In Vivo Photoadduction of Anesthetic Ligands in Mouse Brain Markedly Extends Sedation and Hypnosis.

Photoaffinity ligands are best known as tools used to identify the specific binding sites of drugs to their molecular targets. However, photoaffinity ligands have the potential to further define critical neuroanatomic targets of drug action. In the brains of WT male mice, we demonstrate the feasibility of using photoaffinity ligands in vivo to prolong anesthesia via targeted yet spatially restricted photoadduction of azi-m-propofol (aziPm), a photoreactive analog of the general anesthetic propofol. Systemic administration of aziPm with bilateral near-ultraviolet photoadduction in the rostral pons, at the border of the parabrachial nucleus and locus coeruleus, produced a 20-fold increase in the duration of sedative and hypnotic effects compared with control mice without UV illumination. Photoadduction that missed the parabrachial-coerulean complex also failed to extend the sedative or hypnotic actions of aziPm and was indistinguishable from nonadducted controls. Paralleling the prolonged behavioral and EEG consequences of on target in vivo photoadduction, we conducted electrophysiologic recordings in rostral pontine brain slices. Using neurons within the locus coeruleus to further highlight the cellular consequences of irreversible aziPm binding, we demonstrate transient slowing of spontaneous action potentials with a brief bath application of aziPm that becomes irreversible on photoadduction. Together, these findings suggest that photochemistry-based strategies are a viable new approach for probing CNS physiology and pathophysiology.SIGNIFICANCE STATEMENT Photoaffinity ligands are drugs capable of light-induced irreversible binding, which have unexploited potential to identify the neuroanatomic sites of drug action. We systemically administer a centrally acting anesthetic photoaffinity ligand in mice, conduct localized photoillumination within the brain to covalently adduct the drug at its in vivo sites of action, and successfully enrich irreversible drug binding within a restricted 250 µm radius. When photoadduction encompassed the pontine parabrachial-coerulean complex, anesthetic sedation and hypnosis was prolonged 20-fold, thus illustrating the power of in vivo photochemistry to help unravel neuronal mechanisms of drug action.

Stability of midazolam in syrspend SF and syrspend SF cherry.

Midazolam is a short-acting benzodiazepine central nervous system depressant available as an injection, tablet, or oral syrup. The need for alternative dosage form options for patients unable to take tablets and shortages of other forms of the drug have led compounding pharmacies to seek alternatives, mainly solutions and suspensions. Additionally, some patients are unable to use suspending agents containing alcohol or sorbitol. The objective of this study was to determine the stability of midazolam in sorbitol-free, alcohol-free SyrSpend SF and SyrSpend SF Cherry suspending agents. The studied samples were compounded into a 1-mg/mL suspension and stored in low-actinic plastic bottles at temperatures between 2 degrees C to 8 degrees C and at room temperature conditions. Six samples were assayed at each time point out to 58 days by a stability-indicating high-performance liquid chromatography method. The method was validated for its specificity through forced-degradation studies. The samples remained within 90% to 110% of the initial concentration throughout the course of the study. Based on the data collected, the beyond-use date of these preparations is at least 58 days when protected from light at both refrigerated and room temperature storage conditions.

Stability evaluation of 7 % chloral hydrate syrup contained in mono and multi-dose bottles under room and refrigeration conditions.

PURPOSE: To evaluate the stability of an extemporaneously prepared 7% chloral hydrate syrup under different conditions of storage and dispensing. METHODS: Three batches of 7% chloral hydrate syrup were prepared. Each batch was stored in 50 light-resistant glass containers of 60 mL with child-resistant caps and in two bottles of 1000 mL to simulate two forms of dispensing, mono and multi-dose, respectively. Twenty five mono-dose bottles and a multi-dose bottle of each batch were stored under room conditions (20 ± 1 °C) and the rest of the samples were stored in the fridge (5 ± 2 °C). The physical, chemical and microbiological stability was evaluated for 180 days. Stability was defined as retention of at least 95% of the initial concentration of chloral hydrate, the absence of both visible particulate matter, or color and/or odor changes and the compliance with microbiological attributes of non-sterile pharmaceutical products. RESULTS: At least 98% of the initial chloral hydrate concentration remained throughout the 180-day study period. There were no detectable changes in color, odor, specific gravity and pH and no visible microbial growth. These results were not affected by storage, room or refrigeration conditions or by the frequent opening or closing of the multi-dose containers. CONCLUSIONS: Extemporaneously compounded 7% chloral hydrate syrup was stable for at least 180 days when stored in mono or multi-dose light-resistant glass containers at room temperature and under refrigeration.

Aqueous phototransformation of diazepam and related human metabolites under simulated sunlight.

Phototransformation of the widely used benzodiazepine pharmaceuticals diazepam and human metabolites nordiazepam, temazepam and oxazepam under simulated sunlight in water was investigated. Photolysis experiments were conducted in the presence and absence of humic acids. Half-lives for each of the benzodiazepine pharmaceuticals were <200 h (under all conditions) suggesting that phototransformation is an important process for such chemicals in the photic zone of receiving waters. Due to the observed phototransformation of the benzodiazepines, significant emphasis was placed on identification of the photoproducts. A total of fourteen photoproducts, including benzophenones, acridinones and quinazolinones or quinazolines was identified and measured by liquid chromatography-multistage mass spectrometry (LC-MS(n)). Phototransformation studies were also undertaken on authentic samples of two of the identified photoproducts, 5-chloro-methylaminobenzophenone and 2-amino-5-chlorobenzophenone, in order to establish the phototransformation pathways. Interestingly, these two photoproducts showed relatively higher persistence than some of the benzodiazepines, suggesting that the fate and effects of photoproducts should also be incorporated into future risk assessments and environmental models of the fate of benzodiazepines.

Abuso y dependencia de zopiclona y zolpidem: presentación de tres casos / Zopiclone and zolpidem abuse and dependence: presentation of three cases

La zopiclona y el zolpidem son considerados desde su comercialización fármacos no benzodiacepínicos, eficaces en el tratamiento a corto plazo del insomnio, con pocos efectos secundarios y un riesgo mínimo de producir tolerancia, abuso, dependencia o síntomas de abstinencia. Presentamos 3 tres casos clínicos de abuso y dependencia de estas sustancias, con síntomas de abstinencia graves, en 3 mujeres, dos de ellas con antecedentes de abuso de alcohol. Se discute, tras revisión MEDLINE de la bibliografía, los riesgos de mal uso asociados a la prescripción de estos fármacos, para concluir que, en determinados pacientes, existe un potencial de abuso y dependencia de la zopiclona y zolpidem. Parece necesario revaluar el riesgo de dependencia de los hipnóticos no benzodiacepínicos disponibles. Es aconsejable hacer las mismas recomendaciones a los pacientes en tratamiento con zopiclona y zolpidem que las que habitualmente se hacen al prescribir benzodiacepinas. En algunos casos, la prescripción sin receta de estos medicamentos puede haber contribuido al consumo abusivo sin control médico. Con el objetivo de facilitar la lectura del artículo y el acceso a referencias bibliográficas, abordaremos ambas sustancias por separado, aunque se consideren las conclusiones de forma conjunta (AU)