Emergency Treatment Of Seizures Research Articles

Automated Information Systems as a New Approach to Risk Management of Pharmacotherapy in the Treatment of Epilepsy

Epilepsy is a fairly common disease which challenges social life, therefore the use of information systems and software to support patients with epilepsy is a promising trend in electronic and mobile medicine. The aim of the study was to analyse data on the existing information systems, devices, and mobile applications used to support patients with epilepsy and control risks associated with pharmacotherapy, and to assess the prospects for the development of information systems to support patients with epilepsy. The results of an advanced search and systematisation of literature and Internet data suggest a high demand for mobile and e-health. Mobile applications for patients with epilepsy have a large share of e-health tools. The applications help to monitor seizures, record the frequency of taking medications, receive advice on emergency treatment of seizures, adjust the dosage regimen, and, in general, help to reduce the risks of anticonvulsant therapy, increase patient compliance and the competence of the participants in the treatment process. The analysis of the convenience and functionality of the foreign-produced mobile applications: Epilepsy Journal, Seizure Tracker, Helpilepsy, Seizure First Aide, did not reveal any significant differences between them. The following shortcomings of the mobile applications were identified: lack of Russian language support (except Epilepsy Journal), lack of advertisement blocking options in free applications, incomplete use of video recording capabilities and location-based systems. Global trends in the development of mobile medicine suggest the need for Russian-produced software that would address the identified shortcomings of the existing foreign applications and help support patients with epilepsy.

Intranasal Allopregnanolone Confers Rapid Seizure Protection: Evidence for Direct Nose-to-Brain Delivery

Allopregnanolone, a positive modulator of GABAA receptors with antiseizure activity, has potential in the treatment of seizure emergencies. Instillation of allopregnanolone in 40% sulfobutylether-β-cyclodextrin into the nose in mice rapidly elevated the seizure threshold in the timed intravenous pentylenetetrazol (ED50, 5.6 mg/kg), picrotoxin (ED50, 5.9 mg/kg), and bicuculline seizure tests. The effect peaked at 15 min, decayed over 1 h, and was still evident in some experiments at 6 h. Intranasal allopregnanolone also delayed the onset of seizures in the maximal PTZ test. At an allopregnanolone dose (16 mg/kg) that conferred comparable effects on seizure threshold as the benzodiazepines midazolam and diazepam (both at doses of 1 mg/kg), allopregnanolone caused minimal sedation or motor toxicity in the horizontal screen test whereas both benzodiazepines produced marked behavioral impairment. In addition, intranasal allopregnanolone failed to cause loss-of-righting reflex in most animals, but when the same dose was administered intramuscularly, all animals became impaired. Intranasal allopregnanolone (10 mg/kg) caused a rapid increase in brain allopregnanolone with a Tmax of ~5 min after initiation of the intranasal delivery. High levels of allopregnanolone were recovered in the olfactory bulb (Cmax, 16,000 ng/mg) whereas much lower levels (Cmax, 670 ng/mg) were present in the remainder of the brain. We conclude that the unique ability of intranasal allopregnanolone to protect against seizures without inducing behavioral adverse effects is due in part to direct nose-to-brain delivery, with preferential transport to brain regions relevant to seizures. Benzodiazepines are commonly administered intranasally for acute seizure therapy, including for the treatment of acute repetitive seizures, but are not transported from nose-to-brain. Intranasal allopregnanolone acts with greater speed, has less propensity for adverse effects, and has the ability to overcome benzodiazepine refractoriness. This is the first study demonstrating rapid functional central nervous system activity of a nose-to-brain-delivered steroid. Intranasal delivery circumvents the poor oral bioavailability of allopregnanolone providing a route of administration permitting its evaluation as a treatment for diverse neuropsychiatric indications.

Rapid intranasal delivery of diazepam utilizing prodrug/enzyme formulations: a promising drug delivery strategy for outpatient treatment of seizure emergencies

Rapid intranasal delivery of diazepam utilizing prodrug/enzyme formulations: a promising drug delivery strategy for outpatient treatment of seizure emergencies

Intranasal Coadministration of a Diazepam Prodrug with a Converting Enzyme Results in Rapid Absorption of Diazepam in Rats.

Intranasal administration is an attractive route for systemic delivery of small, lipophilic drugs because they are rapidly absorbed through the nasal mucosa into systemic circulation. However, the low solubility of lipophilic drugs often precludes aqueous nasal spray formulations. A unique approach to circumvent solubility issues involves coadministration of a hydrophilic prodrug with an exogenous converting enzyme. This strategy not only addresses poor solubility but also leads to an increase in the chemical activity gradient driving drug absorption. Herein, we report plasma and brain concentrations in rats following coadministration of a hydrophilic diazepam prodrug, avizafone, with the converting enzyme human aminopeptidase B Single doses of avizafone equivalent to diazepam at 0.500, 1.00, and 1.50 mg/kg were administered intranasally, resulting in 77.8% ± 6.0%, 112% ± 10%, and 114% ± 7% bioavailability; maximum plasma concentrations 71.5 ± 9.3, 388 ± 31, and 355 ± 187 ng/ml; and times to peak plasma concentration 5, 8, and 5 minutes for each dose level, respectively. Both diazepam and a transient intermediate were absorbed. Enzyme kinetics incorporated into a physiologically based pharmacokinetic model enabled estimation of the first-order absorption rate constants: 0.0689 ± 0.0080 minutes-1 for diazepam and 0.122 ± 0.022 minutes-1 for the intermediate. Our results demonstrate that diazepam, which is practically insoluble, can be delivered intranasally with rapid and complete absorption by coadministering avizafone with aminopeptidase B. Furthermore, even faster rates of absorption might be attained simply by increasing the enzyme concentration, potentially supplanting intravenous diazepam or lorazepam or intramuscular midazolam in the treatment of seizure emergencies.

Chirally Pure Prodrugs and Their Converting Enzymes Lead to High Supersaturation and Rapid Transcellular Permeation of Benzodiazepines

Water-soluble prodrugs can be rapidly converted by enzymes to hydrophobic drugs, whose aqueous thermodynamic solubilities are low, but are maintained in aqueous solution at supersaturated concentrations due to slow precipitation kinetics. Recently, we investigated avizafone (AVF) in combination with Aspergillus oryzae protease as a prodrug/enzyme system intended to produce supersaturated diazepam (DZP). Several fold enhancement of permeation of supersaturated DZP across Madin-Darby canine kidney II-wild type (MDCKII-wt) monolayers was observed, compared to saturated DZP solutions. However, prodrug conversion was incomplete, putatively due to partial racemization of AVF and stereoselectivity of A oryzae protease. Here we report synthesis of chirally pure AVF, and demonstrate complete conversion to supersaturated DZP followed by complete DZP permeation at enhanced rates across MDCKII-wt cell monolayers. We also synthesized, for the first time, a chirally pure prodrug of midazolam (MDZ-pro) and carried out the same sequence of studies. A oryzae protease was identified as a benign and efficient activating enzyme for MDZ-pro. The MDZ-pro/A oryzae protease system showed greater than 25-fold increase in absorption rate of MDZ across MDCKII-wt monolayers, compared to saturated MDZ. Such chirally pure prodrug/enzyme systems are promising candidates for efficient intranasal delivery of benzodiazepine drugs used in the treatment of seizure emergencies.

Development of benzodiazepines for out-of-hospital management of seizure emergencies.

Management of seizure emergencies substantially changed after the introduction of rectal diazepam in Europe in the 1970s and in the United States in the 1990s. Although safe and effective, social objections and legal concerns have limited use of rectal diazepam products in out-of-hospital treatment of seizure emergencies. Shortly after the introduction of Diastat (diazepam rectal gel), commercial development of innovative formulations began involving several benzodiazepines and routes of administration, including buccal, IM, nasal, and subcutaneous. All benzodiazepines have the same mechanism of action; however, there are major differences in physicochemical properties and pharmacokinetic characteristics, which affect the choice of drug and route. This article highlights some of those differences and their effect on selection of therapies for treating seizure emergencies. We also present results from key clinical studies of these drugs and provide an update on current status of new products under development.

The role of the newer antiepileptic drugs in the treatment of generalized convulsive status epilepticus

The emergency treatment of seizures is an important practical issue, especially the treatment of generalized convulsive status epilepticus (GCSE). Benzodiazepines or older standard antiepileptic drugs (phenobarbital, phenytoin) have typically been used as initial intravenous treatment of GCSE. As new parenteral antiepileptic drugs are developed, and more are on the horizon, questions are raised regarding their role in the treatment of status epilepticus (SE). This review discusses the evidence for the treatment of GCSE, including the newer agents (valproate, levetiracetam). We correlate the treatment of SE with our modern understanding of the underlying neurophysiology and seizure duration.

A systematic review of the use of buccal midazolam in the emergency treatment of prolonged seizures in adults with learning disabilities

Accessible summary People with a learning disability can have epilepsy and can have long seizures. The treatment for long seizures is rectal diazepam given up the back passage. Some carers and people with epilepsy do not like this. Buccal midazolam is a treatment for long seizures that is given by mouth. Buccal midazolam seems to work as well as rectal diazepam in children with epilepsy. New guidance to doctors says they can use buccal midazolam in adults for long seizures. People with learning disabilities and carers can ask their doctor to prescribe buccal midazolam instead of rectal diazepam to treat long seizures. AbstractBackground Buccal midazolam is widely used in children for the emergency treatment of epilepsy, and these children are graduating into adult learning disability services.Aims The aim of this paper was to appraise the evidence for buccal midazolam as a treatment for prolonged seizures in adults with learning disabilities.Method A literature search was performed and the identified papers appraised.Results The literature search identified only one randomized trial for buccal midazolam as emergency treatment of seizures, and this was in children and adolescents. It showed that buccal midazolam was as effective as rectal diazepam.Conclusions There is evidence that buccal midazolam is effective, but it is unlicensed for this purpose. Rectal diazepam should remain the first choice, but buccal midazolam should be discussed with patients and carers as an alternative.Declaration of interest nil.

Efficacy and safety of intranasal lorazepam versus intramuscular paraldehyde for protracted convulsions in children: an open randomised trial

In sub-Saharan Africa, rectal diazepam or intramuscular paraldehyde are commonly used as first-line anticonvulsant agents in the emergency treatment of seizures in children. These treatments can be expensive and sometimes toxic. We aimed to assess a drug and delivery system that is potentially more effective, safer, and easier to administer than those presently in use. We did an open randomised trial in a paediatric emergency department of a tertiary hospital in Malawi. 160 children aged over 2 months with seizures persisting for more than 5 min were randomly assigned to receive either intranasal lorazepam (100 microg/kg, n=80) or intramuscular paraldehyde (0.2 mL/kg, n=80). The primary outcome measure was whether the presenting seizure stopped with one dose of assigned anticonvulsant agent within 10 min of administration. The primary analysis was by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT00116064. Intranasal lorazepam stopped convulsions within 10 min in 60 (75%) episodes treated (absolute risk 0.75, 95% CI 0.64-0.84), and intramuscular paraldehyde in 49 (61.3%; absolute risk 0.61, 95% CI 0.49-0.72). No clinically important cardiorespiratory events were seen in either group (95% binomial exact CI 0-4.5%), and all children finished the trial. Intranasal lorazepam is effective, safe, and provides a less invasive alternative to intramuscular paraldehyde in children with protracted convulsions. The ease of use of this drug makes it an attractive and preferable prehospital treatment option.

Intravenous valproate as an innovative therapy in seizure emergency situations including status epilepticus—experience in 102 adult patients

The emergency treatment of seizures is an important practical issue, in particular the therapy of status epilepticus. Antiepileptic drugs for this condition should be easy to use, show rapid action, have a long-lasting antiepileptic effect, and have minimal cardiopulmonary and other side-effects. Unfortunately, none of the presently available medications such as phenytoin and barbiturates seems to have all of these four properties. Intravenous valproate became available some years ago and first experiences show promising safety data and efficacy results. We report a series of 102 adult patients who received standardized high dosage intravenous valproate in various emergency situations, including status epilepticus. The therapeutic goal was persistent seizure control, defined as successful interruption of clinical seizure activity within less than 15 min, followed by seizure freedom during intravenous therapy for at least 12h. All side effects were documented. In 83/97 patients (85.6%) the therapeutic goal was achieved. Serious side effects were not documented in any patient. In particular there was no evidence of sedation, cardiorespiratory disturbances and hypotension as often seen in barbiturates and phenytoin. Mild side effects occurred in seven cases (6.9%). The intravenous application of VPA seems to be an easy-to-use, safe and efficient formulation as an alternative to phenytoin in all seizure emergency situations including status epilepticus. Further controlled comparison studies have to be performed in the future.

Coadministration of Flunarizine Prevents Tolerance to Nitrazpam in Mice

Purpose: Benzodiazepines (BZDs) are the most potent drugs available for the emergency treatment of seizures. For the long‐term treatment of epilepsy, however, BZDs are often administered in combination with other antiepileptic drugs(s) (AEDs) because of the development of tolerance. In this study, the influence of concurrently administered AEDs [carbamazepine (CBZ), phenytoin (PHT), zonisamide (ZNS), vigabatrin (VGB), lamotrigine (LTG), or flunarizine (FNR)] on the tolerance to the anticonvulsant action of the BZDs was studied by using an animal tolerance mode. Methods: In the first experiment, adult male mice (ICR, 30–35 g) were given nitrazepam (NZP; 0.6 mg/kg, i.p.) twice daily (8:00 a.m. and 6:00 p.m.) for 0 (acute), 0.5, 1, 3, or 5 days before the test day. On the morning (8:00 a.m.) of the test day, all mice were given pentylenetetrazole (PTZ; 150 mg/kg, i.p.) 30 min after the injection of a single protective dose of NZP (0.6 mg/kg). Mice were then observed for 30 min for the development of unequivocal clonic convulsions (duration, <3 s). In the second experiment, mice were randomly assigned to one of eight groups depending on the coadministered AED. Mice received vehicle, NZP (0.6 mg/kg, i.p.) alone or NZP concurrent with one of the six AEDs (CBZ, 6.25 mg/kg; PHT, 10 mg/kg; ZNS, 20 mg/kg; VGB, 250 mg/kg: LTG, 15 mg/kg; and FNR, 10 mg/kg) twice daily for 5 days. A single dose of CBZ, PHT, ZNS, VGB, LTG, or FNR alone was ineffective against the clonic convulsions induced by PTZ (150 mg/kg). On the test day, several mice were randomly chosen from each group, and blood samples were collected to determine the concentration of NZP at 30 min after the protective injections of NZP. The remaining mice were tested as mentioned. Tolerance to the anticonvulsant action of NZP was considered to develop when the difference in seizure frequency was statistically significant (by the x2 test) between the non‐NZP treatment group (experiment 1, acute group: experiment 2, vehicle‐treated group) and another treatment group. Results: In mice treated with NZP alone, tolerance was evident even after the second dose (1 day) but did not increase further after 3 or 5 days of treatment; significant increases in seizure frequency (45–55%) were found in mice treated with NZP for 1, 3, or 5 days, as compared with the acute group (9.7%), but there were no significant differences between the duration of treatment (1, 3, or 5 days). Tolerance to the anticonvulsant action of NZP developed in mice treated with NZP plus CBZ, PHT, ZNS, VGB, or LTG. On the other hand, mice receiving NZP + FNR showed no tolerance; there was no significant difference in seizure frequency between the vehicle group (four of 21) and NZP + FNR group (four of 21), but a significant difference (p > 0.05) was observed between the NZP alone group (12 of 21) and NZP + FNR group. There were no significant differences in plasma NZP concentrations between three groups (vehicle, 560.8 ± 275.4 ng/ml; NZP alone, 398.6 ± 216.4 ng/ml; and NZP + FNR, 537.9 ± 130.2 ng/ml). Conclusions: These data suggest that coadministration of FNR but not CBZ, PHT, ZNS, VGB, or LTG may delay, if not prevent, the development of tolerance to the anticonvulsant action of BZDs.

Diazepam and intubation in emergency treatment of seizures in children

This study was undertaken to determine the incidence of endotracheal intubation after the use of diazepam compared with phenobarbital or phenytoin in emergency treatment of seizures in children. The records of all children (98) were reviewed in a case-control fashion. A logistic regression model was used to determine whether there was an association between diazepam administration and intubation, adjusting for all other covariates (age, weight, convulsion time before first anticonvulsant was given, response latency, diagnosis, and therapy). All children were treated in an emergency department and then transported to a tertiary pediatric center by a pediatric transport team. All patients were children, with a median age of 2.7 years (range 0.17 to 15.3 years). None. Only the use of diazepam was found to be significantly associated with intubation after adjusting for all other covariates (adjusted odds ratio, 49.4; P less than .001). In the comparison of diazepam versus phenobarbital or phenytoin used as the first anticonvulsant, median response latency did not differ (27.0 vs 32.5 minutes, P greater than .83). A significant association was found between diazepam use and intubation. Response latency was not shorter when diazepam was used as the initial anticonvulsant compared with phenobarbital or phenytoin.

Midazolam: an effective intravenous agent for seizure control.

Midazolam meleate, a water soluble 1,4 benzodiazepine, was used intravenously in 20 patients suffering seizures, of whom 12 were in status epilepticus. In all cases, midazolam in a dose of 2.5-15 mg rapidly terminated the seizure. There were no complications from the use of midazolam. The causes of the seizures were varied but alcohol-withdrawal seizures were the single largest cause. Thirteen patients were taking some form of anticonvulsant medication but only three were in the therapeutic range. Midazolam is seen to be an effective agent in the emergency treatment of seizures.