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PubMed1990

Preferential decrease in dopamine utilization in prefrontal cortex by zopiclone, diazepam and zolpidem in unstressed rats.

This study has compared the effects of a cyclopyrrolone, zopiclone, a benzodiazepine, diazepam, and an imidazopyridine, zolpidem, on dopamine (DA) and DOPAC levels, and DA utilization (DOPAC/DA ratio) in rat striatum and prefrontal cortex. The endogenous levels of DA were significantly increased by both zopiclone (2.5, 10 and 40 mg kg-1 p.o.) and diazepam (10 and 40 mg kg-1 p.o.) in the prefrontal cortex, whereas striatal DA content was significantly increased only with the highest dose of diazepam (40 mg kg-1 p.o.). Diazepam (10 and 40 mg kg-1 p.o.) decreased cortical level of DOPAC more markedly than striatal levels, whereas zopiclone (40 mg kg-1 p.o.) only slightly decreased striatal DOPAC levels. Zopiclone and diazepam dose-dependently decreased DA utilization, an effect which was more marked in prefrontal cortex than in striatum. This result was confirmed with zolpidem, another benzodiazepine ligand. Zopiclone was most potent at decreasing DA utilization at the cortical level. The diazepam-induced decreases in DA metabolism and utilization were antagonized by Ro 15-1788, suggesting that the effects seen were mediated by specific benzodiazepine receptors. Thus, our results clearly show that ligands acting on the benzodiazepine receptor GABA receptor chloride ionophore complex can decrease the utilization of dopamine in unstressed rats. The preferential decrease in cortical DA utilization induced by benzodiazepine ligands may be compared to the well-known activation by stress of the mesocortical DAergic system.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2005

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.

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.

Analgesics↗
PubMed2026

In vitro susceptibility testing of aztreonam-avibactam against predominantly NDM-producing Enterobacterales in Peru.

Metallo-β-lactamase-producing Enterobacterales are distributed worldwide, but some Latin American countries show a higher prevalence. Aztreonam-avibactam (ATM-AVI) may be an option for treating these infections. To evaluate in vitro susceptibility to aztreonam (ATM) alone and ATM-AVI in carbapenem-non-susceptible Enterobacterales isolates, based on the type of carbapenemase production, we prospectively collected carbapenem-non-susceptible Enterobacterales isolates from Peruvian hospitals during 2023-2024. Identification and susceptibility testing were performed by commercial panels and disk diffusion. Carbapenemases were detected by immunochromatography. ATM and ATM-AVI MICs were determined using broth microdilution panels with avibactam fixed at 4 µg/mL. The non-susceptible isolates to ATM-AVI and those with double production of carbapenemases underwent whole-genome sequencing. A total of 438 Enterobacterales isolates were analyzed; carbapenemase production was detected in 422 (96.3%) and NDM was the most frequent (61.9%). Coproduction of NDM + KPC in K. pneumoniae and NDM + OXA-48-like in Escherichia coli was observed. Overall, 99.3% were susceptible to ATM-AVI; MIC50 and MIC90 were 0.12 and 2 µg/mL, respectively. Overall, K. pneumoniae isolates had lower MIC50 and MIC90 values to ATM-AVI (0.12 and 0.5 µg/mL) compared to E. coli (0.5 and 4 µg/mL). Three E. coli isolates were resistant to ATM-AVI (MIC ≥ 8 µg/mL), they belonged to ST410, ST167, and ST10 and harbored a YRIN insertion in PBP3 along with CYM-type, PER-type, and CTX-M-type beta-lactamase genes. ATM-AVI demonstrated potent activity against carbapenem-non-susceptible Enterobacterales, including those producing NDM, which is the carbapenemase most frequently detected in Peruvian hospitals.IMPORTANCEEnterobacterales isolates cause common illnesses in humans. Carbapenems are the antibiotics used to treat several of these infections, and increasingly, isolates resistant to these antibiotics are found. The most important mechanism of resistance to carbapenem among Enterobacterales is the production of enzymes called carbapenemases. Our results allowed us to recognize that NDM is the most frequent type of carbapenemase detected. Most of the antimicrobials available do not cover the Enterobacterales carrying NDM carbapenemase. In this scenario, we found that the new combination of drugs, aztreonam-avibactam, has high in vitro efficacy against most of the carbapenem-resistant isolates and against those isolates carrying NDM carbapenemase.

Aztreonam↗
PubMed2026

Emergence of ceftazidime-avibactam resistance mediated by KPC variants KPC-71 and KPC-78 in ST463 Pseudomonas aeruginosa.

UNLABELLED: Pseudomonas aeruginosa is a well-recognized opportunistic pathogen and a leading cause of healthcare-associated infections. The shrinking effectiveness of available antimicrobial therapies has intensified the global threat posed by carbapenem-resistant P. aeruginosa (CRPA). Here, we elucidate the mechanisms of ceftazidime-avibactam (CZA) resistance mediated by the rare KPC variants, KPC-71 and KPC-78, identified during the treatment of CRPA infections. Two CZA-resistant P. aeruginosa strains, SY-206885 and HZ-231016032, were isolated from critically ill male patients with severe pneumonia. Whole-genome sequencing assigned both isolates to the high-risk sequence type 463 (ST463). Isolate SY-206885 harbors the blaKPC-71 gene, while HZ-231016032 carries blaKPC-78. Cloning and expression of these genes in P. aeruginosa PAO1 conferred a marked increase in the CZA minimum inhibitory concentration. Notably, expression of KPC-71 or KPC-78 conferred CZA resistance while simultaneously reducing carbapenem hydrolytic activity, a trade-off previously described for some KPC variants but still rarely documented in P. aeruginosa. Structural analysis and kinetic profiling showed that, relative to wild-type KPC-2, both KPC-71 and KPC-78 exhibited reduced catalytic turnover but increased substrate affinity for ceftazidime, together with significantly weakened binding to avibactam. In addition, elevated expression of MexAB-OprM and AmpC-related determinants in the clinical isolates likely further enhanced the high-level CZA resistance phenotype. These findings highlight the capacity of the ST463 CRPA lineage to evolve CZA resistance through KPC structural diversification under antimicrobial pressure and underscore the need for close surveillance during therapy. IMPORTANCE: In this study, we report the detection of the uncommon KPC variants KPC-71 and KPC-78 in clinical sequence type 463 (ST463) carbapenem-resistant Pseudomonas aeruginosa isolates exhibiting resistance to ceftazidime-avibactam (CZA). We demonstrate that CZA resistance is driven by specific structural alterations-a serine insertion between residues 182 and 183 or a D179A substitution within the Ω-loop-that reshape the functional balance of the KPC enzyme. These changes appear to create an evolutionary trade-off by improving ceftazidime recognition while weakening avibactam-mediated inhibition. Given the widespread dissemination of the ST463 lineage in China, the emergence of these variants highlights the urgent need for clinicians to monitor for CZA resistance development during therapy. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as ChiCTR2500105846.

Ceftazidime↗
PubMed2026

Outbreak of aztreonam-avibactam-resistant NDM-5-producing Escherichia coli isolates in a hospital of Paris.

The emergence of aztreonam-avibactam resistance among NDM-producing Escherichia coli represents a major therapeutic and infection control concern. Four cases of aztreonam-avibactam-resistant (AZAR) NDM-producing E. coli, recovered from three blood cultures and one rectal surveillance culture in a hospital of Paris, prompted an investigation based on whole-genome sequencing. The three isolates responsible for bloodstream infection, which were clonally related, belonged to the ST405 and produced NDM-5, DHA-1, CTX-M-15, and TEM-1 β-lactamases. They also had a penicillin-binding protein 3 (PBP3) modified by the insertion of four amino acids (YRIK). On the other hand, the isolate recovered from the rectal swab belonged to another sequence type (ST2083). It produced NDM-5, CMY-42, and TEM-1 β-lactamases and had an altered PBP3 by the insertion of four other residues (YRIN). Epidemiological investigation identified endoscopic retrograde cholangiopancreatography as a potential risk factor, leading to the detection of three additional patients infected with the ST405 clone after exposure to the same duodenoscope. The outcome of the bloodstream infections was favorable except for one patient. In total, seven patients infected or colonized by AZAR NDM-5-producing E. coli were identified over a 5-month period in 2025, six with duodenoscope exposure.IMPORTANCEThis study underlines the emergence of aztreonam-avibactam resistance among NDM-producing Escherichia coli isolates in France. To our knowledge, this report describes the first clonal outbreak due to aztreonam-avibactam-resistant NDM-producing E. coli.

Humans↗
PubMedDate not supplied

[Appropriate use of benzodiazepines zolpidem and zopiclone in diseases attended in primary care].

OBJECTIVES: To estimate the proportion of benzodiazepine prescriptions that comply with the guidelines for appropriate prescription. To identify the variables associated with appropriate prescription. DESIGN: Observational, cross-sectional study. SETTING: Monóvar Health Centre in Area IV, Madrid, Spain. SUBJECTS: Random sample of 270 active benzodiazepine prescriptions in adult patients from the prescriptions record of the OMI-AP V. 5.0 computer system. MEASUREMENTS: The chosen dimensions for appropriate prescription were: a) correct diagnostic indication; b) absence of benzodiazepines with long half-life in the elderly; c) existence of support or monitoring visits; d) overall appropriateness or coexistence of correct diagnostic indications and monitoring visits. Independent variables were recorded in relation to patient, person prescribing and prescription. RESULTS: Diagnostic indication, 75.6%; absence of benzodiazepines with long half-life in the elderly, 79.8%; existence of support visits, 63.3%; overall appropriateness, 53%. Main diagnoses: pure anxiety, 29%; anxiety related to other illness, 18.6%; insomnia, 14.8%; cardiovascular illness, 14.8%; alcohol and drug abuse, 4.5%; osteo-muscular illness, 4.4%; schizophrenia, 4.4%. Most prescribed substances: lorazepam, 27.8%; bromazepam, 23.7%. Average life of prescriptions: 18.58 months. Origins: health centre, 68.5%; out-patient psychiatry, 10%; hospital, 10%. The variable that is most closely associated with overall appropriateness, fitted with the rest of the variables, is out-patient psychiatry prescription (OR, 6.67; 95% CI, 1.92-23.18). CONCLUSIONS: The mean duration of the prescriptions infringes all standards. The overall appropriateness or correct coexistence of adequate diagnostic indication with follow-up visits is associated with out-patient Psychiatry prescription.

Aged↗
PubMed1999

Association between delta waves during sleep and negative symptoms in schizophrenia. Pharmaco-eeg studies by using structurally different hypnotics.

We examined the effects of benzodiazepine (BZD) hypnotics and zopiclone (ZPC), a nonbenzodiazepine hypnotic, on sleep and psychiatric symptoms in schizophrenia, as well as the clinical correlates of these variables. Seven male schizophrenic patients chronically taking neuroleptics together with BZD were studied. We replaced BZD with ZPC and performed polysomnography (PSG) and Brief Psychiatric Rating Scale (BRPS) scoring before and after an 8-week ZPC treatment. The replacement of BZD with ZPC increased the mean amplitude of high-amplitude low-frequency delta waves on the frontal derivation recognized by period-amplitude analysis, and it decreased the BPRS negative-symptom score. Under the BZD treatment, the negative-symptom score correlated inversely with the mean amplitude of high-amplitude low-frequency delta waves. This correlation was weak and not significant under the ZPC treatment. Therefore, delta waves during sleep have a close correlation to negative symptoms in schizophrenia, and such a correlation could be influenced by hypnotics. Although these are preliminary findings, it was suggested that, compared with BZD, ZPC might be a beneficial hypnotic in regard to both sleep and negative symptoms of chronic schizophrenic patients.

Adult↗
PubMed2001

Central serotonergic mechanisms on head twitch response induced by benzodiazepine receptor agonists.

Intraperitoneal injection of benzodiazepine receptor agonists (estazolam, zopiclone, triazolam: 0.03-0.24 mmol/kg) induces the head twitch response (HTR). The present study was undertaken to examine the possible participation of the serotonergic system in the mechanism of head twitches induced by benzodiazepine receptor agonists (BZ-RAs). The HTR induced by BZ-RAs was suppressed by pretreatment with ketanserine (1 mg/kg, i.p.), a selective 5-HT(2) receptor antagonist. Pretreatment with fluoxetine (10 mg/kg, i.p.), a 5-HT reuptake inhibitor, and 8-hydroxy-2-(di-n-propylamino)tetralin, a 5-HT(1A) receptor agonist, also suppressed the HTR induced by BZ-RAs. These results suggest that the HTR induced by BZ-RAs may be the result of an activation of postsynaptic 5-HT(2) receptors, probably due to direct action.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1983

Drug effects on the EEG of various species of laboratory animals.

The analysis of the results obtained in different tests--sleep studies, cortical and hippocampal EEG activity, PGO-R spikes--in rats or in cats allows the characterization of different classes of drugs and to establish the relative efficacy of psychoactive drugs in these models. Moreover, the sequential spectral analysis of cortical EEG recordings in curarized rats allows the assessment of EEG modifications, of the presence of hypersynchronized rhythms, of the induction and duration of drug action, of topographic drug effects and interactions between different agents. Thus, the use of EEG techniques in various animal species allows a better classification and definition of the central action of drugs.

5-Hydroxytryptophan↗
PubMed1984

Effects of zopiclone and benzodiazepine hypnotics on search in short-term memory.

The effects of zopiclone 7.5 mg in comparison to flunitrazepam 1 mg, triazolam 0.25 mg and lormetazepam 1 mg on stages of information processing in a memory-scanning task were investigated in 10 normal volunteers using a double-blind placebo-controlled cross-over design. Overall reaction times for the test were significantly increased 1 h following treatment with zopiclone, flunitrazepam and triazolam and in the morning following nighttime medication with flunitrazepam. The effects of zopiclone, flunitrazepam and triazolam were found to be located in the serial comparison and response-selection organization stages of the reaction process although both flunitrazepam and triazolam caused additional impairment of stimulus encoding.

Adult↗
PubMed1992

Pattern recognition by matched filtering: an analysis of sleep spindle and K-complex density under the influence of lormetazepam and zopiclone.

The evaluation of sleep EEG patterns is mostly accomplished by visual analysis. With modern personal computers however, it is possible to perform signal detection within a reasonable length of time automatically. This paper presents a method for signal processing based on matched filtering. This allows the detection of sleep spindles and K-complexes in a sleep EEG recording with a high degree of accuracy. First the technique is described, and the results of a validation study based on the comparison of visual evaluations and computer analysis are presented. Thereafter, results of an application study are presented. Sleep spindle and K-complex density under the influence of lormetazepam and zopiclone were examined. Under both medications sleep spindle density increased while K-complex density decreased. Computation of Pearson's correlation coefficients demonstrated that the interindividual sleep spindle and K-complex variations under both treatments are highly correlated. The data suggest that lormetazepam and zopiclone, although chemically different, have a similar mode of action and display comparable effects on the sleep EEG.

Adult↗
PubMed1992

Topographical analysis of sleep spindle activity.

There is evidence for two types of sleep spindle activity, one with a frequency of about 12 cycles/s (cps) and the other of about 14 cps. Visual examination indicates that both spindle types occur independently, whereby the 12-cps spindles are more pronounced in the frontal and the 14-cps spindles in the parietal region. The purpose of this paper is to provide more information about the exact topography of these patterns. First the occurrence of distinct signals in anterior and posterior brain regions was verified using pattern recognition techniques based on matched filtering. Thus the existence of two distinct sources of activity located in the frontal and parietal region of the brain, respectively, was demonstrated using EEG frequency mapping. Evaluation of sleep recordings showed high stability both in the frequency and location of the presumed spindle generators across sleep. Pharmacological effects of lormetazepam and zopiclone on both spindle types were investigated. Both substances enhanced the sleep spindle activity recorded from the frontal and parietal electrodes, but this increase was more pronounced in the parietal brain region.

Adult↗
PubMed1994

Effects of zopiclone, triazolam, and nitrazepam on standing steadiness.

We examined the effects of the nonbenzodiazepine hypnotic zopiclone and the benzodiazepine hypnotics triazolam and nitrazepam on standing steadiness. Eight healthy volunteers received placebo, zopiclone (7.5 mg), triazolam (0.25 mg), and nitrazepam (5 mg) in a random-order, double-blind crossover design. Postural sway was assessed before and 1 and 2 h after drug administration using a stabilometer connected to a microcomputer. Triazolam significantly impaired standing steadiness. Zopiclone also impaired standing steadiness but the degree of impairment seemed to be less marked. Nitrazepam 5 mg had no significant effects on postural sway. Triazolam 0.25 mg, zopiclone 7.5 mg, and nitrazepam 5 mg, which are reported to be equipotent to each other as hypnotics, are not equipotent with respect to their effects on postural sway.

Adult↗
PubMed1995

ECG activity in the sleep of insomniac patients under the influence of lormetazepam and zopiclone.

The influence of the benzodiazepine hypnotic lormetazepam (1 mg) and the cyclopyrrolone hypnotic zopiclone (7.5 mg) on heart rate activity was studied in 16 elderly insomniacs in a placebo-controlled, randomised, 3-fold crossover trial. After digital preprocessing of the ECG, QRS complexes were automatically recognised by a detection technique based on adaptative thresholds. Both R-R periodicity and heart rate variability were analysed as a function of sleep stages and time of night. Under placebo, heart rate decreased significantly from the first to the second half of the night. The relationship between sleep stages and heart rate remained constant under both hypnotics. Although the two substances significantly modified the distribution of sleep stages, no relevant changes in ECG activity were observed when the proportion of the different sleep stages was taken into consideration.

Aged↗
PubMed1997

Relationship between the effects of a hypnotic drug, zopiclone, on polysomnography and on daytime EEGs.

The correlation between the effects of zopiclone (ZPC), a nonbenzodiazepine hypnotic drug, on sleep polysomnograms and on daytime EEGs was examined in 12 healthy adult male volunteers. Sleep polysomnograms were recorded after a single oral administration of ZPC 10 mg or placebo according to the double-blind crossover method. Daytime EEGs were recorded after the administration of ZPC, 7.5 mg, or placebo in the same manner, and recorded for 3 min with closed eyes at rest. Then, square roots of the absolute power (amplitude) of the delta-, theta-, alpha-, and beta-activities were calculated from the power spectrum obtained by the fast Fourier transform method. As a result, ZPC decreased the percentage of stage 1 sleep in total sleep time, while it increased the percentage of stage 2, total sleep time, and time of slow wave sleep in the first and second sleep cycles (SWS 1 and 2). Changes in SWS 1 and 2 correlated positively with the amplitude changes in daytime resting delta-activity. This indicates that the increase of SWS due to ZPC could be related to the change of delta-activity in the daytime resting EEG.

Adult↗