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Enfermeria Intensiva 2022To identify commonly used intravenous drugs that may produce endothelial damage.
AIMS
To identify commonly used intravenous drugs that may produce endothelial damage.
METHODS
An experimental research study was performed using a sample of 62 intravenous drugs commonly used in emergency care, pH and osmolarity were measured. Subsequently, based on these values, the theoretical capacity to cause irritation or endovascular damage was determined and classified as high, moderate, and low.
RESULTS
Samples from 19 drugs for fluid therapy, 21 antibiotics and 22 drugs for intravenous use were studied. Glucose solutions, sodium bicarbonate 1M and mannitol 10% showed a high capacity to cause venous irritation. Vancomycin, ciprofloxacin, amiodarone, haloperidol, and labetalol solution presented a high capacity for irritation based on their acidic pH. The antibiotics, dexketoprofen, diazepam, digoxin, etomidate, phenytoin, levetiracetam and metamizole also showed high osmotic values in their reconstituted or undiluted presentations. Moreover, osmolarity of diazepam, digoxin and phenytoin remained high despite being diluted in 100 ml of saline.
CONCLUSIONS
Knowing the pH and osmolarity of intravenous drugs allows their capacity to cause endothelial damage to be assessed. The use of comprehensive tables based on the chemical properties of the drugs can be a useful tool to help prevent chemically-induced phlebitis.
Topics: Anti-Bacterial Agents; Diazepam; Digoxin; Humans; Phenytoin; Phlebitis
PubMed: 35941074
DOI: 10.1016/j.enfie.2021.05.003 -
Journal of the American Medical... Aug 2023To describe acute seizure treatment for the long-term care setting, emphasizing rescue (acute abortive) medications for on-site management of acute unexpected seizures... (Review)
Review
OBJECTIVES
To describe acute seizure treatment for the long-term care setting, emphasizing rescue (acute abortive) medications for on-site management of acute unexpected seizures and seizure clusters.
DESIGN
Narrative review.
SETTING AND PARTICIPANTS
People with seizures in long-term care, including group residences.
METHODS
PubMed was searched using keywords that pertained to rescue medications, seizure emergencies/epilepsy, seizure action plans, and long-term care.
RESULTS
Seizure disorder, including epilepsy, is prevalent in long-term care residences, and rescue medications can be used for on-site treatment. Diazepam rectal gel, intranasal midazolam, and diazepam nasal spray are US Food and Drug Administration (FDA)-approved seizure-cluster rescue medications, and intravenous diazepam and lorazepam are approved for status epilepticus. Benzodiazepines differ by formulation, route of administration, absorption, and metabolism. Intranasal formulations are easy and ideal for public use and when rectal treatment is challenging (eg, wheelchair). Intranasal, intrabuccal, and rectal formulations do not require specialized training to administer and are easier for staff at all levels of training compared with intravenous treatment. Off-label rescue medications may have anecdotal support; however, potential disadvantages include variable absorption and onset of action as well as potential risks to patients and caregivers or care partners. Delivery of intravenous-administered rescue medications is delayed by the time needed to set up and deliver the medication and is subject to dosing errors. Seizure action plans that include management of acute seizures can optimize the quality and timing of treatment, which may reduce emergency service needs and prevent progression to status epilepticus.
CONCLUSIONS AND IMPLICATIONS
Seizure disorder is prevalent across all ages but is increased in older adults and in those with intellectual and developmental disabilities. Prompt intervention may reduce negative outcomes associated with acute unexpected seizures and seizure clusters. Seizure action plans that include acute seizures can improve the treatment response by detailing the necessary information for staff to provide immediate treatment.
Topics: United States; Humans; Aged; Anticonvulsants; Long-Term Care; Diazepam; Status Epilepticus; Epilepsy
PubMed: 37253432
DOI: 10.1016/j.jamda.2023.04.015 -
The Journal of Pharmacology and... Dec 2022Although propofol is among the most commonly administered general anesthetics, its mechanism of action is not fully understood. It has been hypothesized that propofol...
Although propofol is among the most commonly administered general anesthetics, its mechanism of action is not fully understood. It has been hypothesized that propofol acts via a similar mechanism as (R)-ethyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate (etomidate) by binding within the GABA receptor transmembrane receptor domain at the two / subunit interfaces with resultant positive allosteric modulation. To test this hypothesis, we leveraged the ability of diazepam to bind to those sites and act as a competitive antagonist. We used oocyte-expressed GABA receptors to define the actions of diazepam (± flumazenil) on currents activated or potentiated by propofol and a zebrafish activity assay to define the impact of diazepam and flumazenil on propofol-induced anesthesia. We found that diazepam increased the amplitudes of GABA receptor-mediated currents at nanomolar concentrations but reduced them at micromolar concentrations. The current amplitude changes produced by nanomolar diazepam concentrations were inhibited by flumazenil whereas those produced by micromolar diazepam concentrations were not. Studies of agonist potentiation showed that the micromolar inhibitory action of diazepam was surmountable by high concentrations of propofol and produced a rightward shift in the propofol concentration-response curve characterized by a Schild slope not statistically significantly different from 1, consistent with competition between diazepam and propofol. Although micromolar concentrations of diazepam (plus flumazenil) similarly reduced GABA receptor currents modulated by propofol and etomidate, it only reduced the anesthetic actions of etomidate. We conclude that while both propofol and etomidate can modulate GABA receptors by binding to the / subunit interfacial sites, propofol-induced anesthesia likely involves additional target sites. SIGNIFICANCE STATEMENT: Although the drug combination of diazepam and flumazenil reverses the GABA receptor positive modulatory actions of both propofol and ()-ethyl 1-(1-phenylethyl)-1-imidazole-5-carboxylate (etomidate), it only reverses the in vivo anesthetic actions of etomidate. These results strongly suggest that distinct mechanisms of action account for the anesthetic actions of these two commonly administered anesthetic agents.
Topics: Animals; Receptors, GABA-A; Propofol; Diazepam; Zebrafish; Etomidate; gamma-Aminobutyric Acid
PubMed: 36167415
DOI: 10.1124/jpet.122.001337 -
Epilepsy & Behavior : E&B Dec 2019Benzodiazepines, including diazepam and midazolam, are the mainstay of treatment for seizure emergencies, including acute repetitive seizures. Nonparenteral dosage forms... (Review)
Review
Benzodiazepines, including diazepam and midazolam, are the mainstay of treatment for seizure emergencies, including acute repetitive seizures. Nonparenteral dosage forms are used when parenteral (intravenous or intramuscular) dosing is not feasible. Currently available nonparenteral dosage forms have limitations in terms of usability, patient and caregiver acceptance, speed of action, and portability. Diazepam buccal film (DBF) is a compact, easily administered diazepam formulation. When placed onto the buccal mucosa inside the cheek, DBF adheres firmly and then rapidly dissolves, delivering diazepam transbucally and via the gastric route. In fasted healthy male volunteers, plasma levels were achieved rapidly after DBF placement in a linear dose-proportional fashion. Bioavailability in adult patients with epilepsy was not significantly different when DBF was applied interictally or periictally (within 5 min of a seizure). Diazepam buccal film was successfully placed and generally used without difficulty, even without patient cooperation immediately after a seizure. In a crossover comparative study with diazepam rectal gel (Diastat®) in adult patients with epilepsy, DBF performed equivalently to the rectal gel, but peak exposures were less variable. Diazepam buccal film is a convenient alternative for out-of-hospital treatment of seizure exacerbations. Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures.
Topics: Acute Disease; Administration, Buccal; Anticonvulsants; Diazepam; Humans; Seizures
PubMed: 31699662
DOI: 10.1016/j.yebeh.2019.106537 -
Biomedicine & Pharmacotherapy =... Nov 2022Diazepam is a benzodiazepine (BZD) used worldwide for a variety of conditions. Long-term use of diazepam increases the risk for developing tolerance and dependence and...
Diazepam is a benzodiazepine (BZD) used worldwide for a variety of conditions. Long-term use of diazepam increases the risk for developing tolerance and dependence and for the occurrence of adverse drug reactions (ADRs). CYP3A4 and CYP2C19 mainly metabolize diazepam and are therefore the primary pharmacogenetic candidate biomarkers. In this work, we aimed to explore the impact of CYP3A4 and CYP2C19 phenotypes and of 99 additional variants in other 31 pharmacogenes (including other CYP, UGT, NAT2 and CES enzymes, ABC and SLC transporters) on diazepam pharmacokinetic variability and safety. 30 healthy volunteers that had participated in a single-dose bioequivalence clinical trial of two diazepam formulations were enrolled in the present candidate gene pharmacogenetic study. CYP2C19 poor metabolizers (PMs) showed an almost 2-fold increase in AUCDW compared to rapid (RMs) or normal (NM) metabolizers, and a 1.46-fold increase compared to intermediate metabolizers (IMs). CYP2B6 PMs showed a 2,74-fold higher AUC/DW compared to RMs, and 2.10-fold compared to NMs (p < 0.007). A dose reduction of 25-50 % may be appropriate for CYP2C19 or CYP2B6 PMs to avoid ADRs, dependence and tolerance. Combined CYP2C19 +CYP2B6 PMs may not use diazepam or sharper dose adjustments (e.g., a dose reduction of 50-70 %) may be advisable. To our knowledge, this is the first work to report a strong relationship between CYP2B6 phenotype and diazepam pharmacokinetics. Additional nominal associations (i.e., 0.007
Topics: Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP2C19; Diazepam; Phenotype; Humans
PubMed: 36162369
DOI: 10.1016/j.biopha.2022.113747 -
Journal of Clinical Neuroscience :... Jul 2016Convulsive status epilepticus (CSE) is a neurological emergency in adults and children. However, whether a particular benzodiazepine is of superior efficacy and safety... (Meta-Analysis)
Meta-Analysis Review
Convulsive status epilepticus (CSE) is a neurological emergency in adults and children. However, whether a particular benzodiazepine is of superior efficacy and safety in management of CSE is controversial. We performed a meta-analysis to compare the outcome of lorazepam and diazepam for treating CSE. We searched the PubMed, Medline, Embase, Cochrane Central Register of Controlled Trials, and Google Scholar databases from 1966 to February 2014. No language restriction was applied. Reference lists of all the selected articles were hand-searched for any additional trials. Trial quality was assessed using the modified Jadad scale and the Consolidated Standards Of Reporting Trials (CONSORT) checklist. Two authors independently extracted data from all eligible studies, including study design, participants, interventions, and outcomes. The data was analyzed using fixed-effects or random-effects models with mean differences and risk ratios for continuous and dichotomous variables, respectively. A total of six studies involving 970 patients were included in this analysis. The majority of patients were children (n=574) and 396 patients were adults. Meta-analysis showed no significant difference between the two treatment groups regarding seizure control and adverse effects regardless of patient age. This meta-analysis demonstrates that diazepam and lorazepam have equal efficacy and side effects for treating CSE in adults and children, and either can be chosen as a reasonable first-line therapy. More high quality randomized controlled trials are needed to support this finding.
Topics: Anticonvulsants; Diazepam; Humans; Lorazepam; Seizures; Status Epilepticus; Treatment Outcome
PubMed: 27052258
DOI: 10.1016/j.jocn.2015.10.038 -
ASN Neuro 2023Pharmacological stimulation/antagonism of astrocyte glio-peptide octadecaneuropeptide signaling alters ventromedial hypothalamic nucleus (VMN) counterregulatory...
Pharmacological stimulation/antagonism of astrocyte glio-peptide octadecaneuropeptide signaling alters ventromedial hypothalamic nucleus (VMN) counterregulatory γ-aminobutyric acid (GABA) and nitric oxide transmission. The current research used newly developed capillary zone electrophoresis-mass spectrometry methods to investigate hypoglycemia effects on VMN octadecaneuropeptide content, along with gene knockdown tools to determine if octadecaneuropeptide signaling regulates these transmitters during eu- and/or hypoglycemia. Hypoglycemia caused dissimilar adjustments in the octadecaneuropeptide precursor, i.e., diazepam-binding-inhibitor and octadecaneuropeptide levels in dorsomedial versus ventrolateral VMN. Intra-VMN diazepam-binding-inhibitor siRNA administration decreased baseline 67 and 65 kDa glutamate decarboxylase mRNA levels in GABAergic neurons laser-microdissected from each location, but only affected hypoglycemic transcript expression in ventrolateral VMN. This knockdown therapy imposed dissimilar effects on eu- and hypoglycemic glucokinase and 5'-AMP-activated protein kinase-alpha1 (AMPKα1) and -alpha2 (AMPKα2) gene profiles in dorsomedial versus ventrolateral GABAergic neurons. Diazepam-binding-inhibitor gene silencing up-regulated baseline (dorsomedial) or hypoglycemic (ventrolateral) nitrergic neuron neuronal nitric oxide synthase mRNA profiles. Baseline nitrergic cell glucokinase mRNA was up- (ventrolateral) or down- (dorsomedial) regulated by diazepam-binding-inhibitor siRNA, but knockdown enhanced hypoglycemic profiles in both sites. Nitrergic nerve cell AMPKα1 and -α2 transcripts exhibited division-specific responses to this genetic manipulation during eu- and hypoglycemia. Results document the utility of capillary zone electrophoresis-mass spectrometric tools for quantification of ODN in small-volume brain tissue samples. Data show that hypoglycemia has dissimilar effects on ODN signaling in the two major neuroanatomical divisions of the VMN and that this glio-peptide imposes differential control of glucose-regulatory neurotransmission in the VMNdm versus VMNvl during eu- and hypoglycemia.
Topics: Rats; Animals; Glucose; Ventromedial Hypothalamic Nucleus; Hypoglycemic Agents; Rats, Sprague-Dawley; Diazepam Binding Inhibitor; Glucokinase; Glycogen; Hypoglycemia; RNA, Messenger; RNA, Small Interfering; Diazepam
PubMed: 38031405
DOI: 10.1177/17590914231214116 -
Expert Review of Neurotherapeutics Feb 2015Benzodiazepines represent the first choice treatment of acute repetitive seizures, and diazepam is one of the main drugs administered to epileptic patients in the... (Review)
Review
Benzodiazepines represent the first choice treatment of acute repetitive seizures, and diazepam is one of the main drugs administered to epileptic patients in the prehospital setting. Currently, Diazepam rectal gel is the only approved therapy for the outpatient management of seizures, but there is a growing need for alternative medications for terminating seizures that may be not only safe and effective but also socially acceptable. According to this, the autoinjector device appears to be a promising tool for the treatment of acute repetitive seizures. Recent studies comparing diazepam autoinjector (AI) with placebo suggest that diazepam AI could be a safe and effective option to treat acute repetitive seizures when administered by trained caregivers in outpatient settings. However, additional studies comparing diazepam AI with a standard treatment are necessary to define possible added benefits of this technique.
Topics: Acute Disease; Administration, Buccal; Animals; Anticonvulsants; Diazepam; Epilepsy; Humans
PubMed: 25614951
DOI: 10.1586/14737175.2015.1003043 -
Current Opinion in Neurology Apr 2016This review discusses advances in the understanding of the mechanisms of status epilepticus and its current treatment approaches. Many of these have been topics at the... (Review)
Review
PURPOSE OF REVIEW
This review discusses advances in the understanding of the mechanisms of status epilepticus and its current treatment approaches. Many of these have been topics at the 5th London-Innsbruck Colloquium on status epilepticus 2015.
RECENT FINDINGS
A new definition and classification of status epilepticus was proposed, which is expected to improve treatment and stimulate research. A better understanding of the failure of seizure suppressing mechanisms and the initiation of self-sustaining seizures begins to translate into the clinical arena. Drugs, such as allopregnanolone, cannabinoids, sec-butylpropylacetamide and valnoctamide, may better target these seizure-perpetuating mechanisms. The concept of combinatorial treatments has further developed, but yet trials in humans are lacking. A new prognostic outcome-score and electroencephalography-criteria for nonconvulsive status epilepticus are ready for clinical use. Alternative routes, such as intranasal or buccal, have been explored in a number of trials suggesting that intramuscular midazolam is at least as effective as intravenous lorazepam and buccal or intranasal midazolam is at least as effective as rectal diazepam.
SUMMARY
Despite progress in basic science, translation into the clinical field remains difficult. There is hope, that the two large phase III studies in the established and refractory status that started recruitment in 2015 will better inform the clinicians in this emergency situation.
Topics: Amides; Anticonvulsants; Diazepam; Humans; Midazolam; Seizures; Status Epilepticus
PubMed: 26886360
DOI: 10.1097/WCO.0000000000000307 -
Drugs in R&D Mar 2022Urine is conventionally used as a specimen to document diazepam-related crimes; however, few reports have described the pharmacokinetics of diazepam and its metabolites...
BACKGROUND
Urine is conventionally used as a specimen to document diazepam-related crimes; however, few reports have described the pharmacokinetics of diazepam and its metabolites in urine.
OBJECTIVE
This study aimed to investigate the pharmacokinetics of diazepam and its metabolites, including glucuronide compounds, in the urine of Chinese participants.
METHODS
A total of 28 volunteers were recruited and each participant ingested 5 mg of diazepam orally. Ten milliliters of urine were collected from each participant at post-consumption timepoints of prior (zero), 1, 2, 4, 8, 12, and 24 h and 2, 3, 6, 12, and 15 days. All samples were extracted by solid-phase extraction and analyzed using high-performance liquid chromatography-tandem mass spectrometry. Diazepam and its main metabolites, except for temazepam, were detected in the urine of volunteers. Pharmacokinetic parameters were analyzed using the pharmacokinetic software DAS according to the non-compartment model.
RESULTS
Urinary diazepam peaked at 2.38 ng/mL (C) and 1.93 h (T). The urinary metabolite nordiazepam peaked at 1.17 ng/mL and 100.21 h; temazepam glucuronide (TG) peaked at 145.61 ng/mL and 41.14 h; and oxazepam glucuronide (OG) peaked at 101.57 ng/mL and 165.86 h. The elimination half-life (t) and clearance (CLz/F) for diazepam were 119.58 h and 65.77 L/h, respectively. The t of the metabolites nordiazepam, TG, and OG was 310.58 h, 200.17 h, and 536.44 h, respectively. Finally, this study found that both diazepam and its main metabolites in urine were detectable for at least 15 days, although there were individual differences.
CONCLUSION
The results regarding diazepam pharmacokinetics in urine would be of great help in forensic science and drug screening.
Topics: China; Chromatography, High Pressure Liquid; Diazepam; Humans; Nordazepam; Solid Phase Extraction
PubMed: 35099786
DOI: 10.1007/s40268-021-00375-y