Analysis of Forty-Two Psychoactive Substances in a Single Hair by Micro-Segmental Technique / 法医学杂志

OBJECTIVES@#To establish an LC-MS/MS method based on single hair micro-segmental technique, and verify the detection of 42 psychoactive substances in 0.4 mm hair segments.@*METHODS@#Each piece of single hair was cut into 0.4 mm segments and extracted by sonication and the segments were immersed in dithiothreitol-containing extraction medium. Mobile phase A was the aqueous solution containing 20 mmol/L ammonium acetate, 0.1% formic acid, and 5% acetonitrile. Mobile phase B was acetonitrile. An electrospray ionization source in positive ion mode was used for data acquisition in multiple reaction monitoring (MRM) mode.@*RESULTS@#The 42 psychoactive substances in hair had a good linear relationship within their respective linear ranges (r>0.99), the limits of detection were 0.2-10 pg/mm, the limits of quantification were 0.5-20 pg/mm, the intra-day and inter-day precisions were 1.5%-12.7%, the intra-day and inter-day accuracies were 86.5%-109.2%, the recovery rates were 68.1%-98.2%, and the matrix effects were 71.3%-111.7%. The method was applied to hair samples collected from one volunteer at 28 d after a single dose of zolpidem, with zolpidem detected in 5 hairs was 1.08-1.60 cm near the root tip, and the concentration range was 0.62-20.5 pg/mm.@*CONCLUSIONS@#The micro-segmental technique of single hair analysis can be applied to the investigation of drug-facilitated sexual assault cases.

Cognitive and balance dysfunctions due to the use of zolpidem in the elderly: a systematic review / Alterações cognitivas e de equilíbrio devido ao uso de zolpidem em idosos: uma revisão sistemática

ABSTRACT. Zolpidem is one of the most widely prescribed hypnotic (non-benzodiazepine) agents for sleep disorder. Recently, an increase in the demand for this drug has been observed, mainly in the elderly population. Objective: This study aims to analyze the acute effect of zolpidem on cognitive and balance dysfunctions in the elderly population. Methods: A study was conducted by two independent researchers in four virtual scientific information bases and included randomized controlled trials. The studies evaluated elderly patients using zolpidem. Cognitive and balance dysfunctions were analyzed. Results: Six articles were included. The mean age of the participants in the studies was 69 years. The following zolpidem dosages were evaluated: 5, 6.25, 10, and 12.5 mg. Comparing zolpidem and placebo, relating to the cognitive dysfunctions, there is no statistically significant difference between the groups. However, in relation to balance dysfunctions, there is a statistically significant difference between the intervention and the comparison, favoring placebo. Conclusions: Zolpidem, even in usual doses (5 mg and 10 mg), has shown to increase the risk for balance dysfunctions. However, this does not occur in relation to cognitive changes.

RESUMO. Zolpidem é um dos agentes hipnóticos (não benzodiazepínicos) mais prescritos para o manejo dos distúrbios do sono. Recentemente, observou-se um aumento na demanda por esse medicamento, principalmente pela população idosa. Objetivo: Este estudo visa analisar o efeito agudo do zolpidem em relação às alterações cognitivas e de equilíbrio na população idosa. Métodos: Uma busca em quatro bases de informação científica virtual foi feita por dois pesquisadores independentes e incluiu ensaios clínicos randomizados. Os estudos avaliaram o uso de zolpidem em pacientes idosos. Alterações cognitivas e de equilíbrio foram analisadas. Resultados: Seis artigos foram incluídos. A média de idade entre os estudos foi de 69 anos. As seguintes posologias foram analisadas: 5; 6,25; 10; e 12,5 mg. Em relação às alterações cognitivas, comparando-se zolpidem com placebo, não há diferença estatisticamente significativa entre os grupos. Entretanto, no desfecho alterações de equilíbrio, há diferença estatisticamente significativa entre intervenção e comparação, a favor do placebo. Conclusões: Zolpidem, mesmo em doses usuais (5 e 10 mg), mostrou aumentar o risco para alterações de equilíbrio, entretanto, isso não ocorre em relação às alterações cognitivas.

Sublingual and oral zolpidem for insomnia disorder: a 3-month randomized trial

Objective: To evaluate the safety and efficacy of a 5 mg sublingual dose of zolpidem, compared to a 10 mg oral dose, at bedtime and "as needed" following middle-of-the-night awakenings. Methods: Participants were randomized into an oral group (oral zolpidem 10 mg and sublingual placebo at bedtime and "as-needed") and a sublingual group (oral placebo and sublingual zolpidem 5 mg at bedtime and "as-needed"). Participants underwent medical evaluation, polysomnography, the psychomotor vigilance test, and completed questionnaires. Results: Of 85 patients, 67 met the criteria for insomnia (48±10 years; 79% women) and were randomized. Of these, 46 completed 92±5 days of treatment. Mild-to-moderate adverse events were reported by 25% of the participants, including headache, sleepiness, and dizziness. Both treatments decreased middle-of-the-night awakenings by an average of -3.1±2.3 days/week and increased total sleep time by 1.5 hours. Changes in sleep quality and insomnia severity scores were also favorable and comparable between groups: variation depended on continuation of treatment. Regarding PSG findings, sleep latency decreased more in the sublingual group than the oral group (-14±42 vs. 10±29 min; p = 0.03). The psychomotor vigilance test showed minor residual effects 30 minutes after awakening, which reversed after 2 hours. Conclusions: The safety and efficacy of both zolpidem formulations are comparable. The sublingual 5 mg dose induced sleep more rapidly. Clinical trial registration: NCT01896336

Treatment with zolpidem after ethanol administration potentiates the expression of ethanol-induced behavioral sensitization in mice

Contradictory findings suggest that the behavioral and abuse-related effects of ethanol are mediated by its action at α1 subunit-containing GABAA (α1GABAA) receptors. In the present study, we investigated the effects of a sub-chronic post-ethanol administration treatment with zolpidem, an α1-preferring positive allosteric modulator at GABAA receptors, on the subsequent expression of ethanol-induced behavioral sensitization in mice. Animals received ethanol (1.8 g/kg, ip) or saline treatments every other day for 15 days (8 treatment sessions) and were subsequently treated with zolpidem (0.5 mg/kg, ip) or vehicle 4 times on alternate days. At the end of the treatment phase, animals were challenged with saline or ethanol on separate days for the evaluation of the expression of conditioned locomotion and behavioral sensitization. Eight-day treatment with ethanol did not lead to the development of ethanol-induced behavioral sensitization. Animals treated with ethanol and subsequently administered vehicle showed similar locomotion frequencies during the last ethanol challenge compared to the control group receiving ethanol for the first time. Animals treated with ethanol and subsequently administered zolpidem expressed behavioral sensitization to ethanol during the ethanol challenge. The present study adds to the literature by providing further evidence of a role of α1GABAA receptors on the behavioral effects of ethanol. Because of the current highly prevalent co-abuse of ethanol and benzodiazepine drugs in humans, the use of zolpidem and other α1GABAA receptor ligands during ethanol withdrawal should be monitored carefully.

Polifarmácia e cognição em pacientes com idade avançada / Polypharmacy and cognition in elderly patients

Objetivo: Avaliar a prevalência da polifarmácia e da prescrição de medicações inapropriadas, bem como suas associações com a capacidade cognitiva e funcional do idoso. Métodos: Estudo observacional transversal, no qual foram analisadas as medicações prescritas em 141 prontuários para pacientes acima de 50 anos, em associação com testes que quantificaram a capacidade funcional e cognitiva deles. Resultados: Observou-se média de 4,41 medicamentos por paciente, sendo que 0,41 deles foram considerados inapropriado, segundo o critério de Beers. Verificou-se também relação estatisticamente significativa quanto ao número de medicações e testes que mediam a capacidade funcional e cognitiva dos idosos. Conclusão: O aumento da polifarmácia e da prescrição de medicações potencialmente inadequadas acarretou significativa piora da capacidade cognitiva e funcional do idoso

Objective: To evaluate the prevalence of polypharmacy and of the prescription of inappropriate medications, as well as their associations with the cognitive and functional capacity of the elderly. Methods: Cross-sectional observational study which analyzed the drugs prescribed in 141 medical records for patients over 50 years of age, associated with tests that quantified their functional and cognitive capacity. Results: An average of 4.41 medications per patient was observed, and 0.41 were considered inappropriate according to the Beers criteria. There was also a statistically significant relation regarding the number of medications and tests that measure the functional and cognitive capacity of the elderly. Conclusion: The increase in polypharmacy and in the prescription of potentially inappropriate medications led to a significant impairment of the cognitive and functional capacity of the elderly

In vitro and in vivo evaluation of nano-based films for buccal delivery of zolpidem

Abstract Insomnia is becoming increasingly prevalent in the world general population. Therapies used by patients include over-the-counter therapies, herbal and dietary supplements, and pharmacological or nonpharmacological treatments. Among these, zolpidem is a pharmacological treatment popularly used for insomnia. Zolpidem is well tolerated and especially efficacious for initiation of sleep, and therefore is effective for the treatment of sleep-onset insomnia. The purpose of the present study was to design and evaluate zolpidem nanoparticle-impregnated buccal films to prolong the duration of its action. Zolpidem nanospheres were prepared by double emulsion solvent evaporation and then loaded into buccoadhesive films (Z1-Z4) comprised of different concentrations of HPMC K100, Eudragit® RL 100, and carbopol 974P. The prepared films were characterized for physicomechanical properties, mucoadhesion, percent hydration, in vitro drug release, ex vivo permeation, and in vivo studies. In vitro drug release was found to depend upon film composition. Ex vivo studies showed that film Z4 had the highest flux. In vivo studies revealed that administration of zolpidem nanosphere-impregnated film enhanced absorption of the drug (p < 0.0001), with a higher peak plasma concentration (52.54 ± 8.22 ng/mL) and area under the curve from time 0 to α (236.00 ± 39.51 ng.h/mL) than oral administration. The increase in time taken to reach the maximum drug concentration (1.5 h) further signifies the potential of these films to provide prolonged drug release. Given these promising results, we concluded that these buccal films could be an alternative route for effective zolpidem delivery.

Tendencias de consumo de medicamentos ansiolíticos e hipnóticos en una población colombiana, 2008-2013 / Trends in the consumption of anxiolytic and hypnotic drugs in a Colombian population

Introducción: En Latinoamérica, los psicofármacos son el tercer grupo de medicamentos más comercializados, especialmente antidepresivos (35%) y ansiolíticos (5%). El objetivo es determinar el comportamiento del consumo y los costos de los ansiolíticos e hipnóticos en una población de pacientes afiliados al Sistema General de Seguridad Social en Salud de Colombia. Material y métodos: Estudio descriptivo observacional. Los datos para el análisis fueron las prescripciones de cualquier ansiolítico o hipnótico, realizadas a pacientes ambulatorios en el periodo comprendido entre enero de 2008 y diciembre de 2013 en una población de 3,5 millones de personas. Se consideraron variables sociodemográficas, farmacológicas, costos globales y costos por mil habitantes y día (CHD). Resultados: El número de pacientes que recibieron los medicamentos estudiados varió de 11.097 a 19.231 entre 2008 y 2013. Los medicamentos más utilizados fueron clonazepam (el 44,1% de las formulaciones), alprazolam (31,2%) y lorazepam (13,2%). El valor facturado de ansiolíticos pasó de 207.673,63 dólares en 2008 a 488.977 dólares en 2013, con un crecimiento del 135,4%. El CHD fue de 0,31 dólares para las benzodiazepinas y 0,02 dólares para los medicamentos Z en 2008 y 0,36 y 0,02 dólares en 2013 respectivamente. Los CHD se redujeron después del año 2010, tras la introducción de medicamentos genéricos. Conclusiones: Los pacientes que reciben benzodiazepinas en Colombia son en su mayoría mujeres, con 55 años de edad promedio, con muy baja frecuencia expresada en CHD comparada con la de otros países.

Introduction: In Latin America, psychotropic medications are the third most marketed drug group, especially antidepressants (35%) and anxiolytics (5%). The objective of this study was to determine the trends in the consumption and the costs of anxiolytic and hypnotic drugs in a population of patients enrolled in the Health System of Colombia. Material and methods: A descriptive, observational study was performed using the data recorded inprescriptions for any anxiolytic or hypnotic drug prescribed to outpatients in the period between January 2008 and December 2013 in a population of 3.5 million people. Sociodemographic, pharmacological variables, overall costs, and cost per thousand inhabitants per day (CHD), were also recorded. Results: The number of patients who received the drugs studied varied from 11,097 to 19,231 between 2008 and 2013. The most used drugs were clonazepam (44.1% of formulations), alprazolam (31.2%), and lorazepam (13.2%). The invoiced value of anxiolytics increased from US$ 207,673.63 in 2008 to US$ 488,977 in 2013, an increase of 135.4%. The CHD was US$ 0.31 for benzodiazepines, and US$ 0.02 for zaleplon, zolpidem and zopiclone (Z drugs) for 2008, and US$ 0.36 and US$ 0.02 in 2013 respectively. The CHD declined after 2010 following the introduction of generic drugs. Conclusions: Patients receiving benzodiazepines in Colombia are mostly women, average age 55 years, with very low frequency in defined daily doses per thousand inhabitants when compared with other countries.

Research Progress on Forensic Toxicology of Z-drugs / 法医学杂志

The Z-drugs (zolpidem, zopiclone, and zaleplon), as the innovative hypnotics, have an improvement over the traditional benzodiazepines in the management of insomnia. Z-drugs have significant hypnotic effects by reducing sleep latency and improving sleep quality, though duration of sleep may not be significantly increased. As benzodiazepines, Z-drugs exert their effects through increasing the transmission of γ-aminobutyric acid. Z-drugs overdose are less likely to be fatal, more likely would result in poisoning. Z-drugs can be detected in blood, urine, saliva, and other postmortem specimens through liquid chromatography-mass spectrometry techniques. Zolpidem and zaleplon exhibit significant postmortem redistribution. Z-drugs have improved pharmacokinetic profiles, but incidence of neuropsychiatric sequelae, poisoning, and death may prove to be similar to the other hypnotics. This review focuses on the pharmacology and toxicology of Z-drugs with respect to their adverse effect profile and toxicity and toxicology data in the field of forensic medicine.

Music therapy in the improvement of quality of sleep among elderly patients: A randomized controlled trial

BACKGROUND: Difficulty of sleeping is a predominant complaint among the elderly occurring in 12-25 percent of healthy seniors. Typical response of most physicians is to provide medications like benzodiazepines. Owing to the side effects of these drugs, alternatives to pharmacologic treatment such as music therapy abound. Music therapy is safe, affordable and may complement other non-pharmacologic interventions, yet there is paucity of evidence from controlled trials to support its efficacy.OBJECTIVE: To determine the efficacy of music therapy in improving quality of sleep among elderly patients with primary insomnia as compared to 1) Zolpidem and 2) Sleep hygiene using the Pittsburgh Sleep Quality Index (PSQI).METHODOLOGY: In a randomized controlled trial involving 78 male and female subjects aged 60-80 with primary insomnia seen at the Family Medicine Clinic, three interventions were employed: Treatment A (Music Therapy), Treatment B (Sleep Hygiene) and Treatment C (Zolpidem). To determine improvement in sleep quality, subjects answered the PSQI questionnaire at baseline and at 14 days after intervention. Comparison of the mean scores before and after intervention and the mean change in the Global PSQI and its sleep components was done to assess the efficacy of music therapy. An intention to treat analysis was done.RESULTS: Of the 90 participants enrolled, 78 completed the treatment protocol (Sleep hygiene = 27, Zolpidem = 24 and Music therapy = 27). Twelve were lost to follow-up. Baseline characteristics showed no significant differences among the three interventions in terms of age, gender, marital status, education, concomitant illnesses and insomnia severity. After 14 days of intervention, significant improvement in sleep quality with regard to 4 important parameters (latency, duration, efficiency, overall sleep quality) was consistently found in all the three intervention groups (p CONCLUSION: This controlled study conveys that music therapy is as efficacious as pharmacologic therapy and sleep hygiene in improving sleep quality. Instituting music therapy for 14 days improved sleep latency, duration, efficiency and overall sleep quality. It provided promising effect as a short term management alternative to primary insomnia. Its sustained effect has to be investigated.

Zolpidem in insomnia 3-year post-marketing surveillance study in the Philippines

A post-marketing surveillance study was conducted in the Philippines in routine practice and involved 1482 patients treated with zolpidem (Stilnox R), an imidazopyridine hypnotic agent. The patient population was 53.24 percent women and 45.28 percent men with a mean age of 47 years old (18.42 percent were over 65 years old). Of the patients, 44.26 percent were treated with a zolpidem dosage of 10 mg/day and 35.96 percent, 5mg/day. The treatment duration range from 2 to 35 days and a mean of 8 days. All adverse events were collected through spontaneous reporting. Thirty-nine patients (2.6 percent) reported 79 adverse events 20 (1.3 percent) of them discontinued treatment. CNS (central nervous system) related adverse events accounted for 70 percent of the total events. The most common events were headache and drowsiness the next day in 0.88 percent and 0.81 percent of the total cases respectivelv. Dizziness, lack of concentration, restlessness, hallucinations, nightmares, incoherence and disorientation were observed in a lower proportion, with one episode of twitching of the lower extremities. No serious adverse event was reported and no new risk factors or at-risk populations were identified. The safety profile of zolpidem is thus consistent with its known pharmacological properties, the results of previous clinical trials, and the cumulative international experience gained with this short-acting hypnotic drug.