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Revista Da Associacao Medica Brasileira... 2015to compare clinical and cost effectiveness of midazolam and diazepam for urgent intubation. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
to compare clinical and cost effectiveness of midazolam and diazepam for urgent intubation.
METHODS
patients admitted to the Central ICU of the Santa Casa Hospital Complex in Porto Alegre, over the age of 18 years, undergoing urgent intubation during 6 months were eligible. Patients were randomized in a single-blinded manner to either intravenous diazepam or midazolam. Diazepam was given as a 5 mg intravenous bolus followed by aliquots of 5 mg each minute. Midazolam was given as an intravenous bolus of 5 mg with further aliquots of 2.5 mg each minute. Ramsay sedation scale 5-6 was considered adequate sedation. We recorded time and required doses to reach adequate sedation and duration of sedation.
RESULTS
thirty four patients were randomized, but one patient in the diazepam group was excluded because data were lost. Both groups were similar in terms of illness severity and demographics. Time for adequate sedation was shorter (132 ± 87 sec vs. 224 ± 117 sec, p = 0.016) but duration of sedation was similar (86 ± 67 min vs. 88 ± 50 min, p = 0.936) for diazepam in comparison to midazolam. Total drug dose to reach adequate sedation after either drugs was similar (10.0 [10.0-12.5] mg vs. 15.0 [10.0-17.5] mg, p = 0.248). Arterial pressure and sedation intensity reduced similarly overtime with both drugs. Cost of sedation was lower for diazepam than for midazolam (1.4[1.4-1.8] vs. 13.9[9.4-16.2] reais, p <0.001).
CONCLUSIONS
intubation using intravenous diazepam and midazolam is effective and well tolerated. Sedation with diazepam is associated to a quicker sedation time and to lower costs.
Topics: Deep Sedation; Diazepam; Female; Humans; Hypnotics and Sedatives; Injections, Intravenous; Intensive Care Units; Intubation, Intratracheal; Male; Midazolam; Middle Aged; Single-Blind Method
PubMed: 25909205
DOI: 10.1590/1806-9282.61.01.030 -
Frontiers in Endocrinology 2023Acyl-CoA-binding protein (ACBP)/diazepam-binding inhibitor has lately been described as an endocrine factor affecting food intake and lipid metabolism. ACBP is...
OBJECTIVE
Acyl-CoA-binding protein (ACBP)/diazepam-binding inhibitor has lately been described as an endocrine factor affecting food intake and lipid metabolism. ACBP is dysregulated in catabolic/malnutrition states like sepsis or systemic inflammation. However, regulation of ACBP has not been investigated in conditions with impaired kidney function, so far.
DESIGN/METHODS
Serum ACBP concentrations were investigated by enzyme-linked immunosorbent assay i) in a cohort of 60 individuals with kidney failure (KF) on chronic haemodialysis and compared to 60 individuals with a preserved kidney function; and ii) in a human model of acute kidney dysfunction (AKD). In addition, mRNA expression was assessed in two CKD mouse models and in two distinct groups of non-CKD mice. Further, mRNA expression of was measured in isolated, differentiated mouse adipocytes - brown and white - after exposure to the uremic agent indoxyl sulfate.
RESULTS
Median [interquartile range] serum ACBP was almost 20-fold increased in KF (514.0 [339.3] µg/l) compared to subjects without KF (26.1 [39.1] µg/l) (p<0.001). eGFR was the most important, inverse predictor of circulating ACBP in multivariate analysis (standardized β=-0.839; p<0.001). Furthermore, AKD increased ACBP concentrations almost 3-fold (p<0.001). Increased ACBP levels were not caused by augmented mRNA expression in different tissues of CKD mice or in indoxyl sulfate-treated adipocytes .
CONCLUSIONS
Circulating ACBP inversely associates with renal function, most likely through renal retention of the cytokine. Future studies need to investigate ACBP physiology in malnutrition-related disease states, such as CKD, and to adjust for markers of renal function.
Topics: Mice; Humans; Animals; Diazepam Binding Inhibitor; Indican; Carrier Proteins; Kidney; Diazepam; RNA, Messenger; Malnutrition
PubMed: 37288304
DOI: 10.3389/fendo.2023.1152444 -
Journal of Critical Care Medicine... Jan 2022This report concerns a young man who attempted suicide by ingesting a cocktail with a lethal dose of chloroquine phosphate and large amounts of diazepam. On...
This report concerns a young man who attempted suicide by ingesting a cocktail with a lethal dose of chloroquine phosphate and large amounts of diazepam. On presentation, the patient was drowsy, unresponsive and in cardiogenic shock with severely impaired left ventricular function. Active charcoal and vasopressors were administered, and despite his intoxication with diazepam, a high-dose diazepam treatment was initiated in the hospital. It is concluded that diazepam in the cocktail played a vital role in the survival of this patient. With a rise in numbers, every emergency and intensive care physician should be familiar with chloroquine poisoning.
PubMed: 35274057
DOI: 10.2478/jccm-2021-0036 -
Human & Experimental Toxicology 2023The present study aimed to clarify the expressions and roles of clock genes involved in drug metabolism in patients taking benzodiazepines (BZDs), as well as the drug...
The present study aimed to clarify the expressions and roles of clock genes involved in drug metabolism in patients taking benzodiazepines (BZDs), as well as the drug metabolism regulators controlled by clock genes for each BZD type. The relationships between the expressions of the clock genes , , and and the drug-metabolizing enzymes and were investigated using livers from BZD-detected autopsy cases. In addition, the effect of BZD exposure on various genes was examined in HepG2 human hepatocellular carcinoma cells. The expressions of , and in the liver were lower in the diazepam-detected group than in the non-detected group. Furthermore, expression correlated with expression. Cell culture experiments showed that the expressions of and decreased, whereas those of and increased after diazepam and midazolam exposure. The results of the analyses of autopsy samples and cultured cells suggested that regulates when exposed to BZD. Understanding the relationship between these clock genes and CYPs may help achieve individualized drug therapy.
Topics: Humans; Benzodiazepines; Cytochrome P-450 CYP3A; ARNTL Transcription Factors; Cytochrome P-450 CYP2C19; Diazepam; Liver Neoplasms; Gene Expression
PubMed: 37072025
DOI: 10.1177/09603271231171643 -
Basic & Clinical Pharmacology &... Dec 2022Several pyrazoloquinolinone (PQ) ligands were recently discovered as functionally selective positive modulators at the PQ site of α6-containing GABA receptors. PQs are...
Behavioural interaction of pyrazoloquinolinone positive allosteric modulators at α6GABA receptors and diazepam in rats: Anti-diazepam-induced ataxia action as a structure-dependent feature.
Several pyrazoloquinolinone (PQ) ligands were recently discovered as functionally selective positive modulators at the PQ site of α6-containing GABA receptors. PQs are also neutral modulators at the benzodiazepine site. We assessed the influence of PQ compounds from three structural groups (PZ-II-029 and related deuterated analogues DK-I-56-1, RV-I-029, DK-I-60-3 and DK-I-86-1; LAU 463 and related analogues DK-I-58-1 and DK-II-58-1; and DK-I-87-1), alone and in combination with diazepam, on the behaviour of male Sprague-Dawley rats. An excellent behavioural safety profile of all tested PQs was demonstrated in the spontaneous locomotor activity, rotarod, loss of righting reflex and pentylenetetrazol tests. In interaction studies, only PZ-II-029 and its analogues prevented the ataxic effects of the benzodiazepine, as assessed in the rotarod test and during monitoring of rat locomotor activity after awakening from the loss of righting reflex. Published electrophysiological profiles of PQ ligands imply that positive modulation elicited at α6-GABA receptors that contain the γ2 and δ subunit, rather than their neutral modulatory action at the benzodiazepine site, may prevent the ataxic action of diazepam. Thus, PZ-II-029 and its deuterated analogues are not prone to untoward interactions with benzodiazepines and may indeed completely abolish their ataxic action, seen at therapeutic, and especially toxic concentrations.
Topics: Animals; Rats; Male; Diazepam; Rats, Sprague-Dawley; Receptors, GABA-A; Benzodiazepines; Ligands; gamma-Aminobutyric Acid; Ataxia; GABA Modulators
PubMed: 36180380
DOI: 10.1111/bcpt.13801 -
Biochimica Et Biophysica Acta.... Sep 2018Nerve agents and some pesticides such as diisopropylfluorophosphate (DFP) cause neurotoxic manifestations that include seizures and status epilepticus (SE), which are...
Nerve agents and some pesticides such as diisopropylfluorophosphate (DFP) cause neurotoxic manifestations that include seizures and status epilepticus (SE), which are potentially lethal and carry long-term neurological morbidity. Current antidotes for organophosphate (OP) intoxication include atropine, 2-PAM and diazepam (a benzodiazepine for treating seizures and SE). There is some evidence for partial or complete loss of diazepam anticonvulsant efficacy when given 30 min or later after exposure to an OP; this condition is known as refractory SE. Effective therapies for OP-induced SE are lacking and it is unclear why current therapies do not work. In this study, we investigated the time-dependent efficacy of diazepam in the nerve agent surrogate DFP model of OP intoxication on seizure suppression and neuroprotection in rats, following an early and late therapy. Diazepam (5 mg/kg, IM) controlled seizures when given 10 min after DFP exposure ("early"), but it was completely ineffective at 60 or 120 min ("late") after DFP. DFP-induced neuronal injury, neuroinflammation, and neurodegeneration of principal cells and GABAergic interneurons were significantly reduced by early but not late therapy. These findings demonstrate that diazepam failed to control seizures, SE and neuronal injury when given 60 min or later after DFP exposure, confirming the benzodiazepine-refractory SE and brain damage after OP intoxication. In addition, this study indicates that degeneration of inhibitory interneurons and inflammatory glial activation are potential mechanisms underlying these morbid outcomes of OP intoxication. Therefore, novel anticonvulsant and neuroprotectant antidotes, superior to benzodiazepines, are desperately needed for controlling nerve agent-induced SE and brain injury.
Topics: Animals; Antidotes; Brain; Diazepam; Disease Models, Animal; Humans; Interneurons; Male; Nerve Agents; Neuroglia; Neurotoxicity Syndromes; Organophosphate Poisoning; Organophosphates; Rats; Rats, Sprague-Dawley; Status Epilepticus; Time Factors; Treatment Outcome
PubMed: 29802961
DOI: 10.1016/j.bbadis.2018.05.016 -
Biochemical Pharmacology Sep 2021GABA-ergic neurotransmission plays a key role in sleep regulatory mechanisms and in brain oscillations during sleep. Benzodiazepines such as diazepam are known to induce...
GABA-ergic neurotransmission plays a key role in sleep regulatory mechanisms and in brain oscillations during sleep. Benzodiazepines such as diazepam are known to induce sedation and promote sleep, however, EEG spectral power in slow frequencies is typically reduced after the administration of benzodiazepines or similar compounds. EEG slow waves arise from a synchronous alternation between periods of cortical network activity (ON) and silence (OFF), and represent a sensitive marker of preceding sleep-wake history. Yet it remains unclear how benzodiazepines act on cortical neural activity during sleep. To address this, we obtained chronic recordings of local field potentials and multiunit activity (MUA) from deep cortical layers of the primary motor cortex in freely behaving mice after diazepam injection. We found that the amplitude of individual LFP slow waves was significantly reduced after diazepam injection and was accompanied by a lower incidence and duration of the corresponding neuronal OFF periods. Further investigation suggested that this is due to a disruption in the synchronisation of cortical neurons. Our data suggest that the state of global sleep and local cortical synchrony can be dissociated, and that the brain state induced by benzodiazepines is qualitatively different from spontaneous physiological sleep.
Topics: Animals; Cross-Over Studies; Diazepam; Electroencephalography; Hypnotics and Sedatives; Male; Mice; Mice, Inbred C57BL; Motor Cortex; Nerve Net; Random Allocation; Sleep; Wakefulness
PubMed: 33713641
DOI: 10.1016/j.bcp.2021.114515 -
The Journal of Physiology May 2022Slow oscillations, the hallmark of non-REM sleep, and their cellular counterpart, Up and Down states (UDSs), are considered a signature of cortical dynamics that reflect...
Slow oscillations, the hallmark of non-REM sleep, and their cellular counterpart, Up and Down states (UDSs), are considered a signature of cortical dynamics that reflect the intrinsic network organization. Although previous studies have explored the role of inhibition in regulating UDSs, little is known about whether this role changes with maturation. This is surprising since both slow oscillations and UDSs exhibit significant age-dependent alterations. To elucidate the developmental impact of GABA and GABA receptors on UDS activity, we conducted simultaneous local field potentials and intracellular recordings ex vivo, in brain slices of young and adult male mice, using selective blockers, CGP55845 and a non-saturating concentration of gabazine, respectively. Blockade of both GABA and GABA signalling showed age-differentiated functions. CGP55845 caused an increase in Down state duration in young animals, but a decrease in adults. Gabazine evoked spike and wave discharges in both ages; however, while young networks became completely epileptic, adults maintained the ability to generate UDSs. Furthermore, voltage clamp recordings of miniature inhibitory postsynaptic currents revealed that gabazine selectively blocks phasic currents, particularly involving postsynaptic mechanisms. The latter exhibit clear maturational changes, suggesting a different subunit composition of GABA receptors in young vs. adult animals. Indeed, subsequent local field potential recordings under diazepam (nanomolar or micromolar concentrations) revealed that mechanisms engaging the drug's classical binding site, mediated by α1-subunit-containing GABA receptors, make a bigger contribution to Up state initiation in young networks compared to adults. Taken together, these findings help clarify the mechanisms that underlie the maturation of cortical network activity and enhance our understanding regarding the emergence of neurodevelopmental disorders. KEY POINTS: Slow oscillations, the EEG hallmark of non-REM sleep, and their cellular counterpart, Up and Down states (UDSs), are considered the default activity of the cerebral cortex and reflect the underlying neural connectivity. GABA - and GABA -receptor-mediated inhibition play a major role in regulating UDS activity. Although slow oscillations and UDSs exhibit significant alterations as a function of age, it is unknown how developmental changes in inhibition contribute to the developmental profile of this activity. In this study, we reveal for the first time age-dependent effects of GABA and GABA signalling on UDSs. We also document the differential subunit composition of postsynaptic GABA receptors in young and adult animals, highlighting the α1-subunit as a major component of the age-differentiated regulation of UDSs. These findings help clarify the mechanisms that underlie the maturation of cortical network activity, and enhance our understanding regarding the emergence of neurodevelopmental disorders.
Topics: Animals; Cerebral Cortex; Diazepam; Inhibitory Postsynaptic Potentials; Male; Mice; Receptors, GABA-A; Receptors, GABA-B; gamma-Aminobutyric Acid
PubMed: 35365894
DOI: 10.1113/JP282736 -
Zhongguo Yi Xue Ke Xue Yuan Xue Bao.... Oct 2023Objective To explore the inhibitory effects and mechanisms of benzodiazepines on (Hp).Methods The Hp international standard strain ATCC43504 was treated with...
Objective To explore the inhibitory effects and mechanisms of benzodiazepines on (Hp).Methods The Hp international standard strain ATCC43504 was treated with benzodiazepines diazepam,midazolam,and remimazolam,respectively.The treatments with amoxicillin and clarithromycin were taken as the positive controls,and that with water for injection as the negative control.The inhibition zone of each drug was measured by the disk diffusion method.The minimum inhibitory concentration(MIC)and minimum bactericidal concentration(MBC)of each drug against Hp were determined.Hp suspension was configured and treated with diazepam and midazolam,respectively.The bacterial suspension without drug added was used as the control group.The concentration of K in each bacterial suspension was measured by an automatic biochemical analyzer before drug intervention(T)and 1(T),2(T),3(T),4(T),5(T),6(T),and 7 h(T)after intervention.Hp urease was extracted and treated with 1/2 MIC diazepam,1 MIC diazepam,2 MIC diazepam,1/2 MIC midazolam,1 MIC midazolam,2 MIC midazolam,1 mg/ml acetohydroxamic acid,and water for injection,respectively.The time required for the rise from pH 6.8 to pH 7.7 in each group was determined by the phenol red coloring method.Results The inhibition zones of diazepam,midazolam,remimazolam,amoxicillin,clarithromycin,and water for injection against Hp were 52.3,42.7,6.0,72.3,60.8,and 6.0 mm,respectively.Diazepam and midazolam showed the MIC of 12.5 μg/ml and 25.0 μg/ml and the MBC of 25 μg/ml and 50 μg/ml,respectively,to Hp.The concentrations of K in the diazepam,midazolam,and control groups increased during T-T compared with those at T(all <0.01).The concentration of K in diazepam and midazolam groups during T-T was higher than that in the control group(all <0.01).The time of inhibiting urease activity in the 1/2 MIC diazepam,1 MIC diazepam,2 MIC diazepam,1/2 MIC midazolam,1 MIC midazolam,and 2 MIC midazolam groups was(39.86±5.11),(36.52±6.65),(38.58±4.83),(39.25±6.19),(36.36±4.61),and(35.81±6.18)min,respectively,which were shorter than that in the acetohydroxamic acid group(all <0.01)and had no significance differences from that in the water for injection group(all >0.05).Conclusion Diazepam and midazolam exerted inhibitory effects on Hp,which may be related to the cleavage of Hp cells rather than inhibiting urease.
Topics: Midazolam; Helicobacter pylori; Urease; Clarithromycin; Benzodiazepines; Diazepam; Amoxicillin; Water; Anti-Bacterial Agents
PubMed: 37927020
DOI: 10.3881/j.issn.1000-503X.15651 -
International Journal of Molecular... Sep 2023In this study, atomistic simulations were carried out to study the difference in the adsorption process between two similar molecules, diazepam and oxazepam, on...
In this study, atomistic simulations were carried out to study the difference in the adsorption process between two similar molecules, diazepam and oxazepam, on Na-montmorillonite. Kinetic and XRD measurements showed a contrasting adsorption mechanism of these two molecules, differing only by the presence/absence of methyl and hydroxyl groups, with a larger adsorption amount and intercalation for the oxazepam. The structural characterization of these molecules was investigated through DFT calculations and showed the vicinity of hydroxyl and carbonyl groups for only the chair conformation of oxazepam compared to the boat conformation. Classical molecular dynamics simulations of diazepam and the two forms of oxazepam on the external surface of Na-montmorillonite highlighted the better coordination of the oxazepam-chair conformation, compared to its boat counterpart and diazepam. This has been confirmed through DFT calculations, from which a coordination energy that is greater by 10 kcal·mol is observed. This strongly suggests that the experimentally observed intercalation of oxazepam occurs only in the chair form because of the strong coordination with the Na cation present in the Na-Mt interlayer. Classical MD simulations of the intercalated oxazepam chair molecule in the Na-Mt interlayer allowed the evaluation of the interlayer spacing d001, which was in very good agreement with the experimental XRD measurement.
Topics: Clay; Bentonite; Adsorption; Oxazepam; Diazepam
PubMed: 37834226
DOI: 10.3390/ijms241914781