-
Obstetrical & Gynecological Survey Jan 2020Hyperemesis gravidarum (HEG) affects 0.3% to 3% of pregnancies and requires additional therapies beyond those commonly used for less severe instances of nausea and... (Review)
Review
IMPORTANCE
Hyperemesis gravidarum (HEG) affects 0.3% to 3% of pregnancies and requires additional therapies beyond those commonly used for less severe instances of nausea and vomiting of pregnancy (NVP). Differentiating between NVP and HEG is a vital yet challenging function for any obstetrician. The literature for management of HEG is lacking compared with that of NVP.
OBJECTIVE
Review etiology of NVP/HEG highlights key considerations in the workup of HEG as they compare to NVP and explore management options for recalcitrant HEG focusing principally on how they affect maternal and fetal outcomes and secondarily on where data are nonprescriptive.
EVIDENCE ACQUISITION
This was a literature review primarily using PubMed and Google Scholar.
RESULTS
Short-course corticosteroids and treatment for have the most favorable risk-reward profiles of the 4 pharmacologic therapies evaluated. Mirtazapine and diazepam may have a place in highly selected patients. If nutritional supplementation is required, enteral nutrition is strictly preferred to parenteral nutrition. Postpyloric feeding approaches are less likely to induce vomiting. Surgically placed feeding tubes are less likely to be dislodged and may be worth the invasive insertion procedure if nasogastric or nasojejunal tubes are not tolerated.
CONCLUSIONS AND RELEVANCE
Hyperemesis gravidarum is a diagnosis reserved for refractory cases of NVP and therefore by definition poses treatment challenges. Any clinical presentation that lent itself to prescriptive, algorithmic management would likely fall short of the diagnostic criteria for HEG. However, data can inform management on a patient-by-patient basis or at least help patient and provider understand risks and benefits of therapies reserved for refractory cases.
Topics: Adrenal Cortex Hormones; Diazepam; Disease Management; Enteral Nutrition; Female; Humans; Hyperemesis Gravidarum; Mirtazapine; Patient Selection; Pregnancy; Prenatal Care
PubMed: 31999353
DOI: 10.1097/OGX.0000000000000746 -
The Journal of Pediatrics May 2021
Topics: Candy; Child; Diazepam; Humans; Illicit Drugs; Male; Tablets; Tranquilizing Agents
PubMed: 33388304
DOI: 10.1016/j.jpeds.2020.12.075 -
Nature Chemical Biology Dec 2021Small molecule drugs form the backbone of modern medicine's therapeutic arsenal. Often less appreciated is the role that small molecules have had in advancing basic... (Review)
Review
Small molecule drugs form the backbone of modern medicine's therapeutic arsenal. Often less appreciated is the role that small molecules have had in advancing basic biology. In this Review, we highlight how resistance mutations have unlocked the potential of small molecule chemical probes to discover new biology. We describe key instances in which resistance mutations and related genetic variants yielded foundational biological insight and categorize these examples on the basis of their role in the discovery of novel molecular mechanisms, protein allostery, physiology and cell signaling. Next, we suggest ways in which emerging technologies can be leveraged to systematically introduce and characterize resistance mutations to catalyze basic biology research and drug discovery. By recognizing how resistance mutations have propelled biological discovery, we can better harness new technologies and maximize the potential of small molecules to advance our understanding of biology and improve human health.
Topics: Alleles; Animals; Diazepam; Drug Discovery; Drug Resistance; Humans; Mutant Proteins; Mutation; Pharmaceutical Preparations; Protein Binding; Protein Conformation; Signal Transduction; Sulfonamides
PubMed: 34799733
DOI: 10.1038/s41589-021-00865-9 -
Expert Opinion on Pharmacotherapy Jan 2021Status epilepticus (SE) is a common neurological and medical emergency. It has high mortality and morbidity rates, which typically correlate with seizure semiology and... (Review)
Review
INTRODUCTION
Status epilepticus (SE) is a common neurological and medical emergency. It has high mortality and morbidity rates, which typically correlate with seizure semiology and duration; therefore, prompt and proper pharmacological intervention is paramount. In a pre-hospital setting, establishing venous access can be difficult, so other routes of drug administration should be considered.
AREAS COVERED
The paper summarizes the data from the literature and provides an evaluation of the efficacy and safety of intramuscular midazolam (IM MDZ) as it pertains to the management of acute seizures and SE.
EXPERT OPINION
The cascade of events involved in the genesis and sustenance of seizures, if not promptly stopped, lead to the perpetuation of the condition and may contribute to the refractoriness of pharmacological treatment. Hence, non-venous routes for drug administration were developed to allow untrained personnel to rapidly stop seizures. Among benzodiazepines (BDZs), IM MDZ is at least as effective and safe as other intravenously administered BDZs. Moreover, thanks to IM MDZ's favorable pharmacodynamic and pharmacokinetic profile, it is a promising alternative to other non-venous drugs such as intranasal-MDZ, buccal-MDZ, and rectal-diazepam in the pre-hospital management of SE cases with motor features.
Topics: Anticonvulsants; Diazepam; Humans; Injections, Intramuscular; Midazolam; Status Epilepticus
PubMed: 32840150
DOI: 10.1080/14656566.2020.1810236 -
Neurobiology of Disease Sep 2023Benzodiazepine (BZ) drugs treat seizures, anxiety, insomnia, and alcohol withdrawal by potentiating γ2 subunit containing GABA type A receptors (GABARs). BZ clinical...
Benzodiazepine (BZ) drugs treat seizures, anxiety, insomnia, and alcohol withdrawal by potentiating γ2 subunit containing GABA type A receptors (GABARs). BZ clinical use is hampered by tolerance and withdrawal symptoms including heightened seizure susceptibility, panic, and sleep disturbances. Here, we investigated inhibitory GABAergic and excitatory glutamatergic plasticity in mice tolerant to benzodiazepine sedation. Repeated diazepam (DZP) treatment diminished sedative effects and decreased DZP potentiation of GABAR synaptic currents without impacting overall synaptic inhibition. While DZP did not alter γ2-GABAR subunit composition, there was a redistribution of extrasynaptic GABARs to synapses, resulting in higher levels of synaptic BZ-insensitive α4-containing GABARs and a concomitant reduction in tonic inhibition. Conversely, excitatory glutamatergic synaptic transmission was increased, and NMDAR subunits were upregulated at synaptic and total protein levels. Quantitative proteomics further revealed cortex neuroadaptations of key pro-excitatory mediators and synaptic plasticity pathways highlighted by Ca/calmodulin-dependent protein kinase II (CAMKII), MAPK, and PKC signaling. Thus, reduced inhibitory GABAergic tone and elevated glutamatergic neurotransmission contribute to disrupted excitation/inhibition balance and reduced BZ therapeutic power with benzodiazepine tolerance.
Topics: Mice; Animals; Diazepam; Alcoholism; Substance Withdrawal Syndrome; Receptors, GABA-A; Benzodiazepines; Brain; Synapses; gamma-Aminobutyric Acid; Synaptic Transmission
PubMed: 37536384
DOI: 10.1016/j.nbd.2023.106248 -
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 -
Journal of Clinical Sleep Medicine :... Oct 2023We conducted a retrospective study to investigate the efficacy and safety of switching from other hypnotics, including benzodiazepines and Z-drugs, suvorexant,...
STUDY OBJECTIVES
We conducted a retrospective study to investigate the efficacy and safety of switching from other hypnotics, including benzodiazepines and Z-drugs, suvorexant, ramelteon, mirtazapine, trazodone, and antipsychotics, to lemborexant, a dual orexin receptor antagonist, for 3 months.
METHODS
Clinical data obtained from the medical records of 61 patients treated at the Horikoshi Psychosomatic Clinic between December 2020 and February 2022 were analyzed, including the Athens Insomnia Scale, Epworth Sleepiness Scale, and Perceived Deficits Questionnaire-5. The primary outcome was the mean change in Athens Insomnia Scale score after 3 months. Secondary outcomes were the mean changes in the Epworth Sleepiness Scale and Perceived Deficits Questionnaire-5 scores over 3 months. We also compared pre- and post-diazepam equivalents.
RESULTS
The mean Athens Insomnia Scale score decreased over 3 months after switching to lemborexant (1 mo: -2.98 ± 5.19, < .001; 2 mo: -3.20 ± 5.64, < .001; 3 mo: -3.38 ± 5.61, < .001). Mean Epworth Sleepiness Scale score did not change from baseline to 1 month (-0.49 ± 3.41, = 0.27), 2 months (0.082 ± 4.62, = .89), or 3 months (-0.64 ± 4.80, = .30). Mean Perceived Deficits Questionnaire-5 score did improve from baseline to 1 month (-1.17 ± 2.47, = .004), 2 months (-1.05 ± 2.97, = .029), and 3 months (-1.24 ± 3.06, = .013). There was also a reduction in the total diazepam equivalent (baseline vs 3 mo: 14.0 ± 20.2 vs 11.3 ± 20.6, < .001).
CONCLUSIONS
Our study showed that, by switching to lemborexant from other hypnotics, the risks associated with benzodiazepines and Z-drugs may be reduced.
CITATION
Horikoshi S, Miura I, Suzuki Y, et al. Switching to lemborexant for the management of insomnia in mental disorders: the SLIM study. . 2023;19(10):1753-1758.
Topics: Humans; Sleep Initiation and Maintenance Disorders; Retrospective Studies; Sleepiness; Hypnotics and Sedatives; Orexin Receptor Antagonists; Benzodiazepines; Diazepam
PubMed: 37243798
DOI: 10.5664/jcsm.10668 -
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