Effects of the N-methyl-D-aspartate receptor antagonist perzinfotel [EAA-090; [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]phosphonic acid] on chemically induced thermal hypersensitivity.
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Perzinfotel [EAA-090; [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]phosphonic acid] is a selective, competitive N-methyl-D-aspartate (NMDA) receptor antagonist with high affinity for the glutamate site. The current study evaluated whether perzinfotel would have antinociceptive effects or block thermal hypersensitivity associated with the administration of chemical irritants in rats. Perzinfotel lacked antinociceptive effects but dose- and time-dependently blocked prostaglandin E(2) (PGE(2))- and capsaicin-induced thermal hypersensitivity in a warm-water tail-withdrawal assay in rats. Doses of 10 mg/kg intraperitoneal or 100 mg/kg oral blocked PGE(2)-induced hypersensitivity by 60 to 80%. The magnitude of reversal was greater than other negative modulators of the NMDA receptor studied, such as uncompetitive channel blockers (e.g., memantine, dizocilpine, and ketamine), a NR2B selective antagonist (e.g., ifenprodil), and other glutamate antagonists [e.g., selfotel, 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), D,L-(E)-2-amino-4-propyl-5-phosphono-3-pentenoic acid (CGP-39653)], up to doses that suppressed operant rates of responding. In contrast to other negative modulators of the NMDA receptor studied, which typically decreased operant rates of responding at doses that lacked antinociceptive effects, perzinfotel did not modify response rates at doses that blocked irritant-induced thermal hypersensitivity. Collectively, these studies demonstrate that perzinfotel has therapeutic ratios for effectiveness versus adverse effects superior to those seen with other competitive and uncompetitive NMDA receptor antagonists studied. (+info)
Zopiclone withdrawal: an unusual cause of delirium in the elderly.
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We report a case of an elderly lady who was admitted for congestive heart failure. She developed delirium during the course of her hospital stay. Multiple investigations were performed but were unremarkable. Finally, a diagnosis of abrupt zopiclone withdrawal causing delirium was made. Zopiclone was resumed at a lower dose and delirium resolved completely. (+info)
Comparative cue generalization profiles of L-838, 417, SL651498, zolpidem, CL218,872, ocinaplon, bretazenil, zopiclone, and various benzodiazepines in chlordiazepoxide and zolpidem drug discrimination.
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The zolpidem discriminative cue is mediated by GABA(A)-alpha1 receptors, whereas the chlordiazepoxide cue may be mediated via non-alpha1 GABA(A) receptors because compounds with selective affinity for GABA(A)-alpha1 receptors fully generalize to the former cue. We predicted that L-838,417 [7-tert-butyl-3-(2,5-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1, 2,4-triazolo[4,3-b]pyridazine], a partial agonist at non-alpha1 GABA(A) receptors and an antagonist at GABA(A)-alpha1 receptors, would generalize to the chlordiazepoxide but not the zolpidem-discriminative cue. SL651498 [6-fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1H-pyridol[3 ,4-b]indol-1-one] is a full agonist at GABA(A)-alpha2 receptors, with lower efficacy at GABA(A)-alpha3 receptors and least efficacy at GABA(A)-alpha1 and GABA(A)-alpha5 receptors. Because SL651498 has efficacy at GABA(A)-alpha1 receptors, we anticipated that it would generalize to both discriminative cues. Rats were trained to discriminate either zolpidem (3 mg/kg) or chlordiazepoxide (5 mg/kg) from vehicle using a two-lever operant procedure. The generalization profiles of L-838,417 and SL651498 were compared with nonselective full agonists, GABA(A)-alpha1-selective ligands zolpidem and CL218,872 [3-methyl-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyridazine], the nonselective partial agonist bretazenil, and the novel anxioselective drug ocinaplon. A nonselective partial agonist was included because L-838,417 and SL651498 are partial agonists at some GABA(A) receptors, and this property may influence their generalization profiles. All nonselective full agonists and ocinaplon fully generalized to both cues. CL218,872 and zolpidem generalized to zolpidem only, whereas L-838,417 fully generalized to chlordiazepoxide only. SL651498 fully generalized to chlordiazepoxide and occasioned significant zolpidem-appropriate responding. Bretazenil was similar to SL651498. In conclusion, at this training dose, the chlordiazepoxide-discriminative stimulus is mediated primarily via non-alpha1 GABA(A) receptors and the generalization profiles of the ligands tested seem to correspond with their in vitro profiles at GABA(A) receptor subtypes. (+info)
Validation of a liquid chromatography-tandem mass spectrometry method for the simultaneous determination of 26 benzodiazepines and metabolites, zolpidem and zopiclone, in blood, urine, and hair.
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A liquid chromatography-tandem mass spectrometry method was developed for the simultaneous quantification of 26 benzodiazepines and metabolites, zolpidem and zopiclone, in blood, urine, and hair. Drugs were extracted from all matrices by liquid-liquid extraction with 1-chlorobutane. Chromatography was achieved using a XTerra MS C18 column eluted with a mixture of methanol and formate buffer. Data were acquired using positive electrospray ionization and multiple reaction monitoring using one precursor ion/product ion transition per compound. Quantification was performed using 13 deuterated analogues. Further confirmation of the identity of the compounds was achieved through a second injection of positive samples, monitoring two transitions per compound. The limits of quantification for all benzodiazepines ranged from 1 to 2 ng/mL in blood, 10 to 25 ng/mL in urine, and 0.5 to 10 pg/mg in hair. Linearity was observed from the limit of quantification of each compound to 200 ng/mL, 1000 ng/mL, and 1000 pg/mg for blood, urine, and hair, respectively (r2 > 0.99). Precision for quality control samples, spiked at three concentrations, was calculated (CV < 20% in most cases). Extraction recoveries for the three matrices ranged from 25.1 to 103.8%, except for one compound (cloxazolam in urine). Ion suppression was studied for all matrices. The validated assay was applied to authentic blood, urine, and hair samples from forensic cases. (+info)
Liquid chromatography-tandem mass spectrometry for detection of low concentrations of 21 benzodiazepines, metabolites, and analogs in urine: method with forensic applications.
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BACKGROUND: Commonly used methods for detecting benzodiazepines (BZPs) and BZP-like substances, such as zolpidem and zopiclone, may not detect low concentrations of these drugs. We developed a liquid chromatographic-tandem mass spectrometric method for identifying these drugs and their relevant metabolites. METHODS: We extracted BZPs from urine by solid-phase extraction with a mixed-mode phase (OASIS HLB cartridges). Chromatographic separation was performed with a Waters XTerra MS C18 [150 x 2.1 mm (i.d.); bead size, 5 microm] reversed-phase column with deuterated analogs of the analytes as internal standards (IS). Detection was performed with a triple-quadruple mass spectrometer that monitored 2 specific transitions per compound in the electrospray, positive-ion selected-reaction monitoring mode. We tested this technique on urine samples from 12 healthy volunteers and 1 forensic sample obtained in a case of alleged drug-facilitated sexual assault. RESULTS: Chromatographic separation was achieved within 18 min. The linear dynamic ranges extended from 0.02 or 0.1 microg/L (depending on the drug or metabolite) to 50 microg/L. Extraction recovery (range) was 77%-110%. Limits of detection were < or = 0.05 microg/L. No ion suppression was seen except for alprazolam, for which baseline decreased by almost 20%. In the forensic urine sample, the method detected alprazolam (3.5 microg/L) and its characteristic metabolite, alpha-hydroxyalprazolam (0.17 microg/L). CONCLUSION: This method measured low concentrations of BZPs and BZP-like substances and might be useful for analyses of urine in suspected drug-facilitated sexual assault cases. (+info)
What's new in clinical pharmacology and therapeutics.
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The US Food and Drug Administration (FDA) has approved several new drugs in the last few years. We have summarized a few of these that should be of interest to a primary care physician. These belong to either a new class of drugs or have a better drug profile in terms of ease of administration, prolonged duration of action, or fewer side effects. Daptomycin is a cyclic lipopeptide, active against methycillin resistant Staphylococcus aureus (MRSA). Telithromycin is a ketolide that can be used in place of macrolide antibiotics. Rifaximin is a semi-synthetic derivative of rifampin approved by the FDA for treatment of traveller's diarrhea. Pramlintide is an injectable synthetic amylin useful in treating type 1 and 2 diabetes. Tiotropium is an anti-cholinergic bronchodilator that can be taken once a day for treatment of chronic obstructive pulmonary disease. Lanthanum Carbonate is useful in treatment of hyperphosphatemia in patients with end stage renal disease. Flumist is an intranasal influenza vaccine. Eszopiclone is a new hypnotic that has fewer side effects. Memantine is in a new class of drugs useful in the treatment of Alzheimer's disease. Ibandronate is a new bisphosphonate approved for once a month use for osteoporosis in postmenopausal women. Acamprosate is approved for treatment of alcohol dependence. (+info)
GPs' attitudes to benzodiazepine and 'Z-drug' prescribing: a barrier to implementation of evidence and guidance on hypnotics.
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Zaleplon, zolpidem, and zopiclone ('Z-drugs') prescribing is gradually rising in the UK, while that of benzodiazepine hypnotics is falling. This situation is contrary to current evidence and guidance on hypnotic prescribing. The aim of this study was to determine and compare primary care physicians' perceptions of benefits and risks of benzodiazepine and Z-drug use, and physicians' prescribing behaviour in relation to hypnotics using a cross-sectional survey. In 2005 a self-administered postal questionnaire was sent to all GPs in West Lincolnshire Primary Care Trust. The questionnaire investigated perceptions of benefits and disadvantages of benzodiazepines and Z-drugs. Of the 107 questionnaires sent to GPs, 84 (78.5%) analysable responses were received. Responders believed that Z-drugs were more effective than benzodiazepines in terms of patients feeling rested on waking (P<0.001), daytime functioning (P<0.001), and total sleep time (P = 0.03). Z-drugs were also thought to be safer in terms of tolerance (P<0.001), addiction (P<0.001), dependence (P<0.001), daytime sleepiness (P<0.001), and road traffic accidents (P = 0.018), and were thought to be safer for older people (P<0.001). There were significant differences between GPs' perceptions of the relative benefits and risk of Z-drugs compared with benzodiazepines. The majority of practitioners attributed greater efficacy and lower side effects to Z-drugs. GPs' beliefs about effectiveness and safety are not determined by current evidence or national (NICE) guidance which may explain the increase in Z-drug prescribing relative to benzodiazepine prescribing. (+info)
Inhibition of the T790M gatekeeper mutant of the epidermal growth factor receptor by EXEL-7647.
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PURPOSE: Agents inhibiting the epidermal growth factor receptor (EGFR) have shown clinical benefit in a subset of non-small cell lung cancer patients expressing amplified or mutationally activated EGFR. However, responsive patients can relapse as a result of selection for EGFR gene mutations that confer resistance to ATP competitive EGFR inhibitors, such as erlotinib and gefitinib. We describe here the activity of EXEL-7647 (XL647), a novel spectrum-selective kinase inhibitor with potent activity against the EGF and vascular endothelial growth factor receptor tyrosine kinase families, against both wild-type (WT) and mutant EGFR in vitro and in vivo. EXPERIMENTAL DESIGN: The activity of EGFR inhibitors against WT and mutant EGFRs and their effect on downstream signal transduction was examined in cellular assays and in vivo using A431 and MDA-MB-231 (WT EGFR) and H1975 (L858R and T790M mutant EGFR) xenograft tumors. RESULTS: EXEL-7647 shows potent and long-lived inhibition of the WT EGFR in vivo. In addition, EXEL-7647 inhibits cellular proliferation and EGFR pathway activation in the erlotinib-resistant H1975 cell line that harbors a double mutation (L858R and T790M) in the EGFR gene. In vivo efficacy studies show that EXEL-7647 substantially inhibited the growth of H1975 xenograft tumors and reduced both tumor EGFR signaling and tumor vessel density. Additionally, EXEL-7647, in contrast to erlotinib, substantially inhibited the growth and vascularization of MDA-MB-231 xenografts, a model which is more reliant on signaling through vascular endothelial growth factor receptors. CONCLUSIONS: These studies provide a preclinical basis for clinical trials of XL647 in solid tumors and in patients bearing tumors that are resistant to existing EGFR-targeted therapies. (+info)