Unpublished trials of alprazolam XR and their influence on its apparent efficacy for panic disorder.

OBJECTIVE: To test for publication bias with alprazolam, the most widely prescribed benzodiazepine, by comparing its efficacy for panic disorder using trial results from (1) the published literature and (2) the US Food and Drug Administration (FDA). METHODS: From FDA reviews, we included data from all phase 2/3 efficacy trials of alprazolam extended-release (Xanax XR) for the treatment of panic disorder. A search for matching publications was performed using PubMed and Google Scholar. Publication bias was examined by comparing: (1) overall trial results (positive or not) according to the FDA v. corresponding publications; (2) effect size (Hedges's g) based on FDA data v. published data. RESULTS: The FDA review showed that five trials were conducted, only one of which (20%) was positive. Of the four not-positive trials, two were published conveying a positive outcome; the other two were not published. Thus, according to the published literature, three trials were conducted and all (100%) were positive. Alprazolam's effect size calculated using FDA data was 0.33 (CI95% 0.07-0.60) v. 0.47 (CI95% 0.30-0.65) using published data, an increase of 0.14, or 42%. CONCLUSIONS: Publication bias substantially inflates the apparent efficacy of alprazolam XR.

Pharmacological treatments in panic disorder in adults: a network meta-analysis.

BACKGROUND: A panic attack is a discrete period of fear or anxiety that has a rapid onset and reaches a peak within 10 minutes. The main symptoms involve bodily systems, such as racing heart, chest pain, sweating, shaking, dizziness, flushing, churning stomach, faintness and breathlessness. Other recognised panic attack symptoms involve fearful cognitions, such as the fear of collapse, going mad or dying, and derealisation (the sensation that the world is unreal). Panic disorder is common in the general population with a prevalence of 1% to 4%. The treatment of panic disorder includes psychological and pharmacological interventions, including antidepressants and benzodiazepines. OBJECTIVES: To compare, via network meta-analysis, individual drugs (antidepressants and benzodiazepines) or placebo in terms of efficacy and acceptability in the acute treatment of panic disorder, with or without agoraphobia. To rank individual active drugs for panic disorder (antidepressants, benzodiazepines and placebo) according to their effectiveness and acceptability. To rank drug classes for panic disorder (selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), mono-amine oxidase inhibitors (MAOIs) and benzodiazepines (BDZs) and placebo) according to their effectiveness and acceptability. To explore heterogeneity and inconsistency between direct and indirect evidence in a network meta-analysis. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Specialised Register, CENTRAL, CDSR, MEDLINE, Ovid Embase and PsycINFO to 26 May 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of people aged 18 years or older of either sex and any ethnicity with clinically diagnosed panic disorder, with or without agoraphobia. We included trials that compared the effectiveness of antidepressants and benzodiazepines with each other or with a placebo. DATA COLLECTION AND ANALYSIS: Two authors independently screened titles/abstracts and full texts, extracted data and assessed risk of bias. We analysed dichotomous data and continuous data as risk ratios (RRs), mean differences (MD) or standardised mean differences (SMD): response to treatment (i.e. substantial improvement from baseline as defined by the original investigators: dichotomous outcome), total number of dropouts due to any reason (as a proxy measure of treatment acceptability: dichotomous outcome), remission (i.e. satisfactory end state as defined by global judgement of the original investigators: dichotomous outcome), panic symptom scales and global judgement (continuous outcome), frequency of panic attacks (as recorded, for example, by a panic diary; continuous outcome), agoraphobia (dichotomous outcome). We assessed the certainty of evidence using threshold analyses. MAIN RESULTS: Overall, we included 70 trials in this review. Sample sizes ranged between 5 and 445 participants in each arm, and the total sample size per study ranged from 10 to 1168. Thirty-five studies included sample sizes of over 100 participants. There is evidence from 48 RCTs (N = 10,118) that most medications are more effective in the response outcome than placebo. In particular, diazepam, alprazolam, clonazepam, paroxetine, venlafaxine, clomipramine, fluoxetine and adinazolam showed the strongest effect, with diazepam, alprazolam and clonazepam ranking as the most effective. We found heterogeneity in most of the comparisons, but our threshold analyses suggest that this is unlikely to impact the findings of the network meta-analysis. Results from 64 RCTs (N = 12,310) suggest that most medications are associated with either a reduced or similar risk of dropouts to placebo. Alprazolam and diazepam were associated with a lower dropout rate compared to placebo and were ranked as the most tolerated of all the medications examined. Thirty-two RCTs (N = 8569) were included in the remission outcome. Most medications were more effective than placebo, namely desipramine, fluoxetine, clonazepam, diazepam, fluvoxamine, imipramine, venlafaxine and paroxetine, and their effects were clinically meaningful. Amongst these medications, desipramine and alprazolam were ranked highest. Thirty-five RCTs (N = 8826) are included in the continuous outcome reduction in panic scale scores. Brofaromine, clonazepam and reboxetine had the strongest reductions in panic symptoms compared to placebo, but results were based on either one trial or very small trials. Forty-one RCTs (N = 7853) are included in the frequency of panic attack outcome. Only clonazepam and alprazolam showed a strong reduction in the frequency of panic attacks compared to placebo, and were ranked highest. Twenty-six RCTs (N = 7044) provided data for agoraphobia. The strongest reductions in agoraphobia symptoms were found for citalopram, reboxetine, escitalopram, clomipramine and diazepam, compared to placebo. For the pooled intervention classes, we examined the two primary outcomes (response and dropout). The classes of medication were: SSRIs, SNRIs, TCAs, MAOIs and BDZs. For the response outcome, all classes of medications examined were more effective than placebo. TCAs as a class ranked as the most effective, followed by BDZs and MAOIs. SSRIs as a class ranked fifth on average, while SNRIs were ranked lowest. When we compared classes of medication with each other for the response outcome, we found no difference between classes. Comparisons between MAOIs and TCAs and between BDZs and TCAs also suggested no differences between these medications, but the results were imprecise. For the dropout outcome, BDZs were the only class associated with a lower dropout compared to placebo and were ranked first in terms of tolerability. The other classes did not show any difference in dropouts compared to placebo. In terms of ranking, TCAs are on average second to BDZs, followed by SNRIs, then by SSRIs and lastly by MAOIs. BDZs were associated with lower dropout rates compared to SSRIs, SNRIs and TCAs. The quality of the studies comparing antidepressants with placebo was moderate, while the quality of the studies comparing BDZs with placebo and antidepressants was low. AUTHORS' CONCLUSIONS: In terms of efficacy, SSRIs, SNRIs (venlafaxine), TCAs, MAOIs and BDZs may be effective, with little difference between classes. However, it is important to note that the reliability of these findings may be limited due to the overall low quality of the studies, with all having unclear or high risk of bias across multiple domains. Within classes, some differences emerged. For example, amongst the SSRIs paroxetine and fluoxetine seem to have stronger evidence of efficacy than sertraline. Benzodiazepines appear to have a small but significant advantage in terms of tolerability (incidence of dropouts) over other classes.

Benefits and risks of off-label olanzapine use for symptom management in cancer patients-a case report.

BACKGROUND: Cancer patients often experience symptoms such as anorexia, anxiety and insomnia, which can impact their quality of life. Randomized placebo-controlled trials support prophylactic use of olanzapine for the prevention of nausea and vomiting due to moderate and high-emetic risk chemotherapy. In the setting of palliative care, olanzapine is increasingly utilized as an off-label treatment of symptoms including anorexia-cachexia, anxiety, and insomnia. The following case reports will highlight the potential benefits and risks of off-label olanzapine use for symptom management in cancer patients. CASE DESCRIPTION: Patient 1 is a female in her 70s with stage IV infiltrating ductal carcinoma of the right breast was having trouble tolerating treatment with letrozole, palbociclib, and denosumab due to uncontrolled nausea resulting in weight loss. Her nausea was refractory to multiple anti-emetics. Low dose olanzapine (2.5 mg) prevented nausea and allowed her to tolerate treatment. Patient 2 is a male in his 50s with renal cell carcinoma, who was receiving treatment with cabozantinib, presented with uncontrolled pain improved with opioid rotation from oxycodone to morphine. He was also experiencing uncontrolled anxiety despite treatment with alprazolam. Alprazolam was weaned and replaced with olanzapine resulting in improvement of his symptoms. Patient 3 is a male in his 60s with pancreatic adenocarcinoma who presented with muscle weakness and fatigue resulting in discontinuation of gemcitabine plus cisplatin. He also had symptoms of depression, poor appetite, and sleep problems. He was prescribed short course of dexamethasone 4 mg by mouth twice daily and olanzapine 5 mg by mouth nightly to improve symptoms. One week after, he presented with confusion and workup revealed hyperammonia which was treated with lactulose, which led to the return of baseline mentation. CONCLUSIONS: Olanzapine antagonizes multiple receptors and has potential to treat a host of symptoms including nausea, anorexia, anxiety, and insomnia, but healthcare providers should be mindful of potential risks and unclear benefits for off-label indications. More research and funding are needed evaluating off-label use of olanzapine for palliation of symptoms in cancer patients who are often frail and susceptible to adverse events.

A randomized phase 2b efficacy study in patients with seizure episodes with a predictable pattern using Staccato® alprazolam for rapid seizure termination.

OBJECTIVE: Alprazolam administered via the Staccato® breath-actuated device is delivered into the deep lung for rapid systemic exposure and is a potential therapy for rapid epileptic seizure termination (REST). We conducted an inpatient study (ENGAGE-E-001 [NCT03478982]) in patients with stereotypic seizure episodes with prolonged or repetitive seizures to determine whether Staccato alprazolam rapidly terminates seizures in a small observed population after administration under direct supervision. METHODS: Adult patients with established diagnosis of focal and/or generalized epilepsy with a documented history of seizure episodes with a predictable pattern were enrolled. They were randomized 1:1:1 to double-blind treatment of a single seizure event with one dose of Staccato alprazolam 1.0 mg or 2.0 mg, or Staccato placebo in an inpatient unit. The primary end point of the study was the proportion of responders in each treatment group achieving seizure activity cessation within 2 min after administration of study drug and no recurrence of seizure activity within 2 h. RESULTS: A total of 273 patients were screened, and 116 randomized patients received treatment with the study drug in the double-blind part. The proportion of treated patients who were responders was 65.8% for each of Staccato alprazolam 1.0 mg (n = 38; p = .0392) and 2.0 mg (n = 38; p = .0392), compared with 42.5% for Staccato placebo (n = 40). Staccato alprazolam was well tolerated when administered as a single dose of 1.0 or 2.0 mg: cough and somnolence were the most common adverse events (AEs) (both 14.5%), followed by dysgeusia (13.2%). AEs were mostly mild or moderate in intensity; there were no treatment-related serious AEs. SIGNIFICANCE: Both 1.0 mg and 2.0 mg doses of Staccato alprazolam demonstrated efficacy in rapidly terminating seizures in an inpatient setting and were well tolerated. The next step is a Phase 3 confirmatory study to demonstrate efficacy and safety of Staccato alprazolam for rapid cessation of seizures in an outpatient setting.

Using machine learning techniques to characterize sleep-deprived driving behavior.

OBJECTIVE: Sleep deprivation is known to affect driving behavior and may lead to serious car accidents similar to the effects from e.g., alcohol. In a previous study, we have demonstrated that the use of machine learning techniques allows adequate characterization of abnormal driving behavior after alprazolam and/or alcohol intake. In the present study, we extend this approach to sleep deprivation and test the model for characterization of new interventions. We aimed to classify abnormal driving behavior after sleep deprivation, and, by using a machine learning model, we tested if this model could also pick up abnormal driving behavior resulting from other interventions. METHODS: Data were collected during a previous study, in which 24 subjects were tested after being sleep-deprived and after a well-rested night. Features were calculated from several driving parameters, such as the lateral position, speed of the car, and steering speed. In the present study, we used a gradient boosting model to classify sleep deprivation. The model was validated using a 5-fold cross validation technique. Next, probability scores were used to identify the overlap of driving behavior after sleep deprivation and driving behavior affected by other interventions. In the current study alprazolam, alcohol, and placebo are used to test/validate the approach. RESULTS: The sleep deprivation model detected abnormal driving behavior in the simulator with an accuracy of 77 ± 9%. Abnormal driving behavior after alprazolam, and to a lesser extent also after alcohol intake, showed remarkably similar characteristics to sleep deprivation. The average probability score for alprazolam and alcohol measurements was 0.79, for alcohol 0.63, and for placebo only 0.27 and 0.30, matching the expected relative drowsiness. CONCLUSION: We developed a model detecting abnormal driving induced by sleep deprivation. The model shows the similarities in driving characteristics between sleep deprivation and other interventions, i.e., alcohol and alprazolam. Consequently, our model for sleep deprivation may serve as a next reference point for a driving test battery of newly developed drugs.

Acute angle closure triggered by oral benzodiazepines / Fechamento angular agudo desencadeado por uso oral de benzodiazepínicos

ABSTRACT Benzodiazepines are psychoactive drugs that are prescribed worldwide with limited information on their ocular side effects. Acute angle closure glaucoma is an adverse event with a high risk of blinding, especially in the elderly. We report two patients under 45 years old who presented with bilateral acute angle closure secondary to use of two long half-life benzodiazepines (clonazepam and alprazolam). In addition to suspending the use of these medications and administering ocular hypotensive drugs, both patients were successfully treated with bilateral peripheral laser iridotomy. To the best of our knowledge, this is the first report of bilateral acute angle closure secondary to the use of clonazepam and alprazolam.(AU)

RESUMO Os benzodiazepínicos são medicamentos psicoativos prescritos em todo o mundo, mas com poucas informações sobre seus efeitos colaterais oculares. O glaucoma por fechamento agudo do ângulo iridocorneano é um dos eventos adversos com maior risco de cegueira, sendo descrito particularmente em idosos. Relatamos aqui dois pacientes com menos de 45 anos de idade, com fechamento agudo do ângulo bilateral secundário ao uso de dois diferentes benzodiazepínicos de meia-vida longa (clonazepam e alprazolam). Além da suspensão dessas medicações e do tratamento clínico com drogas hipotensoras oculares, ambos os casos alcançaram sucesso com iridotomias periféricas bilaterais à laser. Considerando o conhecimento atual, estes são os primeiros relatos de fechamento agudo do ângulo bilateral secundária ao uso de clonazepam e alprazolam.(AU)

Melatonin for preoperative and postoperative anxiety in adults.

BACKGROUND: Anxiety in relation to surgery is a well-known problem. Melatonin offers an alternative treatment to benzodiazepines for ameliorating this condition in the preoperative and postoperative periods. OBJECTIVES: To assess the effects of melatonin on preoperative and postoperative anxiety compared to placebo or benzodiazepines. SEARCH METHODS: We searched the following databases on 10 July 2020: CENTRAL, MEDLINE, Embase, CINAHL, and Web of Science. For ongoing trials and protocols, we searched clinicaltrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform. SELECTION CRITERIA: We included randomized, placebo-controlled or standard treatment-controlled (or both) studies that evaluated the effects of preoperatively administered melatonin on preoperative or postoperative anxiety. We included adult patients of both sexes (15 to 90 years of age) undergoing any kind of surgical procedure for which it was necessary to use general, regional, or topical anaesthesia. DATA COLLECTION AND ANALYSIS: One review author conducted data extraction in duplicate. Data extracted included information about study design, country of origin, number of participants and demographic details, type of surgery, type of anaesthesia, intervention and dosing regimens, preoperative anxiety outcome measures, and postoperative anxiety outcome measures. MAIN RESULTS: We included 27 randomized controlled trials (RCTs), involving 2319 participants, that assessed melatonin for treating preoperative anxiety, postoperative anxiety, or both. Twenty-four studies compared melatonin with placebo. Eleven studies compared melatonin to a benzodiazepine (seven studies with midazolam, three studies with alprazolam, and one study with oxazepam). Other comparators in a small number of studies were gabapentin, clonidine, and pregabalin. No studies were judged to be at low risk of bias for all domains. Most studies were judged to be at unclear risk of bias overall. Eight studies were judged to be at high risk of bias in one or more domain, and thus, to be at high risk of bias overall. Melatonin versus placebo Melatonin probably results in a reduction in preoperative anxiety measured by a visual analogue scale (VAS, 0 to 100 mm) compared to placebo (mean difference (MD) -11.69, 95% confidence interval (CI) -13.80 to -9.59; 18 studies, 1264 participants; moderate-certainty evidence), based on a meta-analysis of 18 studies. Melatonin may reduce immediate postoperative anxiety measured on a 0 to 100 mm VAS compared to placebo (MD -5.04, 95% CI -9.52 to -0.55; 7 studies, 524 participants; low-certainty evidence), and may reduce delayed postoperative anxiety measured six hours after surgery using the State-Trait Anxiety Inventory (STAI) (MD -5.31, 95% CI -8.78 to -1.84; 2 studies; 73 participants; low-certainty evidence). Melatonin versus benzodiazepines (midazolam and alprazolam) Melatonin probably results in little or no difference in preoperative anxiety measured on a 0 to 100 mm VAS (MD 0.78, 95% CI -2.02 to 3.58; 7 studies, 409 participants; moderate-certainty evidence) and there may be little or no difference in immediate postoperative anxiety (MD -2.12, 95% CI -4.61 to 0.36; 3 studies, 176 participants; low-certainty evidence). Adverse events Fourteen studies did not report on adverse events. Six studies specifically reported that no side effects were observed, and the remaining seven studies reported cases of nausea, sleepiness, dizziness, and headache; however, no serious adverse events were reported. Eleven studies measured psychomotor and cognitive function, or both, and in general, these studies found that benzodiazepines impaired psychomotor and cognitive function more than placebo and melatonin. Fourteen studies evaluated sedation and generally found that benzodiazepine caused the highest degree of sedation, but melatonin also showed sedative properties compared to placebo. Several studies did not report on adverse events; therefore, it is not possible to conclude with certainty, from the data on adverse effects collected in this review, that melatonin is better tolerated than benzodiazepines. AUTHORS' CONCLUSIONS: When compared with placebo, melatonin given as premedication (as tablets or sublingually) probably reduces preoperative anxiety in adults (measured 50 to 120 minutes after administration), which is potentially clinically relevant. The effect of melatonin on postoperative anxiety compared to placebo (measured in the recovery room and six hours after surgery) was also evident but was much smaller, and the clinical relevance of this finding is uncertain. There was little or no difference in anxiety when melatonin was compared with benzodiazepines. Thus, melatonin may have a similar effect to benzodiazepines in reducing preoperative and postoperative anxiety in adults.

ANTECEDENTES: La ansiedad relacionada con la cirugía es un problema conocido. La melatonina ofrece un tratamiento alternativo a las benzodiazepinas para mejorar esta afección en los períodos pre y posoperatorio. OBJETIVOS: Evaluar los efectos de la melatonina en la ansiedad pre y posoperatoria en comparación con el placebo o las benzodiazepinas. MÉTODOS DE BÚSQUEDA: Se realizaron búsquedas en las siguientes bases de datos el 10 de julio de 2020: CENTRAL, MEDLINE, Embase, CINAHL y Web of Science. Para los ensayos y protocolos en curso, se buscó en clinicaltrials.gov y en la Plataforma de registros internacionales de ensayos clínicos de la Organización Mundial de la Salud (OMS). CRITERIOS DE SELECCIÓN: Estudios aleatorizados controlados con placebo o controlados con tratamiento estándar, o ambos, que evaluaron los efectos de la melatonina administrada de forma preoperatoria para la ansiedad preoperatoria o posoperatoria. Se incluyeron pacientes adultos de ambos sexos (15 a 90 años de edad) a los que se les realizó cualquier clase de procedimiento quirúrgico donde fue necesario utilizar anestesia general, regional o tópica. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Un autor de la revisión realizó la extracción de los datos por duplicado. Los datos que se extrajeron incluyeron información acerca del diseño del estudio, el país de origen, el número de participantes y los detalles demográficos, el tipo de cirugía, el tipo de anestesia, la intervención y el régimen de dosis, medidas de desenlace de ansiedad preoperatoria y medidas de desenlace de ansiedad posoperatoria. RESULTADOS PRINCIPALES: Se incluyeron 27 ensayos controlados aleatorizados (ECA), con 2319 participantes, que evaluaron la melatonina para el tratamiento de la ansiedad preoperatoria, la ansiedad posoperatoria o ambas. Veinticuatro estudios compararon la melatonina con el placebo. Once estudios compararon la melatonina con una benzodiazepina (siete estudios con midazolam, tres estudios con alprazolam y un estudio con oxazepam). Otros comparadores en un escaso número de estudios fueron la gabapentina, la clonidina y la pregabalina. No se consideró que ningún estudio tuviera un riesgo bajo de sesgo en todos los dominios. La mayoría de los estudios se consideraron con riesgo incierto de sesgo en general. Se consideró que ocho estudios tenían un alto riesgo de sesgo en uno o más dominios y, por lo tanto, un alto riesgo de sesgo en general. Melatonina versus placebo La melatonina probablemente da lugar a una reducción de la ansiedad preoperatoria medida por una escala visual analógica (EVA, 0 a 100 mm) en comparación con el placebo (diferencia de medias [DM] ­11,69; intervalo de confianza [IC] del 95%: ­13,80 a ­9,59; 18 estudios, 1264 participantes; evidencia de certeza moderada), sobre la base de un metanálisis de 18 estudios. La melatonina podría reducir la ansiedad posoperatoria inmediata medida en una EVA de 0 a 100 mm en comparación con el placebo (DM ­5,04; IC del 95%: ­9,52 a ­0,55; siete estudios, 524 participantes; evidencia de certeza baja), y podría reducir la ansiedad posoperatoria tardía medida seis horas después de la cirugía mediante el State­Trait Anxiety Inventory (STAI) (DM ­5,31; IC del 95%: ­8,78 a ­1,84; dos estudios; 73 participantes; evidencia de certeza baja). Melatonina versus benzodiazepinas (midazolam y alprazolam) La melatonina probablemente da lugar a poca o ninguna diferencia en la ansiedad preoperatoria medida en una EVA de 0 a 100 mm (DM 0,78; IC del 95%: ­2,02 a 3,58; siete estudios, 409 participantes; evidencia de certeza moderada) y podría haber poca o ninguna diferencia en la ansiedad posoperatoria inmediata (DM ­2,12; IC del 95%: ­4,61 a 0,36; tres estudios, 176 participantes; evidencia de certeza baja). Eventos adversos Catorce estudios no informaron sobre los eventos adversos. Seis estudios informaron específicamente que no se observaron efectos secundarios y los siete estudios restantes informaron casos de náuseas, somnolencia, mareos y cefalea; sin embargo, no se informaron eventos adversos graves. Once estudios midieron la función psicomotora y cognitiva, o ambas, y en general, estos estudios encontraron que las benzodiazepinas deterioraron la función psicomotora y cognitiva más que el placebo y la melatonina. Catorce estudios evaluaron la sedación y en general encontraron que la benzodiazepina causaba el mayor grado de sedación, pero la melatonina también mostró propiedades sedantes en comparación con el placebo. Varios estudios no informaron sobre los efectos adversos; por lo tanto, no es posible concluir con certeza, a partir de los datos sobre los efectos adversos obtenidos en esta revisión, que la melatonina se tolera mejor que las benzodiazepinas. CONCLUSIONES DE LOS AUTORES: Cuando se compara con el placebo, la melatonina administrada como premedicación (en forma de comprimidos o sublingual) probablemente reduce la ansiedad preoperatoria en los adultos (medida entre 50 y 120 minutos después de la administración), lo que es potencialmente relevante desde el punto de vista clínico. El efecto de la melatonina sobre la ansiedad posoperatoria en comparación con el placebo (medido en la sala de recuperación y seis horas después de la cirugía) también fue evidente, pero fue mucho menor, y la relevancia clínica de este hallazgo no está clara. Hubo poca o ninguna diferencia en la ansiedad cuando la melatonina se comparó con las benzodiazepinas. Por lo tanto, la melatonina puede tener un efecto similar al de las benzodiazepinas en la reducción de la ansiedad pre y posoperatoria en los adultos.

Estudio comparativo de la calidad biofarmacéutica de Alprazolam 0, 5 mg comercializadas en el mercado peruano / Comparative study of the biopharmaceutical quality of Alprazolam 0. 5 mg commercialized in the Peruvian market

El Alprazolam pertenece a las benzodiazepinas. Sus efectos se atribuyen a que actúa sobre receptores de membrana específicos, lo cual facilita la acción inhibitoria presináptica y postsináptica del ácido γ-aminobutírico (GABA), especialmente en la formación reticular ascendente. Se utiliza para el tratamiento de los estados de ansiedad, crisis de angustia, ataques de pánico y estrés intenso. Este estudio se realizó para analizar los parámetros comparativos de control de calidad in vitro mediante la evaluación de la variación de peso, friabilidad, dureza, tiempo de desintegración, perfil y eficiencia de disolución entre el medicamento innovador (Xanax®) y multifuentes que son comercializados en el mercado peruano. Para realizarlo, se seleccionaron tabletas de Alprazolam 0,5 mg multifuente de diferentes laboratorios comparándolos con el medicamento innovador y se evaluaron las características fisicoquímicas y biofarmacéuticas. Los ensayos farmacopeicos se evaluaron según lo establecido en la USP 42. Los resultados de las pruebas fisicoquímicas indicaron que las muestras analizadas no tenían diferencia significativa y estaban dentro de lo establecido en la farmacopea, así mismo el perfil y eficiencia de disolución permitieron establecer que el comportamiento biofarmacéutico de las mismas era muy similar para ambos tipos de molécula. Se estableció que las tabletas multifuentes de Alprazolam 0,5 mg de esta investigación son bioequivalentes con el innovador, por lo que permite proponer a la comunidad científica la determinación de la equivalencia biofarmacéutica como elemento de apoyo en la toma de decisiones de compra en el servicio farmacéutico

Alprazolam belongs to benzodiazepines. Its effects are attributed to the fact that it acts on specific membrane receptors, which facilitates the presynaptic and postsynaptic inhibitory action of γ-aminobutyric acid (GABA), especially in the ascending reticular formation. It is used to treat anxiety states, panic attacks, and intense stress. This study was carried out to analyze comparative parameters of in vitro quality control by evaluating the variation in weight, friability, hardness, disintegration time, profile and dissolution efficiency between the innovative drug (Xanax®) and multi-sources tablets that are marketed in the Peruvian market. To perform this, Alprazolam 0.5 mg multi-source tablets were selected from different laboratories comparing them with the innovative medicine and the physicochemical and biopharmaceutical characteristics were evaluated. Pharmacopoeial trials were evaluated as established in USP 42. The results of physicochemical tests indicated that analyzed samples did not have a significant difference and were within the established in the pharmacopoeia, as well as the profile and dissolution efficiency allowed to establish that their biopharmaceutical behavior was very similar for both types of molecules. It was established that Alprazolam 0.5 mg multi-source tablets from this research are bioequivalent with innovator, which makes it possible to propose to scientific community determination of biopharmaceutical equivalency as a support element in decision-making process for purchasing services pharmacist

Differential effects of alprazolam against methylphenidate-induced neurobehavioral alterations.

BACKGROUND: In the previous decade, abuse of several types of prescription drugs, particularly anxiolytics, opioid analgesics, and stimulants has increased significantly worldwide. Methylphenidate (MPH) and Alprazolam (ALZ) are extensively used drugs for the treatment of attention deficit hyperactivity disorder (ADHD) and anxiety disorders, respectively. However, these drugs have a high risk of being misused or abused alone, and their combination in some peculiar cases has shown their deleterious effects. In this study, we evaluated the extent of damage both these drugs (MPH and ALZ) may cause in the brain at different dosages. METHODS: Female Wistar rats were administered with MPH (10, 20, 40mg/kg) and ALZ (5, 10, 20mg/kg) alone and in combination. Following the treatment, neurobehavioral studies were conducted, and later brain tissue was removed for studying the extent of oxidative stress and inflammation in the hippocampus and cortex region of the brain. Further histopathological parameters, along with neurotransmitter levels, were also assessed. RESULTS: Both MPH and ALZ, in combination, enhanced oxidative stress, inflammation, and neurobehavioral alterations in a dose-dependent manner. These toxic effects were associated with histopathological alterations and neurotransmitters levels CONCLUSIONS: In this study, it is found that the combination of psychostimulant (MPH) and depressant (ALZ) tends to enhance toxicity in the brain, and their long-term usage is a significant public health concern. Therefore, their co-administration should be strictly monitored by medical practitioners, and under compulsive circumstances, their use must be restricted to lower doses.

Little Helpers No More: A Framework for Collaborative Deprescribing of Benzodiazepines in Older Adults.

Benzodiazepines are a class of medications that tend to fly "under the radar" within the general population but nonetheless post a significant risk to older adults when not used appropriately. The current article aims to shine a spotlight on this medication class along with a framework for a team-based approach to successfully de-escalate use when clinically appropriate. [Journal of Psychosocial Nursing and Mental Health Services, 58(1), 23-28.].

Abuse Potential of Lasmiditan: A Phase 1 Randomized, Placebo- and Alprazolam-Controlled Crossover Study.

Lasmiditan is a centrally penetrant, highly selective 5-hydroxytryptamine (serotonin) receptor 1F (5HT1F ) agonist under development as a novel therapy for acute treatment of migraine. A phase 1 randomized, placebo- and positive-controlled crossover study assessed the abuse potential of lasmiditan in adult recreational polydrug users. Following a qualification phase, subjects were randomized into treatment sequences, each consisting of 5 study treatments: placebo, alprazolam 2 mg, lasmiditan 100, 200 (lasmiditan 100 and 200 mg are proposed therapeutic doses), and 400 mg (supratherapeutic). The abuse potential of lasmiditan was investigated and compared with alprazolam and with placebo using the maximal effect score (Emax ) of the Drug-Liking Visual Analog Scale as the primary end point. Lasmiditan was not similar to placebo in drug-liking scores at all doses tested, with a maximum difference observed with the lasmiditan 400-mg dose (upper 90% confidence limit on difference in least-squares [LS] means > 14 for all lasmiditan doses). Drug-liking scores for lasmiditan 400 mg were not significantly different from alprazolam (lower 90% confidence limit on difference in LS means < 5), but drug-liking scores at lower doses (100 and 200 mg) were significantly different from alprazolam. During the treatment phase, the incidence of treatment-emergent adverse events (TEAEs) increased with increasing dose of lasmiditan; all TEAEs reported with lasmiditan treatment were mild. Subjective drug-liking effects for lasmiditan versus placebo and versus alprazolam, and the safety and tolerability profile of lasmiditan suggest that lasmiditan has a low potential for abuse.

A prospective randomized study of efficacy of 2 treatment protocols in preventing recurrence of clinical signs in 51 male cats with obstructive idiopathic cystitis.

BACKGROUND: Urethral obstruction (UO) is a common complication of feline idiopathic cystitis (FIC). Robust treatment recommendations to prevent its recurrence are scarce. OBJECTIVES: To evaluate meloxicam treatment for prevention of clinical recrudescence in male cats with obstructive FIC. ANIMALS: Fifty-one client-owned cats. METHODS: Prospective, randomized clinical trial. Every male cat with FIC-associated UO was deemed eligible for the study and was recruited during hospitalization. After discharge, cats were treated with phenoxybenzamine and alprazolam for 2 weeks, with (24 cats) or without (27 cats) low-dose meloxicam (0.025 mg/kg/day PO) and monitored for 6 months. RESULTS: Cumulative number (%) of cats with recurrent UO at 10 days, 1-, 2-, and 6-months after discharge was 1 (2%), 2 (4%), 4 (8%), and 8 (16%), respectively. Overall, 12 (24%) cats experienced signs of recurrent FIC within 6 months, with (8 cats) or without (4 cats) concurrent UO. No difference in the cumulative incidence of UO within 6 months was detected with addition of meloxicam (odds ratio [95% confidence interval], 0.63 [0.13-2.97]; P = .70). All cats were alive at 6 months. CONCLUSIONS AND CLINICAL IMPORTANCE: No clinical benefit was detected with the addition of low-dose meloxicam to phenoxybenzamine and alprazolam treatment for 2 weeks after discharge. Nevertheless, this study was underpowered to identify potential differences, and its findings must be corroborated in larger studies.

Inhaled alprazolam rapidly suppresses epileptic activity in photosensitive participants.

OBJECTIVE: Treatment options for seizure clusters are limited; the need for easy-to-administer treatments remains. The Staccato system delivers drug deep into the lung via inhalation. In this phase 2a study, we investigated the ability of three different doses of Staccato alprazolam to suppress the electroencephalographic (EEG) photoparoxysmal response (PPR) compared with placebo in participants with photosensitive seizures. METHODS: Adults (18-60 years) with a diagnosis and history of PPR on EEG with or without an epilepsy diagnosis were eligible to participate. Participants received Staccato alprazolam 0.5, 1.0, and 2.0 mg, and Staccato placebo (twice) in random order. Intermittent photic stimulation and clinical assessments were performed at one predose and seven postdose time points. The primary endpoint of the study was the change in standardized photosensitivity range (SPR) in participants receiving each dose of Staccato alprazolam. RESULTS: Fifteen participants with a prior epilepsy diagnosis were screened; five were enrolled, randomized, and completed the study. All participants were white females with a mean (SD) age of 27.2 (6.8) years. All doses of Staccato alprazolam reduced the SPR at 2 minutes; the effect was sustained through 4 hours for the 0.5-mg dose and 6 hours for the 1.0- and 2.0-mg doses. The magnitude and duration of sedation and sleepiness were dose-related. Four participants (80%) experienced ≥1 adverse event (AE); none was severe or serious. Cough, diarrhea, dysgeusia, oral dysesthesia, sedation, and somnolence were experienced by two participants (40%) each. SIGNIFICANCE: This proof-of-concept study demonstrated that Staccato alprazolam 0.5, 1.0, and 2.0 mg rapidly suppressed epileptiform activity in photosensitive participants with epilepsy. The AE profile of Staccato alprazolam was similar to what has been reported for alprazolam for other indications. The results support further development of Staccato alprazolam as a rescue medication for the acute treatment of seizures.

Efectividad de una intervención no sedativa para prevenir las reacciones ansiosas y claustrofóbicas en la resonancia magnética / Effectiveness of a non-sedative intervention to prevent anxious and claustrophobic reactions in magnetic resonance imaging

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In session extinction and outcome in Virtual Reality Exposure Therapy for PTSD.

Recent research emphasizes emotional engagement and between-session extinction, but no longer within-session extinction, as the primary mechanisms underlying exposure therapy for the treatment of PTSD. No previous studies have examined change in subjective units of distress (SUDS) in virtual reality exposure (VRE) for PTSD despite its potential facilitation of engagement (see McLay et al., 2012; Reger & Gahm, 2008). Using in session data from Rothbaum et al. (2014) we examined patterns of within- and between-session SUDS change in veterans receiving VRE for PTSD augmented by d-cycloserine, alprazolam, or placebo. The number of treatment sessions significantly predicted SUDS rating (t = -7.74, p < 0.001). Time in session continued to serve as a significant predictor of SUDS (t = 13.44, p < 0.001). Specifically, engagement increased within session and then reduction (extinction/habituation) was apparent across sessions. Treatment group was a predictor of SUDS rating within treatment sessions (t = 2.26, p < 0.05) but not across sessions, such that participants receiving medication experienced greater increases in SUDS within-session than those receiving placebo. Responder status was a predictor of SUDS reduction across treatment sessions (t = -4.43, p < 0.001) but did not produce an overall or within-session effect on SUDS. Thus, medications impact within-session SUDS changes but do not impact between-session reductions in SUDS- the change most consistently and closely related to magnitude of therapeutic change and responder status.

Anticholinergic and sedative drug burden in community-dwelling older people: a national database study.

OBJECTIVES: The Drug Burden Index (DBI) tool quantifies individual exposure to anticholinergic and sedative medications. The DBI has been internationally validated against adverse health outcomes in older people. DBI exposure has not been reported in the Irish older population. This study aimed to: (1) develop a list of drugs with clinically significant anticholinergic and/or sedative effects (DBI medications) relevant to Ireland; (2) examine, using the DBI formula, the prevalence of exposure to DBI medications in Irish older people and (3) explore patient factors associated DBI exposure. DESIGN: A cross-sectional national pharmacy claims database study. SETTING: Community setting using the General Medical Services (GMS) scheme pharmacy claims database maintained by the Health Service Executive Primary Care Reimbursement Services. PARTICIPANTS: Irish older individuals (aged ≥65 years) enrolled in the GMS scheme and dispensed at least one prescription item in 2016 (n=428 516). MAIN OUTCOME MEASURES: Prevalence of exposure to DBI medications and patient factors associated with DBI exposure. RESULTS: 282 874 (66%) of the GMS population aged ≥65 years were exposed to at least one DBI medication in 2016. Prevalence of exposure to DBI medications was significantly higher in females than males (females 71.6% vs males 58.7%, adjusted OR 1.65, 95% CI 1.63 to 1.68). Prevalence of DBI exposure increased progressively with the number of chronic drugs used, rising from 42.7% of those prescribed 0-4 chronic drugs to 95.4% of those on ≥12 chronic drugs (adjusted OR 27.8, 95% CI 26.7 to 29.0). The most frequently used DBI medications were codeine/paracetamol combination products (20.1% of patients), tramadol (11.5%), zopiclone (9.5%), zolpidem (8.5%), pregabalin (7.9%) and alprazolam (7.8%). CONCLUSIONS: The majority of older people in Ireland are exposed to medications with anticholinergic and/or sedative effects, particularly females and those with multiple comorbidities. The high use of low-dose codeine/paracetamol combination products, Z-drugs and benzodiazepines, suggests there are opportunities for deprescribing.

[Acupuncture at back-shu points of five zang, Geshu (BL 17) and Shenmen (HT 7) for the treatment of menopausal insomnia].

OBJECTIVE: To compare the clinical efficacy differences between acupuncture at back-shu points of five zang, Geshu (BL 17), Shenmen (HT 7) and regular medication for the treatment of menopausal insomnia. METHODS: A total of 128 female patients of menopausal insomnia were randomly divided into an observation group and a control group, 64 cases in each one. Four patients in the observation group and 2 patients in the control group dropped out during the treatment. The patients in the observation group were treated with acupuncture at Feishu (BL 13), Xinshu (BL 15), Pishu (BL 20), Ganshu (BL 18), Shenshu (BL 23), Geshu (BL 17) and Shenmen (HT 7), once a day, and there was an interval of 2 days between every 5 days of treatment. The patients in the control group were treated with oral administration of alprazolam (0.4 mg or 0.8 mg) before sleep. Three-week treatment was taken as one course, and totally three courses were given in the two groups. Pittsburgh sleep quality index (PSQI), levels of estradiol (E2), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were observed before treatment and 30 days after treatment; the efficacy was evaluated 30 days after treatment. RESULTS: Each item score and total score of PSQI 30 days after treatment were lower than those before treatment in the two groups (all P<0.05), the scores in the observation group were lower than those in the control group (all P<0.05). The levels of E2 30 days after treatment were higher than those before treatment in the two groups (both P<0.05), but the level of FSH and LH 30 days after treatment were lower than those before treatment in the two groups; the level in the observation group was superior to that in the control group (all P<0.05). The total effective rate was 98.3% (59/60) in the observation group, which was better than 95.2% (59/62) in the control group (P<0.05). CONCLUSION: Acupuncture at Feishu (BL 13), Xinshu (BL 15), Ganshu (BL 18), Pishu (BL 20), Shenshu (BL 23), Geshu (BL 17), and Shenmen (HT 7) has better efficacy for menopausal insomnia than alprazolam.