Randomized clinical trials are needed to evaluate new treatment protocols, which should not only stop the seizures more effectively but also be safer and include some neuroprotective elements to halt the cascade of neuronal injury and minimize the risk for neurologic morbidity caused by the convulsive status epilepticus.

Randomized, controlled studies show that these two drugs have similar onsets of action and adverse effects (res- piratory depression and impaired consciousness), and they are both clinically efficient in 2—3 min [26].

The pharmacologic treat- ment of refractory CSE is general anesthesia with continuous intravenous anesthetics administered in doses, which abolish all clinical and electrographic epileptic activity often requiring sedation to the point of burst suppression in the electro- encephalogram (EEG).

According to present knowledge, the availability of nonrectal application routes favors the use of MDL (buccally) — although it is currently unlicensed for this indication and should be used only following training accord- ing to individualized instructions drawn by the specialist.

Current schematic treatment phases of early, established and refractory convulsive status epilepticus and how they might be optimized in the future with drug options available at the moment.

The temporal and spatial determinants of status epi- lepticus are also relatively unknown; experimental studies suggest there is induction of reverberating sei- zure activity between, for example, hippocampal and parahippocampal structures and that the seizures pro- gress through a sequence of distinct electrographic changes.

Electroencephalographic monitoring should be used for any patient who has received a relatively long acting paralytic agent, remains unconscious af- ter the initial phase of antiepileptic-drug treatment, or requires prolonged therapy for refractory status ep- ilepticus (discussed below).

The choice of drugs and the recommended sequence of administration are based on the rapid on- set and extended duration of the effect of lorazepam and the presumed value of an additional long-acting ⴢ April 2, 1998 AQUESTIVE EXHIBIT 1101 Page 0003 The New England Journal of Medicine Downloaded from nejm.org by DEEANN JEHNING on January 15, 2020.

Nonetheless, the results of the study suggest that treatment with lorazepam alone may be sufficient and may obviate the need for intravenous phenytoin or fosphenytoin loading when status epilepticus is caused by a rapidly reversible process (e.g., the ef- fects of subtherapeutic antiepileptic-drug concentra- tions or metabolic derangement).

A gel formulation of diazepam in a prefilled syringe for rectal administration (Diastat, Athena Neurosciences, South San Francisco, Calif.) has recently become available in the United States for the treatment of seizure clusters in children and adults.

The Journal of Clinical Pharmacology http://www.jclinpharm.org Bioavailability and pharmacokinetics of lorazepam after intranasal, intravenous, and intramuscular administration DP Wermeling, JL Miller, SM Archer, JM Manaligod and AC Rudy 2001; 41; 1225 J. Clin.

Volume of distribution at steady state and for elimination (Vss and Vz) were deter- mined by moment curves.13 Statistical Considerations Sample size was determined by clinical feasibility rather than standard calculations using alpha and power estimates.

The rela- tively small variation present in the pharmacokinetic Back pain Bad taste Blurred vision Burning/coolness in nose Burning/coolness in throat Ceiling moving Chemical smell Dazed/confused Diarrhea Disconnected/incoherent Dizziness/lightheaded Drowsiness/sleepiness Euphoria/giddiness Eyes heavy Eyes watery Floating sensation Flu/cold-like symptoms Groggy/heavy feeling Headache Hiccups Muscle tension/soreness Nausea Pain at injection site Pallor Phlegm in throat Postnasal drainage Pulse elevated Relaxed Slow response time Thirsty Warm IV, intravenous; IM, intramuscular; IN, intranasal.

However, this enzyme exists in multiple forms, only one of which was analyzed in that particular study.24 Last, as evi- denced by the second peak (Figure 2), partial oral ab- sorption of the dose could have played a role in the bioavailability, especially if nasal clearance took place.

Sev- eral of these studies found no significant pharmacokinetic differences between genders.29-31 Al- ternatively, Yonkers et al32 conducted a literature re- view and concluded that young women may require lower doses of benzodiazepines.

The large surface area of the nasal mucosa affords a rapid onset of therapeutic effect, potential for direct-to-central nervous system delivery, no first-pass metabolism, and non-invasiveness; all of which may maximize patient convenience, comfort, and compliance.

Improved delivery to the brain via the IN route has been reported for some low-molecular- weight drugs (Sakane et al., 1991, 1994, 1995; Kao et al., 2000; Chow et al., 2001; Al-Ghananeem et al., 2002; Costantino et al., 2005; Barakat et al., 2006), as well as therapeutic peptides and proteins (Frey et al., 1997; Dufes et al., 2003; Banks et al., 2004; Thome et al., 2004; Ross et al., 2004; Lerner et al., 2004).

While the therapeutic areas are diverse, the common theme among them is an advantage for IN dosing, such as patient convenience and preference, rapid drug onset, avoidance of GI-related side-effects, and more consistent delivery for disease states associated with gastric dysmotility.

Examples of excipients shown to improve nasal permeation include bile salts (Moses et al., 1983; Aungst and Rogers, 1988; Hosoya et al., 1999; Bagger et al., 2001), alkyl glycosides (Ahsan et al., 2001; Pillion et al., 2002; Nakamura et al., 2002; Mustafa et al., 2004), polymers (e.g., poly-L-arginine (Ohtake et al., 2002), gelatin (Wang et al., 2002), and chitosan (Illum et al., 1994; Prego et al., 2005)), tight junction modulating peptides (Johnson and Quay, 2005; Chen et al., 2006), lipids and surfactants (Coates et al., 1995; Laursen AQUESTIVE EXHIBIT 1118 Page 0007 HR.

They also found that the addition of an enhancer with a known profound effect on the cell membrane (STDHF), as compared with one positioned mainly to affect the tight junctions (B-CD), did not alter the route of transport of these hydrophilic compounds (which remained paracellular).

Carers can give rectal diazepam and it may avoid the necessity of sending for medical help or preventing hospital admission.5 Other benzodiazepines, i.e. clobazam are often prescribed prophylactically for epilepsy cluster events.6 Within this Learning Disability Service (LDS) the clinicians found that in the community settings many of the support * Corresponding author.

This is important information for doctors as it aids distinguishing the preictal, ictal and postictal stages which can be difficult to detect when they co-exist with psychiatric and behavioural symptoms.14–16 Many studies have highlighted the complications of monitoring and diagnosing seizures due to the dual diagnosis in the learning disability population.17,18 The patients IEG’s were produced in consultation with carers, relatives and significant others, i.e. day/residential placements; respite care services staff and health professionals (nurses, psychiatrists, neurologists and general practitioners (GP)).

Fortunately the advantages compensate for this as it increases patient/carers satisfaction as affirmed by the results of this survey, prevents hospital admissions, and enables the person to receive emergency treatment by familiar people.

The plan is in the future for adult learning disability patients to use buccal midazolam medication (an alternative to rectal diazepam which is less intrusive) and develop guidelines using this process.30 Acknowledgements Thanks to Dr M Shah, Dr Bhandarkar, and Laura Findlay for their support during this project, and thanks also to the anonymous reviewers at Seizure Journal for their helpful comments.

McIntyre S, Robertson S, Norris E, Appleton R, Whitehouse WP, Phillips B, et al. Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomised controlled trial.

The nasal mucosa - Fitonasal 2Act Page 1 of 2 How does the nose work?

Underneath the epithelium is a dense network of capillary blood vessels.

The nasal mucosa is essential to correct operation of the entire respiratory system.

The nose works as it does thanks to various defensive mechanisms: its epithelium and dense network of capillaries, its mucus, the vibrating cilia which move the mucus, the cells of the immune system and many substances capable of combating bacteria and viruses and harmful substances.

The nasal mucosa - Fitonasal 2Act Page 2 of 2 The mucus traps harmful substances (viruses, bacteria, dust, pollens, etc.) on the surface of the mucosa and the vibratory cilia move the mucus toward the pharynx to eliminate it.