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A method for the determination of zolpidem and its main metabolites in urine without extraction using capillary electrophoresis with UV laser-induced fluorescence detection with a He-Cd laser was reported by Hempel and Blaschke. No organic solvents are necessary. This procedure is very simple and fast. A 10-nl sample of urine can be directly applied to the capillary. Read full chapter. The separation is carried out within 10 min, and the limit of detection is 2 ng/ml.
23 In 2012, compounds like 16 (triazolo-quinoxalines) were identified to be dual PDE2 and PDE10 inhibitors. The compounds in Table 4.2 represent an improvement in terms of CNS drug-likeness over the compounds in Table 4.1. The exemplified compound 17 was highlighted in a publication that discussed the SAR and in vivo potency as a dual inhibitor (PDE2 IC 50 = 2.8 nM; PDE10 IC 50 = 35 nM). 8,9 This compound has relatively poor human PK properties, but reportedly was possible to achieve full target coverage by using a modified release formulation. A recent publication includes selective PDE2 inhibitors 18 and 4, with the latter compound owing its selectivity to the 5-trifluoromethyl-pyridin-2-yl group. 24 In 2013, a patent application appeared on the same scaffold and again dual inhibitors were identified. 26 From the extensive data in the patent applications, it is evident that the 3-phenoxy-propan-1-ol moiety is responsible for the exquisite PDE2 selectivity for the highlighted compound 16 (PDE2 IC 50 = 14 nM; PDE10 IC 50 > 1000 nM). Recent disclosures include tetraaza-cyclopentanaphthalenes like 12 and 13 as PDE10 inhibitors, with a number of these compounds being dual inhibitors of both PDE10 and PDE2. Read full chapter. 25 The application additionally contains several radioligands and claims their use as diagnostics. 22 However, structurally related 14 (benzoimidazo-triazines) and 15 (pentaaza-cyclopentanaphthalenes) were found to be primarily PDE10 inhibitors, or compounds showing additional significant inhibitory activity versus PDE2.
Briggs, M. C.A. Gopalakrishnan, in Comprehensive Medicinal Chemistry II, 2007.
Examples of clinically available compounds include clonazepam, prazepam, tofisopam, cloxazolam, pinazepam, estazolam, flunitrazepam, camazepam, temazepam, nimetazepam, delorazepam, clobazam, ketazolam, lormetazepam, alprazolam, halazepam, oxazolam, doxefazepam, flutazolam, mexazolam, quazepam, flutoprazepam, metaclazepam, and cinolazepam. Flumazenil is a benzodiazepine antagonist marketed for benzodiazepine or alcohol overdose. Many were launched in the mid 1970s to mid 1980s. Benzodiazepines are well-known CNS therapeutics whose sedative/hypnotic, antiepileptic, and anxiolytic activities are primarily due to positive allosteric modulation of GABA A LGIC. Nonbenzodiazepines that appear to act through the benzodiazepine GABA A modulatory site include thiazoles such as clomethiazole, thienodiazepines like clotiazepam, etizolam, and brotizolam, benzoxazines like etifoxine, the benzothienodiazepine bentazepam, the piperazinecarboxylic acid zopiclone, the pyrazolopyrimidine zaleplon, and the cyclopyrrolone pagoclone.
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The proposed method is a rapid procedure of analysis in cases of deliberate poisoning with the sedative–hypnotic drug, zolpidem. An ingestion of an unknown quantity of Ivadal (zolpidem) tablets in a case of drug abuse is described by Keller et al. Quantitation of zolpidem was performed by ethyl acetate extraction from alkalinized body fluids before GC/MS analysis. The authors report a new and fast method of analyzing and determining the zolpidem concentration in postmortem specimens. The analyses were performed without any complex sample clean-up steps and with little sample material. Postmortem concentrations of zolpidem in body fluids are given.
Read full chapter. Agents launched primarily for the treatment of epilepsy include tiagabine, a GABA reuptake inhibitor that acts indirectly by increasing extracellular GABA levels, and vigabatrin, a compound that acts as both a GABA aminotransferase inhibitor, which would increase GABA levels, and a dopamine receptor antagonist. Other compounds thought to exert a component of their actions at GABA A LGIC include: pregabalin (diabetic neuropathy, epilepsy), a GABA analog that acts as a GABA A LGIC agonist (also α2δ Ca2+ channel ligand); substituted thiophenes (e.g., Merck's 6,6-dimethyl-3-(2-hydroxyethyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one) and naphthyridenes (AC-3933) that are GABA A inverse agonists for cognitive impairment; TP-003 that is a GABA A α3 selective modulator for cognitive impairment, anxiety, and epilepsy; ELB-139, a GABA A α3 selective modulator/inverse agonist for anxiety, psychoses, and epilepsy; THIP, a muscimol analog and GABA A agonist sedative–hypnotic. Another approach to potentiation of GABA A LGIC takes advantage of the neurosteroid example, as exemplified with alphadolone and ganaxolone. Other GABA A agonist anxiolytic molecules include ocinaplon, SL 651498, and PNU 101017.
Meagher, R. T.P. Murugan, in Comprehensive Heterocyclic Chemistry III, 2008.
Interest in 2,3-benzodiazepines continues because of their therapeutic potential in CNS disorders <2001RMC243, 2000MI309>. Unlike 1,4-benzodiazepines, such as diazepam (Valium) and chlordiazepoxide (Librium), they have nonsedative character and lack the potential undesirable side effects when combined with other drugs or alcohol.
These factors should be considered as potential confounding variables for the outcome of the pregnancy, including the occurrence of oral clefts. Alprazolam, chlordiazepoxide, diazepam and oxazepam were the primary substances recorded. Read full chapter. In a meta-analysis by Dolovich (1998), the collected data of cohort studies with pregnant women who were treated with benzodiazepines showed no increased risk for anomalies. However, conclusion of an analysis of the available retrospective case-control studies revealed an increased risk for major malformations or for isolated oral clefts after treatment with benzodiazepines ( Dolovich 1998 ). An update of the 1998 Dolovich meta-analysis, which incorporated cohort studies with a total of more than 4,000 pregnant women ( Enato 2011 ), did not reveal any increased risk of malformations (OR 1.07; 95% CI 0.91–1.25). The doubling of the frequency of oral clefts would mean that, based on a background risk of 8.5/10,000, one additional oral cleft could be expected in every 1,000 fetuses exposed in the first trimester. Wikner (2007a) stressed that women who take benzodiazepines tend to smoke more frequently, take other psychotropic medications and have less education. In this updated meta-analysis, two additional large cohort studies with a total of 3,000 pregnant women exposed in the first trimester ( Oberlander 2008, Wikner 2007a ) were included.
Read full chapter. The 1,2-diazepine Cilazapril 98 is an angiotensin-converting enzyme inhibitor and its design and synthesis have been reported <1986J(P1)1011, 1999WO99/55724>.
21 Nevertheless, compound 11 is a potent PDE2 inhibitor (IC 50 = 1.8 nM). One of the first PDE2 inhibitor programs culminated in the identification of a very potent and selective compound 5 (Bay. A recent disclosure explored 9 ( tofisopam ) 15 and related compounds. 13 Despite good calculated properties, the best compound, 6 (ND70010), is a Pgp substrate. Both of these scaffolds appear to have relatively poor CNS drug-like characteristics. Additionally, two structurally distinct chemotypes: pyridopyrimidines 7, with poor CNS drug-like properties, and oxindoles 8 that display promising calculated profiles have been reported. 12 In 2004 and 2007, a series of benzodiazepinones as PDE inhibitors were reported. More recently, two different (but structurally somewhat related) chemotypes have been disclosed as PDE2 inhibitors, namely 8-aminoquinolines ( 10 ) and dihydro-quinolin-2-ones ( 11 ). This moiety is present in 23% of the exemplified compounds, while 36% contain a nitrile in that position, suggesting that it is possible to reduce the HBD count by two and still maintain the topological polar surface area in a favorable range. Furthermore, a majority of compounds contain the mono-substituted thiophene, a structural alert. One can speculate that the two hydrogen bond donors in the carboxamide are responsible for the poor CNS penetration. 17 Additional work may have been discontinued on these structural classes, 18 perhaps due to the lack of rotatable bonds, the secondary amide linker, and the tricyclic core suggesting that the solubility may have been an issue. 19,20 Compounds from this series contain a (4-amino-pyridin-3-yl)-methanol substructure; an advantage being that an intramolecular hydrogen bond may mask one of the two hydrogen bond donors. 16 These compounds have potential issues for CNS applications; in particular, two or more phenolic hydrogen bond donors, leading to concerns with respect to brain penetration and phase II metabolism. 11 The combination of a relatively high molecular weight and topological polar surface area and the presence of a hydrogen bond donor are probably responsible for the p -glycoprotein liabilities associated with the lead compound. 10 In general, the compounds from this series are characterized by poor CNS drug-like properties as illustrated by the data in Table 4.1. Additionally, some of these compounds feature an ester group instead of the primary alcohol, raising concerns with respect to plasma stability and potential BBB penetration issues for the corresponding carboxylic acids. 12 Nevertheless, it was efficacious in animal assays of anxiety 14 and was advanced to phase I clinical trials in 2005.
Nagwa H. Ali, in Profiles of Drug Substances, Excipients and Related Methodology, 2012. Foda, Shaimaa M.
Both methods have been successfully applied to pharmaceutical formulations. Another HPLC method was developed by El Zeany et al. HPLC was performed on a Bondapak C 18 column. The results obtained were statistically compared with those obtained by applying the reported methods. The pH was adjusted to 3.5 ± 0.1. Flow rate was 1.2 ml/min. Calibration graphs were linear in the range of 0.5–5 μg/ml with UV detection at 245 nm. The mobile phase was composed of a mixture of acetonitrile 0.01 M KH 2 PO 4 (40:60).
The most experience is with diazepam. In connection with benzodiazepine therapy in the first trimester, heart malformations, lip and palate clefts, inguinal hernias and other, complex, malformations were described ( McElhatton 1994 ). However, they did find an association between anal atresia and lorazepam. Bonnot (2001) found no evidence of increased risk with benzodiazepines for malformations.
Two case-control studies with around 400 pregnant women exposed to chlordiazepoxide ( Czeizel 2004 ), as well as 10 patients with alprazolam, about 100 with clonazepam ( Chapter 2.10 ), 18 with medazepam, 18 with nitrazepam and 13 with tofisopam, there was also no indication of any birth defects ( Lin 2004, Eros 2002 ).
Katherine L Wisner, Christof Schaefer, in Drugs During Pregnancy and Lactation (Third Edition), 2015.
Later, varied distinctive mental retardation, attention disorders and hyperkinesis were observed. These case presentations were criticized because the kind and scope of the exposure was not sufficiently certain and, in one case, Zellweger syndrome could not be ruled out. Laegreid (1989) described eight children whose mothers abused prescription drugs throughout the entire pregnancy with at least 30 mg diazepam or at least 75 mg oxazepam daily. In follow-up examinations, an improvement in the symptoms of the 18-month-old children was observed ( Laegreid 1992 ). All of the children had facial dysmorphia, and some also had microcephaly as well as postpartum toxic symptoms (apnea) and withdrawal symptoms.
for the rapid and precise determination of two new hypnotics, zolpidem and zopiclone, in serum at concentrations > 5 ng/ml. A gas chromatographic (GC) method using a short, high-resolution capillary column connected to a specific thermo-ionic detector and requiring a simple and short extraction step without evaporation was developed by Debruyne et al. The method was validated and then used to analyze zolpidem serum concentrations in nine rabbits after oral administration of 0.5 mg/kg and zopiclone serum concentrations in six patients treated orally with a 7.5-mg dose. The assay was linear between 5 and 200 ng/ml, with coefficients of intra- and interassay variation < 5% for both.
Morten Jørgensen, . Lena Tagmose, in Annual Reports in Medicinal Chemistry, 2013.
After a liquid–liquid extraction, the extract is injected into a capillary gas chromatograph with an OV-1 fused-silica column coupled to a nitrogen-phosphorus detector. The method described is reproducible and linear over a range of concentrations, rendering it suitable for use for pharmacokinetic studies or toxicological evaluations. A simple, specific, and selective method for the simultaneous determination of zolpidem and zopiclone in human plasma is described by Stanke et al. Absolute identification of the chromatographed compounds is accomplished by gas chromatography–mass spectrometry in both electron-impact and positive-ion chemical ionization modes. The detection limits are 1 and 2 ng/ml for zolpidem and zopiclone, respectively.
A small number of case studies from the Hungarian malformation register on overdoses by women during suicidal attempts with alprazolam ( Gidai 2008c ), chlordiazepoxide ( Gidai 2008b ), diazepam ( Gidai 2008a ) and nitrazepam, Gidai (2010) reported malformations in offspring. However, the number of cases is small and the anomalies observed are heterogeneous; which makes drawing conclusions from these data difficult.
Most studies have been done more than a decade ago; however, a recent review drew a similar conclusion to older studies that little evidence for major malformations associated with benzodiazepines exists ( Bellantuono 2013 ).
Prazepam was used as internal standard. This first SPE of imidazopyridines (alpidem and zolpidem) provides faster, more efficient, and cheaper sample preparation than the traditional liquid–liquid procedure. Limits of quantification allow toxicological or pharmacological determinations, except for buspirone: only toxic blood levels can be quantified by this method. The drugs were isolated from 1 ml of plasma by solid-phase extraction (SPE) onto a C 8 reversed-phase sorbent and recovered with 0.5% acetic acid in methanol. Identical fused-silica Ultra 2 (5% phenyl methyl silicone) columns were connected to nitrogen-phosphorus and electron-capture detectors. Gaillard et al. The method was found appropriate for the quantification in a single run of alpidem, alprazolam, buspirone, chlordiazepoxide, clobazam, clotiazepam, diazepam, estazolam, flunitrazepam, lorazepam, midazolam, oxazepam, tofisopam, triazolam, and zolpidem within 30 min. developed a rapid twin-column GC method for simultaneous screening and determination of commonly prescribed benzodiazepines and other new anxiolytics from plasma. This GC analysis of alpidem and zolpidem is also the first described procedure for simultaneous quantification of all different classes of anxiolytics. The eluate was reconstituted with isopropanol which was found suitable for on-column injection.
Linearity range was 0.5–4 μg/spot with mean recovery percentage (99.98 ± 0.988%). El Zeany et al. The first method was a TLC-UV densitometric one in which the mobile phase methanol:water (20:80) was used for developing the TLC plates. The R f of zolpidem hemitartrate was found to be 0.29 ± 0.01 and that of its degradation product was 0.59 ± 0.01. described two methods for the determination of zolpidem hemitartrate in presence of its degradation product.
The analysis is performed in 12 min. developed a high-performance liquid chromatographic (HPLC) assay with diode-array detection for the in-process control of zolpidem synthesis and for the analysis of the drug and its synthetic intermediates. reversed-phase Kromasil C 18 (150 mm) column, 5 μm particle size with a gradient elution mode of acetonitrile, and 0.02 M NH 4 OAc (adjusted to pH 8.0) as the mobile phase (flow rate 1.0 ml min− 1). The method is simple, rapid, and highly specific. Laviana et al. The separation uses a 4.6 mm i.d.Zolpidem vs clonazepam