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Psychopharmacology Oct 2014The orexin-hypocretin system is important for translating peripheral metabolic signals and central neuronal inputs to a diverse range of behaviors, from feeding,... (Randomized Controlled Trial)
Randomized Controlled Trial
RATIONALE
The orexin-hypocretin system is important for translating peripheral metabolic signals and central neuronal inputs to a diverse range of behaviors, from feeding, motivation and arousal, to sleep and wakefulness. Orexin signaling is thus an exciting potential therapeutic target for disorders of sleep, feeding, addiction, and stress.
OBJECTIVES/METHODS
Here, we investigated the low dose pharmacology of orexin receptor antagonist, SB-649868, on neuroendocrine, sympathetic nervous system, and behavioral responses to insulin-induced hypoglycemic stress, in 24 healthy male subjects (aged 18-45 years; BMI 19.0-25.9 kg/m(2)), using a randomized, double-blind, placebo-controlled, within-subject crossover design. Alprazolam, a licensed benzodiazepine anxiolytic, was used as a positive comparator, as it has previously been validated using the insulin tolerance test (ITT) model in humans.
RESULTS
Of the primary endpoints, ITT induced defined increases in pulse rate, plasma cortisol, and adrenocorticotropic hormone in the placebo condition, but these responses were not significantly impacted by alprazolam or SB-649868 pre-treatment. Of the secondary endpoints, ITT induced a defined increase in plasma concentrations of adrenaline, noradrenaline, growth hormone (GH), and prolactin in the placebo condition. Alprazolam pre-treatment significantly reduced the GH response to ITT (p < 0.003), the peak electromyography (p < 0.0001) and galvanic skin response (GSR, p = 0.04) to acoustic startle, the resting GSR (p = 0.01), and increased appetite following ITT (p < 0.0005). SB-649868 pre-treatment produced no significant results.
CONCLUSION
We concluded that the ITT model may be informative for assessing the effects of drugs directly acting on the neuroendocrine or sympathetic nervous systems, but could not be validated for studying low dose orexin antagonist activity.
Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Alprazolam; Anti-Anxiety Agents; Benzofurans; Cross-Over Studies; Double-Blind Method; Growth Hormone; Heart Rate; Humans; Hypoglycemia; Insulin; Intracellular Signaling Peptides and Proteins; Male; Middle Aged; Neuropeptides; Neurosecretory Systems; Norepinephrine; Orexin Receptor Antagonists; Orexins; Prolactin; Sympathetic Nervous System; Thiazoles; Young Adult
PubMed: 24770625
DOI: 10.1007/s00213-014-3520-7 -
Toxicology and Applied Pharmacology Apr 2023Designer benzodiazepines, including flualprazolam and flubromazolam, are clandestinely produced to circumvent federal regulations. Although flualprazolam and...
Designer benzodiazepines, including flualprazolam and flubromazolam, are clandestinely produced to circumvent federal regulations. Although flualprazolam and flubromazolam are structurally similar to alprazolam, they do not have an approved medical indication. Flualprazolam differs from alprazolam by the addition of a single fluorine atom. Whereas, flubromazolam differs by the addition of a single fluorine atom and substitution of a bromine for a chlorine atom. The pharmacokinetics of these designer compounds have not been extensively evaluated. In the present study, we evaluated flualprazolam and flubromazolam in a rat model and compared the pharmacokinetics of both compounds to alprazolam. Twelve male, Sprague-Dawley rats were given a 2 mg/kg subcutaneous dose of alprazolam, flualprazolam and flubromazolam and plasma pharmacokinetic parameters were evaluated. Both compounds displayed significant two-fold increases in volume of distribution and clearance. Additionally, flualprazolam displayed a significant increase in half-life leading to a nearly double half-life when compared to alprazolam. The findings of this study demonstrate that fluorination of the alprazolam pharmacophore increases pharmacokinetic parameters including half-life and volume of distribution. The increase in these parameters for flualprazolam and flubromazolam leads to an overall increased exposure in the body and a potential for greater toxicity than alprazolam.
Topics: Male; Rats; Animals; Alprazolam; Fluorine; Designer Drugs; Substance Abuse Detection; Rats, Sprague-Dawley; Benzodiazepines
PubMed: 36907383
DOI: 10.1016/j.taap.2023.116459 -
Clinical Case Reports Sep 2023A 31-year-old female with a diagnosis of bipolar disorder developed black hairy tongue after alprazolam therapy. Her symptom resolved 10 days after the cessation of...
KEY CLINICAL MESSAGE
A 31-year-old female with a diagnosis of bipolar disorder developed black hairy tongue after alprazolam therapy. Her symptom resolved 10 days after the cessation of alprazolam.
ABSTRACT
Alprazolam is a widely used antidepressant and antianxiety drug. Mild to moderate side effect of alprazolam was commonly seen, including lethargy, dizziness, headache, dry mouth, nausea, fatigue, constipation, and blurred vision. In this case, we reported a patient developed black hairy tongue after alprazolam intake, and her symptom resolved after 10-day discontinuation of alprazolam. This rare adverse event should be of concern to clinicians. This is the first paper to report an alprazolam-induced BHT. This rare side effect of alprazolam should be concern of clinicians; we hope our report will promote the understand of BHT and acknowledge clinicians of this rare side effect of alprazolam.
PubMed: 37636887
DOI: 10.1002/ccr3.7831 -
The Journal of Pharmacology and... Dec 2022This study evaluated the reinforcing effects of fentanyl, alone or in combination with the benzodiazepine alprazolam, in rhesus monkeys (3 females, 3 males). Subjects...
This study evaluated the reinforcing effects of fentanyl, alone or in combination with the benzodiazepine alprazolam, in rhesus monkeys (3 females, 3 males). Subjects were trained to self-administer the opioid remifentanil (0.3 g/kg/injection) under a progressive-ratio schedule of reinforcement. The reinforcing effects of fentanyl (0.1-10 g/kg/injection) or alprazolam (1.0-100 g/kg/injection) alone, or in combinations of fixed proportions (1:1, 1:3, and 3:1 fentanyl:alprazolam, with 1:1 based on the potencies of drugs alone) were evaluated in single-day test sessions (with double determinations). Dose-equivalence analysis was used to determine the extent to which fentanyl and alprazolam combinations differed from additivity. Fentanyl functioned as a positive reinforcer in all monkeys, while alprazolam was a reinforcer in 3 of 6 monkeys only. Therefore, drug combination data were grouped as "alprazolam-taking" and "non-alprazolam-taking" monkeys. For alprazolam-taking monkeys, we observed additive effects for the 3:1 and 1:3 combinations, and a significant supra-additive interaction for the 1:1 combination of fentanyl and alprazolam. For 2 of the 3 non-alprazolam-taking monkeys, the combination of fentanyl and alprazolam resulted in enhanced reinforcing effects relative to either drug alone. However, the one monkey showed primarily inhibitory, or suppressive effects, with the 3:1 dose combination resulting in a relatively modest rightward shift in the fentanyl dose-response function. In summary, our findings show that combining fentanyl and alprazolam generally result in proportion-dependent additive or supra-additive enhancements. These data raise the possibility that the prevalence of opioid-benzodiazepine polydrug abuse may reflect a unique enhancement of these drugs' reinforcing effects, although individual differences may exist. SIGNIFICANCE STATEMENT: Addressing the critical question of the degree to which benzodiazepines can modulate the abuse-related effects of opioids may provide improved pathways to treatment of this common form of polydrug addiction. In the present study, we show that combinations of the opioid fentanyl and the benzodiazepine alprazolam can be more reinforcing than either drug alone in a rhesus monkey model, suggesting that enhancement of reinforcement processes may underlie this prevalent form of polydrug use disorder.
Topics: Animals; Male; Female; Fentanyl; Macaca mulatta; Analgesics, Opioid; Alprazolam; Dose-Response Relationship, Drug; Self Administration; Benzodiazepines; Substance-Related Disorders; Cocaine; Reinforcement Schedule
PubMed: 36153004
DOI: 10.1124/jpet.122.001191 -
Psychiatria Danubina Mar 2011Side-effects arising on the grounds of antidepressant administration pose as a substantial obstacle hindering successful depressive disorder treatment. Side-effects,...
Side-effects arising on the grounds of antidepressant administration pose as a substantial obstacle hindering successful depressive disorder treatment. Side-effects, especially those severe or those manifested through dramatic clinical presentations such as panic attacks, make the treatment far more difficult and shake patients' trust in both the treatment and the treating physician. This case report deals with a patient experiencing a moderately severe depressive episode, who responded to duloxetine treatment administered in the initial dose of 30 mg per day with as many as three panic attacks in two days. Upon duloxetine withdrawal, these panic attacks ceased as well. The patient continued tianeptine and alprazolam treatment during which no significant side-effects had been seen, so that she gradually recovered. Some of the available literature sources have suggested the possibility of duloxetine administration to the end of generalised anxiety disorder and panic attack treatment. However, they are outnumbered by the contributions reporting about duloxetine-related anxiety, aggressiveness and panic attacks. In line with the foregoing, further monitoring of each and every duloxetine-administered patient group needs to be pursued so as to be able to evaluate treatment benefits and weigh them against risks of anxiety or panic attack onset.
Topics: Alprazolam; Anti-Anxiety Agents; Antidepressive Agents; Antidepressive Agents, Tricyclic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Duloxetine Hydrochloride; Female; Follow-Up Studies; Humans; Middle Aged; Oxazepam; Panic Disorder; Thiazepines; Thiophenes
PubMed: 21448113
DOI: No ID Found -
Drug and Alcohol Dependence Oct 2023Alprazolam, also known by trade-name Xanax, is regularly detected along with alcohol in blood samples of drivers injured or killed in traffic collisions. While their... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Alprazolam, also known by trade-name Xanax, is regularly detected along with alcohol in blood samples of drivers injured or killed in traffic collisions. While their co-consumption is principally legal, policy guidelines concerning fitness-to-drive are lacking and methods to index impairment are underdeveloped.
METHODS
In this randomized, double-blind, placebo-controlled, crossover trial, we examined whether legally permissible levels of alcohol [target 0.04% blood alcohol concentration (BAC)], alprazolam (1mg), and their combination impacts driving performance, and whether driving impairment can be indexed by ocular activity. Participants completed a test battery consisting of a 40-minute simulated highway drive with ocular parameters assessed simultaneously, the Karolinska Sleepiness Scale, and a confidence to drive assessment following four separate treatment combinations. The predictive efficacy of ocular parameters to identify alcohol and alprazolam-related driving impairment was also examined.
RESULTS
Among 21 healthy, fully licensed drivers (37% female, mean age 28.43, SD ± 3.96), driving performance was significantly impacted by alprazolam, alcohol, and their combination. Linear regression models revealed that the odds of an out-of-lane event occurring increased five-fold under the influence alprazolam alone and when combined with alcohol. An increase in gaze transition entropy (GTE) demonstrated the strongest association with the odds of an out-of-lane event occurring in the same minute, with both microsleeps and fixation rate achieving moderate accuracy across treatments.
CONCLUSIONS
Alprazolam and alcohol, alone and in combination, impaired select aspects of vehicle control over time. GTE, microsleeps, and fixation rate show potential as real-time indicators of driving impairment and crash risk associated with alcohol and alprazolam consumption.
Topics: Humans; Female; Adult; Male; Alprazolam; Blood Alcohol Content; Ethanol; Double-Blind Method; Accidents, Traffic; Automobile Driving
PubMed: 37611483
DOI: 10.1016/j.drugalcdep.2023.110919 -
Journal of Pain and Symptom Management Nov 1994There has been long-standing debate regarding whether benzodiazepines possess analgesic properties that are independent of their effects on mood and alertness. A careful... (Review)
Review
There has been long-standing debate regarding whether benzodiazepines possess analgesic properties that are independent of their effects on mood and alertness. A careful review of the literature reveals insufficient evidence to support the contention that the benzodiazepines have meaningful analgesic properties in most clinical circumstances. Treatment with the benzodiazepines may reduce complaints of pain, but this seems to be an indirect effect related to their psychotropic properties, such as alleviation of anxiety and, in selected cases, depression. In the absence of definitive data, clinical experience suggests a potential role for treatment with benzodiazepines for acute muscle spasm, concomitant chronic pain and anxiety, and lancinating neropathic pain, in which case clonazepam and alprazolam may be the agents of choice. They should probably not be considered as first-line choices even for the above indications, since potential benefits must be considered in the context of potential for the development of cognitive impairment, physical and psychological dependence, worsening depression, overdose, and other side effects.
Topics: Adjuvants, Pharmaceutic; Analgesics; Benzodiazepines; Clinical Trials as Topic; Humans; Palliative Care
PubMed: 7531735
DOI: 10.1016/0885-3924(94)90112-0 -
Scientific Reports Mar 2024This study aims to evaluate the safety of Alprazolam by analyzing the FAERS database, provide data analysis for monitoring adverse drug reactions. This research...
This study aims to evaluate the safety of Alprazolam by analyzing the FAERS database, provide data analysis for monitoring adverse drug reactions. This research encompasses adverse event (AE) reports related to Alprazolam from the first quarter of 2004 to the second quarter of 2023. Four signal mining and analysis methods were utilized, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM). Further exploration was conducted regarding patient characteristics and types of AEs. A total of 23,575 AE reports in which Alprazolam was the primary suspect drug were collected, identifying 347 Preferred Term (PT) signals and 27 System Organ Classes (SOCs). The number of AE reports increased annually, especially in 2015, 2018, 2019, and 2020. The main affected groups were females and the age range of 18 to 45. Psychiatric disorders, Nervous system disorders, and Gastrointestinal disorders were the most common the organ system in which the AEs occurred. There is a certain risk of drug abuse and suicide with Alprazolam. Most notably, several AEs not recorded in the Alprazolam leaflet appeared among the top 30 PTs in signal strength, including but not limited to Benzodiazepine drug level abnormal, Acquired amegakaryocytic thrombocytopenia, Cutaneous T-cell dyscrasia, and Coronary No-reflow Phenomenon. For the first time, AEs related to the cardiovascular system and platelet function were unveiled. The severe AE reports that resulted in "hospitalization" and "death" accounted for 30.96% and 21.86%. This study highlights the risks of suicide and misuse of Alprazolam. Other potential severe or fatal AEs, such as those related to the cardiovascular system, platelet function, and others, require further research to determine their precise mechanisms and risk factors.
Topics: Female; Humans; Male; Alprazolam; Bayes Theorem; Benzodiazepines; Risk Factors; Drug-Related Side Effects and Adverse Reactions; Risk Assessment
PubMed: 38553504
DOI: 10.1038/s41598-024-57909-y -
Drug and Alcohol Dependence Nov 2021To assess GABA receptor subtypes involved in benzodiazepine tolerance and dependence, we evaluated the ability of subtype-selective and non-selective ligands to...
BACKGROUND
To assess GABA receptor subtypes involved in benzodiazepine tolerance and dependence, we evaluated the ability of subtype-selective and non-selective ligands to substitute for (i.e., produce "cross-tolerance") or precipitate withdrawal during chronic alprazolam treatment.
METHODS
Four female rhesus monkeys (Macaca mulatta) were implanted with chronic intravenous catheters and administered alprazolam (1.0 mg/kg every 4 h). Following 14+ days of chronic alprazolam, acute administration of selected doses of non-selective and subtype-selective ligands were substituted for, or administered with, alprazolam, followed by quantitative behavioral observations. The ligands included alprazolam and midazolam (positive modulators, non-selective), zolpidem (positive modulator, preferential affinity for α1-containing GABA receptors), HZ-166 (positive modulator, preferential efficacy at α2- and α3-containing GABA receptors), and βCCT (antagonist, preferential affinity for α1-containing GABA receptors).
RESULTS
Acutely, alprazolam and midazolam both induced observable ataxia along with a mild form of sedation referred to as "rest/sleep posture" at a lower dose (0.1 mg/kg, i.v.), whereas at a higher dose (1.0 mg/kg, i.v.), induced deep sedation and observable ataxia. With chronic alprazolam treatment, observable ataxia and deep sedation were reduced significantly, whereas rest/sleep posture was unchanged or emerged. Zolpidem showed a similar pattern of effects, whereas no behaviors engendered by HZ-166 were changed by chronic alprazolam. Administration of βCCT, but not HZ-166, resulted in significant withdrawal signs.
CONCLUSIONS
These results are consistent with a role for α1-containing GABA receptor subtypes in tolerance and dependence observed with chronic alprazolam, although other receptors may be involved in the withdrawal syndrome.
Topics: Alprazolam; Animals; Benzodiazepines; Drug Tolerance; Female; Macaca mulatta; Midazolam; Receptors, GABA-A; Substance Withdrawal Syndrome; Zolpidem
PubMed: 34500240
DOI: 10.1016/j.drugalcdep.2021.108985 -
Psychiatry and Clinical Neurosciences Feb 1998Double-blind, placebo-controlled trials of pharmacotherapy for personality disorders (PD) were reviewed, and the indications concluded were as follows: (1) Severe cases... (Review)
Review
Double-blind, placebo-controlled trials of pharmacotherapy for personality disorders (PD) were reviewed, and the indications concluded were as follows: (1) Severe cases of both Borderline Personality Disorder (BDP) and Schizotypal Personality Disorder (SPD) respond to low dose antipsychotic drugs resulting in improvement of a broad spectrum of symptoms. They also respond to monoamine oxidase inhibitor (MAOI). Amitriptyline causes a paradoxical effect. (2) Borderline personality disorder with behavioral dyscontrol responds to carbamazepine which reduces actual episodes of dyscontrol, to an antipsychotic drug and to MAOI. Alprazolam is associated with an increase in suicidality and dyscontrol. Borderline personal disorder or Histrionic Personality Disorder with a tendency to suicide, responds to a depot antipsychotic drug. Personality disorders with aggressive behavior respond to lithium. Moderately severe PD with explosive behavior respond to oxazepam, but at a dose where the side effect is sedation. (3) Borderline personality disorder and SPD with psychotic symptoms respond to an antipsychotic drug which improves psychotic symptoms as well as neurotic symptoms. Emotionally Unstable Character Disorder with a disturbance of mood swings, responds to lithium. Adolescent PD respond to an antipsychotic drug. (4) Comorbid atypical depression of histrionic personality and BPD respond to MAOI or imipramine. Comorbid neurotic disorder of PD responds to dothiepin. Comorbid social phobia of avoidant and dependent PD responds to MAOI.
Topics: Antipsychotic Agents; Clinical Trials as Topic; Double-Blind Method; Humans; Personality Disorders; Psychotropic Drugs
PubMed: 9682928
DOI: 10.1111/j.1440-1819.1998.tb00967.x