Violence against women and drug-facilitated sexual assault (DFSA): A review of the main drugs.

Sexual violence is a universal phenomenon without restriction to sex, age, ethnicity or social class that causes devastating effects in the physical and mental health spheres, in the short-term and long-term, such as pregnancy, sexually transmitted infections (STI) and greater susceptibility to psychiatric symptoms, especially depression. Some cases of sexual assault and rape are based on the use of so-called drug-facilitated sexual assault (DFSA), which cause victims' loss of consciousness and inability to defend, making them vulnerable to violence. Thus, this article aimed to review the literature on gender violence and the drugs used to facilitate sexual assault, addressing their mechanism of action and pharmacokinetics, as well as drug detection times in human body and types of forensic identification. It is understood that the knowledge of these drugs and their pharmacological and diagnostic mechanisms should be widely disseminated, especially about sensitivity tests and the time the drug remains in the body, which would validate the promotion of evidence to prove abuse, and, thus, being able to give a promising outcome to cases of aggression, which is extremely beneficial for women.

Fragmentation studies of selected drugs utilized in palliative care.

The results of research on selected drugs used in palliative care are presented, including fentanyl, tramadol, metoclopramide, hyoscine butylbromide, midazolam, haloperidol, levomepromazine and clonazepam. Interpretation of their ESI mass spectra obtained by the use of a triple quadrupole linear ion trap mass spectrometer is given. As a result, fragmentation pathways described in the literature are complemented and presented with more details. On their basis, transitions for quantitative analysis are selected and chromatographic conditions for the determination of the palliative care drugs are proposed as well. These results enable future studies on palliative care drugs in elderly patients including both their quantitation in body fluids and easier identification of their metabolites.

Clonidine complexation with hydroxypropyl-beta-cyclodextrin: From physico-chemical characterization to in vivo adjuvant effect in local anesthesia.

Clonidine (CND), an alpha-2-adrenergic agonist, is used as an adjuvant with local anesthetics. In this work, we describe the preparation and characterization of an inclusion complex of clonidine in hydroxypropyl-beta-cyclodextrin (HP-ß-CD), as revealed by experimental (UV-vis absorption, SEM, X-ray diffraction, DOSY- and ROESY-NMR) and theoretical (molecular dynamics) approaches. CND was found to bind to HP-ß-CD (Ka=20M(-1)) in 1:1 stoichiometry. X-ray diffractograms and SEM images provided evidence of inclusion complex formation, which was associated with changes in the diffraction patterns of the pure compounds. NMR experiments revealed changes in the chemical shift of H3HP-ß-CD hydrogens (Δ=0.026ppm) that were compatible with the insertion of CND in the hydrophobic cavity of the cyclodextrin. Molecular dynamics simulation with the three CND species that exist at pH 7.4 revealed the formation of intermolecular hydrogen bonds, especially for the neutral imino form of CND, which favored its insertion in the HP-ß-CD cavity. In vitro assays revealed that complexation retarded drug diffusion without changing the intrinsic toxicity of clonidine, while in vivo tests in rats showed enhanced sensory blockade after the administration of 0.15% CND, with the effect decreasing in the order: CND:HP-ß-CD+bupivacaine>CND+bupivacaine>bupivacaine>CND:HP-ß-CD>clonidine. The findings demonstrated the suitability of the complex for use as a drug delivery system for clinical use in antinociceptive procedures, in association with local anesthetics.

A potential new metabolite of gamma-hydroxybutyrate: sulfonated gamma-hydroxybutyric acid.

Detection of gamma-hydroxybutyric acid (GHB) became crucial in many clinical and forensic settings due to its increasing use for recreational purposes and drug-facilitated sexual assault. Its narrow window of detection of about 3-12 h in urine represents a major problem. Analogous to ethyl glucuronide, the recently identified GHB-glucuronide exhibits a longer window of detection than the parent drug. It appeared reasonable that a sulfonated metabolite of GHB (GHB-SUL) will also be formed. Due to the lack of an appropriate standard, GHB was incubated with a human liver cytosolic fraction to produce GHB-SUL. Following development of a liquid chromatography/tandem mass spectrometry (LC-MS/MS) assay to measure GHB and GHB-SUL, authentic urine samples (n = 5) were tested for GHB-SUL. These investigations revealed detectable signals of both GHB and GHB-SUL, strongly indicating that GHB is not only glucuronidated but also sulfonated. Given that sulfonated metabolites generally have longer half-life times than the corresponding free drugs, GHB-SUL may serve as a biomarker of GHB misuse along with its glucuronide.

Injectable sodium pentobarbital: Stability at room temperature.

INTRODUCTION: Sodium pentobarbital (Nembutal) is a barbiturate used in research as an anesthetic in many animal models. The injectable form of this drug has lately become difficult to procure and prohibitively expensive. Due to this lack of availability, researchers have begun to compound injectable sodium pentobarbital from so-called "nonpharmaceutical" pentobarbital. Some oversight agencies have objected to this practice, claiming a lack of quality control and degradation of the drug. We sought with this study to establish both: 1) a protocol for the preparation of injectable sodium pentobarbital, and 2) standard operating procedures to monitor the quality of the preparation and degradation of the drug over time. METHODS: Our preparation consists of a mixture of sodium pentobarbital in alkaline aqueous solution, propylene glycol, and ethanol. Pentobarbital content in this preparation was assayed by high-pressure liquid chromatography (HPLC). We also assayed pentobarbital content over time in preparations of various ages up to 6 years old. RESULTS: We determined that the drug degraded at a maximum of 0.5% per year in our preparation (alkaline water/propylene glycol/ethanol) when stored in the dark at room temperature. A yellow discoloration developed after about 2 years, which we have arbitrarily determined disqualifies the preparation from use as an anesthetic. Attempts to spectroscopically assay this discoloration were not successful. CHEMICALS: Pentobarbital sodium (CID: 14075609).

Rapid determination of scopolamine in evidence of recreational and predatory use.

In recent years, scopolamine has become a drug of common use for recreational and predatory purposes and several ways of administration have been devised. A method for the rapid analysis of suspicious samples was developed, using a portable capillary electrophoresis with contactless conductivity detection. The method allows the separation of scopolamine from atropine which has a similar structure and is present along with scopolamine in some samples. The method was demonstrated to be useful for the fast analysis of several types of evidential items which have recently been reported to have been abused with fatal consequences or employed for criminal purposes. An infusion of Datura stramonium L., in which scopolamine and atropine naturally coexist, was analyzed for being frequently consumed for recreational purposes. A spiked moisturizing cream and six spiked alcoholic beverages were also analyzed. In spite of the complexity of the specimens, the sample pre-treatment methods developed were simple and fast.

Experimental design in formulation of diazepam nanoemulsions: physicochemical and pharmacokinetic performances.

With the aid of experimental design, we developed and characterized nanoemulsions for parenteral drug delivery. Formulations containing a mixture of medium-chain triglycerides and soybean oil as oil phase, lecithin (soybean/egg) and polysorbate 80 as emulsifiers, and 0.1 M phosphate buffer solution (pH 8) as aqueous phase were prepared by cold high-pressure homogenization. To study the effects of the oil content, lecithin type, and the presence of diazepam as a model drug and their interactions on physicochemical characteristics of nanoemulsions, a three factor two-level full factorial design was applied. The nanoemulsions were evaluated concerning droplet size and size distribution, surface charge, viscosity, morphology, drug-excipient interactions, and physical stability. The characterization revealed the small spherical droplets in the range 195 -220 nm with polydispersity index below 0.15 and zeta potential between -30 and - 60 mV. Interactions among the investigated factors, rather than factors alone, were shown to more profoundly affect nanoemulsion characteristics. In vivo pharmacokinetic study of selected diazepam nanoemulsions with different oil content (20%, 30%, and 40%, w/w) demonstrated fast and intense initial distribution into rat brain of diazepam from nanoemulsions with 20% and 30% (w/w) oil content, suggesting their applicability in urgent situations.

Benefits of methylated cyclodextrins in the development of midazolam pharmaceutical formulations.

Midazolam (MDZ) is a benzodiazepine commonly administered in preanesthesia of children by oral or by sublingual routes. To mask its bitter taste and enhance its aqueous solubility, we already developed a 0.2% (w/v) MDZ oral solution containing γ-cyclodextrin (γ-CD), which proves to be better accepted by children in pediatrics at University Hospital of Amiens. To improve the MDZ solubility, its closed form proportion in acidobasic equilibrium and its chemical stability, nuclear magnetic resonance, liquid chromatography-electrospray-high-resolution mass spectrometry, and tandem mass spectrometry methods were used to highlight the advantages of using partially methylated CD (2,6 di-O-methyl-ß-cyclodextrin) and randomized methylated-ß-cyclodextrin (RAMEB). The formation of 1:1 inclusion complex offered an improvement of the MDZ solubility and an increase of the closed and pharmacologically active form with a 33% gain when compared with the aqueous solution without CD. It was also demonstrated that RAMEB had a protecting effect on the MDZ degradation because it was found in almost 95% of remaining MDZ solution after 3 months at 40°C.

Advances in drug safety.

The operating room offers a unique setting where anesthetics, preoperative medications, patient comorbidities, and surgery all merge. Anesthesiologists are responsible for combining these concerns into a dependable and safe approach. From formulation to administration, enhancements in nearly every aspect of a given drug have improved the ability of anesthesiologists to accomplish this. Some of these methodologies, including novel anesthetics and analgesics, drug delivery and administration including infusion pumps, antithrombotics, and a reappraisal of previous medications are highlighted in this review. While these advancements are significant, patients and healthcare systems globally are rightfully demanding safer application of drugs at every level. On May 1, 2012, a report issued by the Institute of Medicine advised the United States Food and Drug Administration to undertake a much more rigorous patient-centered effort to evaluate a drug's safety over its entire life-cycle. This recommendation is in agreement with the objectives of the Anesthesia Patient Safety Foundation. With these mutual goals shared by many stakeholders and their continued efforts, the future of the estimated 200 million global surgeries to be undertaken this year hopefully provides a safer experience while under anesthesia.

The use of sodium oxybate to treat narcolepsy.

Narcolepsy is a life-long neurodegenerative disorder that causes considerable impairment to quality of life. Until the 1970s, the treatment for one of the main symptoms, excessive daytime sleepiness, was restricted to stimulants, whereas the second core symptom, cataplexy, was treated with antidepressants, and the resultant fragmented night-time sleep with hypnotics. Sodium oxybate (Xyrem(®), UCB Pharma, Brussels, Belgium) is an efficacious drug for all three symptoms which improves the quality of life of narcoleptic patients. Owing to its metabolic pathway, there is very little pharmacokinetic interaction with other drugs. In combination with modafinil, some of its therapeutic benefits are enhanced. Adverse events and side effects are moderate when taken according to indication and as recommended. Essential limitations have to be considered before starting the treatment (sleep-related breathing disorders, alcohol intake, hypnotic and sedative comedication, and epilepsy). This article gives an overview of sodium oxybate, which has been US FDA approved for the treatment of cataplexy and excessive daytime sleepiness in patients with narcolepsy, and EMA approved for the treatment of narcolepsy-cataplexy.

Simultaneous quantification of triazolam and its metabolites in human urine by liquid chromatography-tandem mass spectrometry.

A simple, simultaneous, sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS-MS) method for the determination of triazolam and its metabolites, α-hydroxytriazolam (α-OHTRZ) and 4-hydroxytriazolam (4-OHTRZ), in human urine was developed and validated. Triazolam-d4 was used as the internal standard (IS). This analysis was carried out on a Thermo(®) C(18) column, and the mobile phase was composed of acetonitrile/H(2)O/formic acid (35:65:0.2, v/v/v). Detection was performed on a triple-quadrupole tandem MS using positive ion mode electrospray ionization, and quantification was performed by multiple reaction monitoring mode. The MS-MS ion transitions monitored were m/z 343.1 → 308.3, 359.0 → 331.0, 359.0 → 111.2, and 347.0 → 312.0 for triazolam, α-OHTRZ, 4-OHTRZ, and triazolam-d(4), respectively. The lower limits of quantification of the analytical method were 0.5 ng/mL for triazolam, 5 ng/mL for α-OHTRZ, and 0.5 ng/mL for 4-OHTRZ. The within- and between-run precisions were less than 15%, and accuracy was -12.33% to 9.76%. The method was proved to be accurate and specific, and it was applied to a urinary excretion study of triazolam in healthy Chinese volunteers.

Assessment of the densities of local anesthetics and their combination with adjuvants: an experimental study.

BACKGROUND AND OBJECTIVES: The relative density of a local anesthetic in relation to that of the cerebrospinal fluid (CSF) at 37 degrees C is one of the most important physical properties that affect the level of analgesia obtained after the subarachnoid administration of the drug. The objective of this study was to determine the density of local anesthetic solutions, with and without glucose, and the combination of the local anesthetic with adjuvants at 20 degrees C, 25 degrees C, and 37 degrees C. METHODS: The density (g.mL(-1)) was determined by using a DMA 450 densimeter with a sensitivity of +/- 0.00001 g.mL(-1). The densities, and variations, according to the temperature were obtained for all local anesthetics and their combination with opioids at 20 degrees C, 25 degrees C, and 37 degrees C. The solution is hyperbaric if its density exceeds 1.00099, hypobaric when its density is lower than 1.00019, and isobaric when its density is greater than 1.00019 and lower than 1.00099. RESULTS: The densities of both local anesthetics and adjuvants decrease with the increase in temperature. At 37 degrees C, all glucose-containing solutions are hyperbaric. In the absence of glucose, all solutions are hypobaric. At 37 degrees C, morphine, fentanyl, sufentanil, and clonidine are hypobaric. CONCLUSIONS: The densities of local anesthetics and adjuvants decrease with the increase in temperature and increase when glucose is added. The knowledge of the relative density helps select the most adequate local anesthetic to be administered in the subarachnoid space.

Dexmedetomidine: a useful adjunct to consider in some high-risk situations.

Dexmedetomidine is a relatively selective alpha2 agonist with sympatholytic, sedative, amnestic, and analgesic properties. It is indicated for the short-term sedation of patients needing mechanical ventilation in the intensive care unit. Recent reports have been published describing dexmedetomidine as a useful adjunct in both regional and general anesthesia. A few case studies have demonstrated successful use of dexmedetomidine as a replacement agent for opioids in patients in whom airway compromise was a concern. This article will provide the reader with a comprehensive review of the pharmacology, pharmacokinetics, and adverse effects of dexmedetomidine. A thorough understanding of this drug will enable the anesthesia provider to determine situations in which dexmedetomidine may be a useful drug to consider, whether as an adjunct or as a sole agent.

Articaine: an effective adjunctive local anesthetic for painless surgery at the depth of the muscular fascia.

BACKGROUND: Articaine is a unique amide anesthetic that contains a thiophene ring and an additional ester group. The rapid diffusion and enhanced tissue-penetrating properties of articaine enable its use for infiltrative anesthesia. OBJECTIVE: To describe the effective use of articaine as an adjuvant local anesthetic for surgical excisions requiring dissection at the level of the muscular fascia. METHODS AND MATERIALS: We discuss the successful adjunctive use of articaine to provide effective infiltrative anesthesia of muscular fascia. We review the composition, the pharmacologic properties, and the safety profile of articaine. RESULTS: Adjuvant local anesthesia using articaine results in painless surgery at the level of the muscular fascia without any perioperative complications. CONCLUSION: Articaine is not only well tolerated but also rapidly effective for anesthesia in the fascial plane of the trunk and extremities. We recommend it be considered as an adjunctive local anesthetic for consistently painless cutaneous surgery near the muscular fascia.

Extractionless GC/MS analysis of gamma-hydroxybutyrate and gamma-butyrolactone with trifluoroacetic anhydride and heptafluoro-1-butanol from aqueous samples.

gamma-Hydroxybutyrate (GHB) is a DEA Schedule I drug of abuse commonly spiked into beverages to incapacitate victims of sexual assault. GHB is a challenging drug for analysis by GC/MS because of its small size, charged nature, low volatility, and intramolecular esterification leading to gamma-butyrolactone (GBL). In this work an extractionless technique has been developed that allows for the use of an aqueous sample for direct derivatization. The technique uses a solution of trifluoroacetic anhydride (TFAA) and 2,2,3,3,4,4,4-heptafluoro-1-butanol (HFB) to derivatize the active hydrogens of GHB. The conversion of GBL into GHB can be forced under alkaline conditions by diluting the sample in 10 mM borate buffer, pH 12. GBL found in beverages intended for human consumption is treated as a Schedule I control substance analogue. Spikes of the two compounds into several beverage matrices gave quantitative recovery of GHB by GC/MS. The derivatization produces higher molecular mass products whose fragmentation pattern provides multiple peaks for confirmation and quantification. The concentration of GBL can also be indirectly determined by the method developed. Therefore, this extractionless technique is rapid, sensitive, and selective for the confirmation of the presence of GHB and GBL in commercial beverages.

GHB: a new and novel drug of abuse.

There has been increasing attention in the United States to problems of abuse of gamma-hydroxybutyrate (GHB), with some evidence for problems in other parts of the world as well. In vitro and animal research show that, while GHB shares some properties with abused central nervous system depressant drugs, it has unique aspects of its pharmacology as well, including actions at a specific neural receptor which probably mediates many of its effects. Abuse potential assessment of GHB using standard animal models has not yielded a picture of a highly abusable substance, but little human testing has yet been done. Very little systematic data exist on tolerance and dependence with GHB, but both have been seen in human users. Quantitative data on the prevalence of GHB abuse is incomplete, but various qualitative measures indicate that a mini-epidemic of abuse began in the late 1980s and continues to the present. GHB is often included with the group of 'club drugs', and can be used as an intoxicant. It also has been used as a growth promoter and sleep aid and has been implicated in cases of 'date rape', usually in combination with alcohol. Undoubtedly the easy availability of GHB and some of its precursors has contributed to its popularity. Recent changes in the control status of GHB in the US may reduce its availability with as yet unknown consequences for the scope of the public health problem. Drug abuse experts need to familiarize themselves with GHB as possibly representing a new type of drug abuse problem with some unique properties.

Gamma-hydroxybutyrate, gamma-butyrolactone, and 1,4-butanediol: a case report and review of the literature.

GHB, GBL, and 1,4-BD are prevalent drugs of abuse in the United States. Unfortunately, attempts to regulate GHB have been circumvented by clandestine trafficking through the Internet and marketing of "natural" chemical precursors . Despite repeated FDA warnings to the public about their dangers as well as recent federal scheduling of GHB and GBL, they remain accessible as "club drugs" on Internet websites, as natural dietary supplements in health food stores, and as illicit products manufactured at home or in clandestine laboratories. EDs and poison control centers nationwide will undoubtedly continue to manage GHB, GBL, and 1,4-BD toxicities.