Epilepsy: expert opinion on emerging drugs in phase 2/3 clinical trials.

INTRODUCTION: Despite the existence of over 30 anti-seizure medications (ASM), including 20 over the last 30 years, a third of patients with epilepsy remain refractory to treatment, with no disease-modifying or preventive therapies until very recently. The development of new ASMs with new mechanisms of action is therefore critical. Recent clinical trials of new treatments have shifted focus from traditional common epilepsies to rare, genetic epilepsies with known mechanistic targets for treatment and disease-specific animal models. AREAS COVERED: ASMs in phase 2a/b-3 clinical trials target cholesterol, serotonin, sigma-1 receptors, potassium channels and metabotropic glutamate receptors. Neuroinflammation, protein misfolding, abnormal thalamocortical firing, and molecular deficiencies are among the targeted pathways. Clinically, the current phase 2a/b-3 agents hold promise for variety of epilepsy conditions, from developmental epileptic encephalopathies (Dravet Syndrome, Lennox-Gastaut syndrome, CDKL5 and PCDH19, Rett's Syndrome), infantile spasms, tuberous sclerosis as well as focal and idiopathic generalized epilepsies and acute rescue therapy for cluster seizures. EXPERT OPINION: New delivery mechanisms increase potency and site-specificity of existing drugs. Novel mechanisms of action involve cholesterol degradation, mitochondrial pathways, anti-inflammation, and neuro-regeneration. Earlier identification of genetic conditions through genetic testing will allow for earlier use of disease specific and disease-modifying therapies.

Rabs on the fly: Functions of Rab GTPases during development.

The organization of intracellular transport processes is adapted specifically to different cell types, developmental stages, and physiologic requirements. Some protein traffic routes are universal to all cells and constitutively active, while other routes are cell-type specific, transient, and induced under particular conditions only. Small GTPases of the Rab (Ras related in brain) subfamily are conserved across eukaryotes and regulate most intracellular transit pathways. The complete sets of Rab proteins have been identified in model organisms, and molecular principles underlying Rab functions have been uncovered. Rabs provide intracellular landmarks that define intracellular transport sequences. Nevertheless, it remains a challenge to systematically map the subcellular distribution of all Rabs and their functional interrelations. This task requires novel tools to precisely describe and manipulate the Rab machinery in vivo. Here we discuss recent findings about Rab roles during development and we consider novel approaches to investigate Rab functions in vivo.

Multiple dose pharmacokinetics of inhaled loxapine in subjects on chronic, stable antipsychotic regimens.

This randomized, double-blind, placebo-controlled, parallel-group study was to determine the pharmacokinetic characteristics, safety, and tolerability of multiple doses of inhaled loxapine aerosol in subjects on a stable, oral, chronic antipsychotic regimen. Loxapine was delivered by means of a unique thermally generated aerosol comprising drug particles of a size designed for deep lung delivery and absorption. Thirty-two subjects were randomized 1:1:1:1 to receive inhaled loxapine (total doses of 15, 20, or 30 mg) or inhaled placebo administered in 3 divided doses, given 4 hours apart. Following inhalation, the median Tmax was 2 minutes, and concentrations declined to about half Cmax approximately 5 minutes later across the 3 dose levels. The dose proportionality across data from this study combined with data from the single-dose study showed a slope (90%CI) of log AUCinf versus log dose of 0.818 (0.762-0.875) across the 8 doses (n = 60 subjects) studied, indicating reasonable dose proportionality. The most common adverse events were cough (3 of 32, 9%), sedation (3 of 32, 9%), and dysgeusia (2 of 32, 6%). The inhalation of multiple doses of inhaled loxapine were well tolerated in study subjects and provided a safe, well-tolerated means for rapidly and reliably achieving therapeutic plasma concentrations of loxapine. ClinicalTrials.gov identifier: NCT00555412.

Inhaled loxapine: a new treatment for agitation in schizophrenia or bipolar disorder.

The treatment of acute agitation in psychiatric patients has traditionally involved the use of oral or intramuscular benzodiazepines, antipsychotics or their combination. However, oral medication may have too slow an onset and while the intramuscular route is faster, it carries an increased risk of adverse events and needle-stick injury. A new delivery modality has been devised using an inhalation-activated, thermally generated drug aerosol which can produce peak plasma concentrations in a few minutes. Using this delivery method, loxapine was assessed for its antiagitation effects in schizophrenia and bipolar I disorder patients. It produced a rapid calming effect without undue sedation. It was generally well tolerated, with dysgeusia being the most common adverse event.

Role of transcatheter aortic valve implantation (TAVI) versus conventional aortic valve replacement in the treatment of aortic valve disease.

Conventional aortic valve replacement (AVR) surgery has been in clinical use since 1960. Results, particularly in high-risk populations such as the very elderly and frail, continue to improve in response to the challenges posed by this growing segment of the patient population. Transcatheter aortic valve implantation (TAVI) is a fairly recent development, performed for the first time in 2002. The last decade has seen an exponential growth in the application of this technology in higher-risk populations. Results of recent randomized prospective trials demonstrate both the future promise and current problems of the TAVI approach. Many patients deemed inoperable for AVR have been treated successfully by TAVI. However, elevated procedural and late mortality rates, excessive early and late stroke, and a significant incidence of periprosthetic aortic valve insufficiency and patient-prosthesis mismatch all suggest caution in extending this technology to patients able to undergo conventional AVR with a low risk of early or late complications.

Dysfunctional voiding: A review of the terminology, presentation, evaluation and management in children and adults.

Dysfunctional voiding (DV) is a voiding disorder characterized by dyssynergic striated sphincteric activity in the absence of a proven neurological etiology. It can present at any age with a spectrum of storage and voiding symptoms that may resemble florid neurogenic bladder. There is a striking lack of clarity regarding what this entity represents, the diagnostic methodology and treatment. The limitations of existing guideline documents are analyzed. Specifically, use of the term "habitual", the assumption that bladder changes are secondary to the outlet, the emphasis on "staccato" voiding and the implication of striated urethral sphincter are discussed. Literature shows that DV may also present with continuous slow flow or normal flow. Dyssynergia may be at the level of the striated urethral sphincter, the pelvic floor or both, better termed "striated urethral sphincter-pelvic floor complex" (SUS-PFC).A diagnostic algorithm is provided so that patients are evaluated on merit rather than on the basis of different philosophies of individual centers. High-risk markers such as hydronephrosis, vesicoureteral reflux, renal failure or marked voiding difficulty should prompt a formal urodynamics evaluation and imaging for neurological etiology. Patients with predominantly storage symptoms with incidental staccato voiding can be managed initially, on the basis of non-invasive evaluation. Conservative urotherapy including biofeedback is appropriate initial management for patients without high risk factors. Treatment and evaluation should be escalated based on response. Patients with severe DV will need treatment similar to neurogenic bladder including clean intermittent catheterization and measures to control storage pressures.