam completely abolished it. In the apomorphine-induced aggression, adinazolam suppressed both aggressivity and stereotypy, while diazepam slightly potentiated it. Alprazolam did not modify the effect of aggression induced by apomorphine. On the whole, while adinazolam seemed to develop an activity closer to that of a classical antidepressant like desipramine, alprazolam appeared to be more similar to the benzodiazepines on clonidine-induced aggression in mice. Compared to desipramine and diazepam, adinazolam left these two effects induced by apomorphine almost unchanged. The experiments performed showed differences between the profiles of action of the two triazolobenzodiazepines studied.     

Antidepressant and anxiolytic effects of alprazolam versus the conventional antidepressant desipramine and the anxiolytic diazepam in the forced swim test in rats.

The antidepressant and anxiolytic effects of alprazolam were compared to those of desipramine, diazepam and buspirone in the forced swim test. Subchronic alprazolam induced a reduction in immobility similar to that of desipramine in 'non-pretested' and 'pretested' rats. In 'non-pretested' rats, the anti-immobility effect of desipramine was potentiated by diazepam and alprazolam, given before subchronic desipramine, while the anti-immobility effect of subchronic alprazolam was counteracted by diazepam. Diazepam, administered before the pretest session, counteracted, 24 h later, the anti-immobility effect of subchronic desipramine and alprazolam; alprazolam counteracted the anti-immobility effect of alprazolam but not of desipramine, buspirone at the highest doses tested potentiated the anti-immobility effect of subchronic desipramine but not of alprazolam. These data provide further support for the hypothesis that the GABA/benzodiazepine/Cl complex is directly implicated in the action of antidepressants and that systems other than the GABA system are involved in the antidepressant and anxiolytic effects of alprazolam.     

Discriminative stimulus effects of alprazolam and diazepam: generalization to benzodiazepines, antidepressants and buspirone

Rats in one group were trained to discriminate alprazolam (1.0mg/kg, i.p.) and in another group diazepam (3.0mg/kg, i.p.) from saline in a two-lever drug discrimination procedure. Food presentation occurred after 10 consecutive responses on the lever associated either with the training drug or with saline. Alprazolam, diazepam, lorazepam and chlor diazepoxide increased responding on the drug-associated lever in a comparable dose-related manner in both groups of rats: the relative order of potency was lorazepam >/= alprazolam > diazepam >/= chlordiazepoxide. Flumazenil (10.0mg/kg, i.p.) attenuated the effects of the training drugs. A range of doses of buspirone and four drugs having antidepressant properties (amitriptyline, fluoxetine, cericlamine, imipramine) then were studied in both groups of rats. All five drugs caused approximately 40% increases (group mean) in drug-appropriate responding in alprazolam-trained rats whereas only amitriptyline partially substituted for diazepam. The results indicate that alprazolam has interoceptive stimulus effects that overlap with the stimulus effects of diazepam, yet the effects of alprazolam may not be identical to those of diazepam because the antidepressant drugs and buspirone substituted partially for alprazolam but generally not for diazepam.     

A double blind comparison of alprazolam,diazepam and placebo in the treatment of anxious out-patients

The anxiolytic effects of alprazolam, a triazolobenzodiazepine, were evaluated in a double-blind 28-day comparison with diazepam and placebo in 46 out-patients suffering from anxiety states of moderate to severe intensity. Alprazolam 1.5-3 mg per day was found to be of at least equivalent anxiolytic effect to 15-30 mg diazepam per day, and there was evidence of antidepressant activity by alprazolam, but not diazepam, in neurotic depression. Side-effects occurred least often with alprazolam and were minor in nature. Laboratory data showed no changes attributable to alprazolam even in a patient who swallowed 15 capsules (7.5 mg). It was concluded that alprazolam is a safe and effective anxiolytic which is well-tolerated and also shows some antidepressant activity.     

Alprazolam and diazepam in the treatment of generalized anxiety

In a 4-week double-blind study comparing alprazolam with diazepam treatments, 48 outpatients suffering from mild to moderate generalized anxiety were evaluated after a 5-day placebo washout, and then after 1, 2, and 4 weeks of treatment. The optimal therapeutic doses without excessive sedation averaged 2 mg for alprazolam and 15.8 mg for diazepam. Results from the Hamilton Anxiety Rating Scale, the Clinical Global Impression Scale, a behavior checklist questionnaire, and a symptomatic patients' self-rating scale indicated that patients improved in both treatment groups. Results from the comparative phase suggest that diazepam is more efficient than alprazolam in the reduction of several symptoms of anxiety and depression in particular. Assuming that the first 2-week ratings depend on accuracy of dose adjustment and that week 4 ratings are an important evaluation of long-term efficacy, results from this study suggest that adequate control of anxiety is obtained more readily with diazepam and that symptoms of depression might benefit more from that drug. Few side effects were reported: mainly, drowsiness, tremor, light- headedness , and dry mouth. A toxic reaction to alprazolam, possibly allergic, was observed. Either alprazolam or diazepam appeared to be effective in the treatment of generalized anxiety disorder, and the statistically significant differences between the two drugs were not clinically striking.     

Behavioural responsiveness to picrotoxin and desipramine in adult rats prenatally exposed to different benzodiazepine receptor agonists

The behavioural responsiveness to picrotoxin and desipramine was investigated in adult rats prenatally exposed to different benzodiazepine receptor agonists such as diazepam, alprazolam and zolpidem. Prenatal exposure to diazepam and alprazolam similarly potentiated the anti-immobility effect on the forced swimming test and the inhibitory effect on spontaneous motor activity of picrotoxin and desipramine and increased the seizure sensitivity to picrotoxin. Prenatal zolpidem seems to be ineffective. These data suggest that, despite the differences in their pharmacodynamic profile, prenatal exposure to diazepam and alprazolam, but not zolpidem, may have similar permanent consequences on the behavioural effects of drugs acting on the GABA_A receptors.     

Quantitative and comparative analyses of pro-aggressive actions of benzodiazepines in maternal aggression of rats

The pro-aggressive effects of low doses of benzodiazepines on maternal aggression in rats were studied. Chlordiazepoxide, diazepam, oxazepam and alprazolam produced bell-shaped dose-response curves, with increased aggression at low doses. Only alprazolam significantly reduced aggression at higher doses. A comparison of the drug effects on different aggressive elements revealed that chlordiazepoxide and oxazepam increased the frequency of more elements of the aggressive repertoire than diazepam or alprazolam. Thus, although all benzodiazepine receptor agonists increased aggression, there were significant quantitative differences in their effects.     

Human behavioral pharmacology of benzodiazepines: Effects on repeated acquisition and performance of response chains

One scientific concern with benzodiazepine is their effects on learning (acquisition). One procedure that permits a detailed study of learning processes is the repeated acquisition of behavioral chains procedure. The repeated acquisition of behavioral chains allows for the repeated study of learning in individual subjects and also permits a comparison with comparable performance behavior. This paper reviews the effects of acute and chronic benzodiazepines on the repeated acquisition and performance of response chains. With acute administration, diazepam, alprazolam, and triazolam are all found to produce dose-related increases in percent errors in the acquisitions component, while generally not affecting percent errors in the performance component. Diazepam showed less activity than either alprazolam or triazolam. With chronic administration, acquisition showed tolerance to the errors-increasing effects of diazepam at a slower rate than did performance. Clinical implications of these findings are discussed.     

Lack of interaction between disulfiram and alprazolam in alcoholic patients

Summary Certain interactions between disulfiram and benzodiazepines, especially diazepam and chlordiazepoxide, have previously been reported. The influence of disulfiram on the pharmacokinetics of alprazolam, a triazolobenzodiazepine, metabolized by hepatic microsomal oxidation, has been evaluated in 11 chronic alcoholic patients (6 males, 5 females) undergoing treatment for the alcohol withdrawal syndrome. Each patient received alprazolam 2 mg on the first day (control) followed by two weeks of treatment with disulfiram 0.5 g/d, and then further oral dose of alprazolam 2 mg. No significant change was found in any of the kinetic parameters.Thus, a therapeutic dose of disulfiram did not significantly alter the clearance or half-life of alprazolam in chronic alcoholic patients.     

Alprazolam: a review of its pharmacodynamic properties and efficacy in the treatment of anxiety and depression

Alprazolam is a triazolobenzodiazepine which is related to diazepam and other 1,4-benzodiazepines, and has a similar pharmacological profile. Relative to the newer benzodiazepines, alprazolam has an intermediate half-life of 10 to 12 hours in healthy young subjects. In placebo-controlled and double-blind comparative trials in patients with anxiety, alprazolam was of comparable efficacy to diazepam and generally caused a lower incidence of drowsiness. Alprazolam has antidepressant activity and has been shown to be similar in efficacy to imipramine in the treatment of unipolar depression. Thus, alprazolam may be particularly useful in patients with mixed anxiety/depression. However, its general acceptance as an antidepressant awaits further studies.     

Comparative Study of the Abuse Liability of Alprazolam,Lorazepam, Diazepam,Methaqualone, and Placebo

Subjective effects of two benzodiazepines–alprazolam and lorazepam– were compared with two drugs of known abuse potential–diazepam and methaqualone–and placebo. This double-blind, crossover trial tested 30 casual recreational sedative users in a seminaturalistic setting. Methaqualone was more euphoriant and less sedative than the benzodiazepines. Diazepam and lorazepam were more euphoriant than placebo; alprazolam's euphoriant effect did not differ from these treatments. On other measures of abuse liability the benzodiazepines rated similarly, diazepam rating highest.     

Role of beta-adrenergic receptors in the mechanism of action of second-generation antidepressants

The effect of chronic intravenous infusion of desmethylimipramine (DMI), amitriptyline, mianserin, bupropion, alprazolam, or diazepam on the density of beta-adrenergic receptors in the rat cerebral cortex has been investigated in this study. DMI and amitriptyline significantly decreased the density of beta-adrenergic receptors. Mainserin, bupropion, alprazolam, and diazepam had no significant effect on the density of beta-adrenergic receptors. Results of this study indicate that mechanisms other than beta-adrenergic receptors may be involved in the antidepressant activity of these drugs.     

Comparison of several benzodiazepine receptor ligands in two models of anxiolytic activity in the mouse: an analysis based on fractional receptor occupancies

This study compared the effects of the -carboline anxiolytic, abecarnil, with other benzodiazepine receptor (BZR) ligands, including the full agonists diazepam and alprazolam, and the partial agonists ZK 95962 and bretazenil (Ro 16-6028), and alpidem, in the mouse four-plate test and plus-maze. The efficacy and potency of each compound was related to the fraction of BZR occupied by the drug. Abecarnil was efficacious in both tests and showed anxiolytic effects comparable with alprazolam and diazepam. In the four-plate test, abecarnil, bretazenil, and ZK 95962 had selective effects on releasing exploratory locomotor activity suppressed by footshock (punished crossings). None of these compounds significantly altered non-punished crossings. In contrast, diazepam and alprazolam increased both unpunished and punished crossings at low to medium doses (receptor occupancies of approximately 20–60%). The number of punished and unpunished crossings fell to control levels or below at higher, more sedative doses (approximately 80% receptor occupancy). Alpidem had very weak anxiolytic-like effects in this test and markedly reduced unpunished crossings at relatively low receptor occupancies (> 15%). In the plus-maze, abecarnil increased the time spent in the open arms and the percentage open arm entries to an extent equal to that observed following diazepam or alprazolam administration. Bretazenil and ZK 95962 had weak effects on the measures of anxiolytic activity in this test. Alpidem also had little anxiolytic-like activity in the plus-maze but markedly reduced the total number of arm entries. The fractional BZR occupancies required to increase the time spent in the open arms of the maze to 250% of control levels were approximately 45% for abecarnil and alprazolam, 60% for diazepam, and 100% for ZK 95962. Bretazenil did not reach this potentiation at the doses tested (up to 89% receptor occupancy). Abecarnil appeared to act as a full agonist on the measures of anxiolytic activity in both tests (i.e. required low fractional BZR occupancies) but on the measures of stimulation or sedation was more similar to the BZR partial agonists (i.e. had no significant effects even at receptor occupancies approaching 100%). On this basis abecarnil could be described as a selective agonist. In general, the four-plate test was more sensitive than the plus-maze. For example, lower BZR occupancies were needed to produce significant anxiolytic effects in the four-plate test than in the plus-maze. In addition, the partial agonists bretazenil and ZK 95962, which both produced weak effects in the plus-maze, had similar anxiolytic potencies to the full BZR agonists, diazepam and alprazolam, in the four-plate test.     

Alprazolam (Xanax, the Upjohn Company)

Alprazolam is a triazolobenzodiazepine, a derivative of the benzodiazepines. Comparison studies of alprazolam and diazepam or chlordiazepoxide in patients suffering from clinical anxiety secondary to anxiety neurosis or chronic alcohol withdrawal suggest an equal efficacy of those agents. Studies examining the use of alprazolam for the treatment of "primary depression" suggest that it is as effective as imipramine in the treatment of exogenous (reactive) depression. Although alprazolam may be effective in patients with exogenous depression, no extrapolation can be made to the treatment of endogenous depression. Mechanisms of action have not been fully elucidated, but probably are similar to those of other benzodiazepines. Peak blood levels are reached in 0.7-1.6 hours and the elimination half-life after steady state is approximately 19 hours. Daily dosages established from clinical studies ranged from 1 to 6 mg. Clinically, alprazolam appears to be ten times more potent than diazepam. Drowsiness, headaches, lightheadedness, dry mouth, and depression appear to be the most common side effects of the drug. It is concluded that alprazolam offers no striking therapeutic advantage over currently marketed benzodiazepines.     

Effects of single doses of alprazolam and diazepam,alone and in combination with ethanol,on psychomotor and cognitive performance and on autonomic nervous system reactivity in healthy volunteers

Summary Effects of alprazolam, alone and in combination with ethanol, on psychomotor and cognitive performance were studied in healthy male volunteers and compared to effects of diazepam. Alprazolam 2 mg produced relatively long-lasting impairments on tests of tracking, verbal and nonverbal information processing, and memory, and decreased blood pressure without a change in heart rate or plasma norepinephrine levels. Although ethanol consumption was demonstrated to produce additive decrements in performance on certain tasks, there was little evidence to support a synergistic effect. Alprazolam 2 mg was accompanied by increased selfreports of side effects, especially drowsiness. Low dose alprazolam, diazepam, and ethanol produced significantly fewer side effects than 2 mg alprazolam, but significantly more than placebo.     

Antidepressant activity of alprazolam in a reserpine-induced model of depression

The effect of chronic (14–21 day) administration of reserpine (0.1 mg/kg/day), imipramine (10 mg/kg/day), alprazolam (5, 10 and 15 mg/kg/day), and diazepam (10 and 30 mg/kg/day) on beta-adrenergic receptors in the cerebral cortex and body weight has been reported in this study. Chronic treatment with both imipramine and alprazolam significantly blocked reserpine-induced increases in beta-adrenergic receptors and loss in body weight. However, diazepam under similar conditions had no significant effect.     

Effects of psychoactive drugs on plasma catecholamines during stress in rats

In unstressed rats, morphine, pentobarbital, diazepam and alprazolam were without effect on plasma norepinephrine (NE) and epinephrine (E) levels. Amphetamine increased the levels of both catecholamines. In stressed rats, morphine did not affect the stress induced increases in NE and E. Amphetamine enhanced the catecholamine stress-response further. Diazepam reduced stress-induced increases of NE levels. Pentobarbital and alprazolam attenuated stress-induced increases of both NE and E levels; this effect was particularly marked with alprazolam.The rise in plasma norepinephrine (NE) and epinephrine (E) levels during stress has been well documented (DeTurck and Vogel, 1982; McCarty and Kopin, 1979). Considerably less is known about the effects of drugs on these stress-induced increases in biogenic amine levels. In rats, ganglionic blockade by chlorisondamine and blockade of NE release by bretylium has been shown to decrease or reverse stress-induced increases in plasma NE and/or E (McCarty and Kopin, 1979). These effects are not surprising, due to the known action of these drugs on the autonomic nervous system. However, drugs unrelated to the autonomic nervous system can also affect the biogenic amine levels during stress. Fentanyl-oxygen anesthesia reduces plasma NE and E in man during surgery (Stanley, Berman, Green and Robertson, 1980), and diazepam reduces NE levels during third molar extraction without affecting E level (Goldstein, Dionne, Sweet, Gracely, Brewer, Gregg and Keiser, 1982). Recently, we observed that ethanol can reduce stress-induced increases in rat plasma levels of both NE and E (DeTurck and Vogel, 1982). In that case, it has been speculated that this reduction is due to the sedative or anxiolytic properties of alcohol (DeTurck and Vogel, 1982). To test the possibility that these properties can indeed affect stress-induced increases in NE and E, we measured the effects of several psychoactive drugs on plasma catecholamine levels during stress. The drugs were the stimulant amphetamine, the sedative drugs morphine and pentobarbital, and the anxiolytic/sedative drugs diazepam and alprazolam.     

我院口服二类精神药品使用分析

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Alprazolam: pharmacokinetics, clinical efficacy, and mechanism of action

Alprazolam, a triazolobenzodiazepine, is the first of this new class of benzodiazepine drugs to be marketed in the United States and Canada. It achieves peak serum levels in 0.7 to 2.1 hours and has a serum half-life of 12 to 15 hours. When given in the recommended daily dosage of 0.5 to 4.0 mg, it is as effective as diazepam and chlordiazepoxide as an anxiolytic agent. Its currently approved indication is for the treatment of anxiety disorders and symptoms of anxiety, including anxiety associated with depression. Although currently not approved for the treatment of depressive disorders, studies published to date have demonstrated that alprazolam compares favorably with standard tricyclic antidepressants. Also undergoing investigation is the potential role of alprazolam in the treatment of panic disorders. Alprazolam has been used in elderly patients with beneficial results and a low frequency of adverse reactions. Its primary side effect, drowsiness, is less than that produced by diazepam at comparable doses. Data on toxicity, tolerance, and withdrawal profile are limited, but alprazolam seems to be at least comparable to other benzodiazepines. Drug interaction data are also limited, and care should be exercised when prescribing alprazolam for patients taking other psychotropic drugs because of potential additive depressant effects.