A Practical Guide to Advanced Topical Drug Delivery Systems in Dermatology.

Dermatological diseases such as atopic dermatitis, acne, and psoriasis result in significant morbidity and decreased quality of life. The first line of treatment for such diseases is often topical medications. While topical delivery allows active drug to be delivered directly to the target site, the skin is a virtually impermeable barrier that impedes delivery of large molecules. Thus, the formulation and delivery system are integral elements of topical medications. Patients also have preferences for the properties of topical formulations and these preferences can positively or negatively impact adherence. Therefore, the choice of topical formulation is a key consideration. Recent developments in drug delivery systems have produced enhanced topical treatments that improve efficacy, safety, and patient acceptability. Awareness of the delivery system in which drugs are formulated is critical as this can have profound implications on treatment success. This paper provides an overview and clinical commentary on advances in topical delivery systems and their impact on dermatological practice.

Economic evaluation of the impact of memantine on time to nursing home admission in the treatment of Alzheimer disease.

OBJECTIVE: An observational study showed that combining memantine with a cholinesterase inhibitor (ChEI) treatment significantly delayed admission to nursing homes in patients with Alzheimer disease (AD). Our study aimed to evaluate the economic impact of the concomitant use of memantine and a ChEI, compared with a ChEI alone, in a Canadian population of patients with AD. METHOD: A cost-utility analysis using a Markov model during a 7-year time horizon was performed according to a societal and Canadian health care system perspective. The Markov model includes the following states: noninstitutionalized, institutionalized, and deceased. The model includes transition probabilities for institutionalization and death, adjusted with mortality rates specific to AD. Utilities associated with institutionalization and noninstitutionalization were included. For the health care system perspective, costs of medication as well as costs of care provided in the community and in nursing homes were considered. For the societal perspective, costs of direct care and supervision provided by caregivers were added. RESULTS: From both perspectives, the concomitant use of a ChEI and memantine is a dominant strategy, compared with the use of a ChEI alone. On a per patient basis, there was a gain of 0.26 quality-adjusted life years with the treatment including memantine and cost decreases of Can$21 391 and Can$30 512, respectively, for the societal and health care system perspective. CONCLUSIONS: This economic evaluation indicates that institutionalization is the largest cost component in AD management and that the use of memantine, combined with a ChEI, to treat AD is a cost-effective alternative, compared with the use of a ChEI alone.

Quality of life outcomes in patients with obsessive-compulsive disorder: relationship to treatment response and symptom relapse.

OBJECTIVE: Data were analyzed from 2 prospective, double-blind, placebo-controlled trials of escitalopram in obsessive-compulsive disorder (OCD) to characterize the baseline levels of functional disability and impairment in health-related quality of life (HRQoL) and to assess the relationship between treatment outcomes (response or relapse) and disability or HRQoL. METHOD: Data from a 24-week, placebo-controlled, fixed-dose trial (N = 466) of escitalopram (10-20 mg/d) or paroxetine (40 mg/d) and from a 40-week, flexible-dose (escitalopram 10-20 mg/d), placebo-controlled relapse-prevention trial (N = 468) were analyzed. Obsessive-compulsive disorder symptoms (DSM-IV criteria) were assessed using the Yale-Brown Obsessive Compulsive Scale (YBOCS), functioning was assessed using the Sheehan Disability Scale (SDS), and HRQoL was assessed using the Medical Outcomes Study Short Form (SF-36). Baseline data were pooled for patients across both studies. For patients in the fixed-dose study, SDS and SF-36 scores were compared across treatment groups and for responders versus nonresponders. In the relapse-prevention trial, SDS and SF-36 scores were compared for relapsed versus nonrelapsed patients. RESULTS: Patients with more severe baseline symptoms (YBOCS > or = 27) reported significantly greater impairment on the SDS (P < .001) and SF-36 (except for bodily pain). Patients receiving escitalopram or paroxetine reported significant improvements on most SF-36 dimensions and on the SDS compared to placebo; however, improvements in work-related functioning were seen earlier for patients receiving escitalopram (20 mg/d). At the study endpoints, SDS and SF-36 scores were significantly better for patients who were responders (versus nonresponders) and for patients who did not relapse (versus relapsers). CONCLUSIONS: Obsessive-compulsive disorder is associated with significant impairment in functioning and HRQoL. Significant differences in disability and HRQoL between responders and nonresponders or relapsers and nonrelapsers suggest a relationship between symptomatic and functional outcomes. TRIAL REGISTRATION: lundbecktrials.com Identifiers: 10205 and 10193.

Escitalopram in the treatment of major depressive disorder in primary-care settings: an open-label trial.

BACKGROUND: The present trial was designed to assess the efficacy and safety of escitalopram prescribed to patients seeking treatment of major depressive disorder (MDD) in a Canadian primary-care setting. METHODS: Investigators (mainly primary-care physicians) enrolled patients with MDD from their daily practice. Patients were treated with escitalopram (flexible dose 10-20 mg/day) for up to 24 weeks. Efficacy assessments included the Montgomery-Asberg Depression Rating Scale (MADRS), the Clinical Global Impression-Improvement and -Severity scales (CGI-I, CGI-S), the Patient Global Evaluation (PGE), and the Medical Outcome Study 36-item Short Form (SF-36). RESULTS: Out of the 647 patients enrolled, 461 (71%) completed 24 weeks of treatment. The most common reason for discontinuation was adverse events (10%). The mean MADRS score decreased from 30.7 at baseline to 10.9 at the end of 24 weeks (last observation carried forward, LOCF). Remission (MADRS

Role of calcium in neurotensin-evoked enhancement in firing in mesencephalic dopamine neurons.

Neurotensin (NT) increases neurotransmission within the mesolimbic dopamine system by enhancing the firing rate of dopaminergic (DAergic) neurons and by acting at the nerve terminal level. The signal transduction pathways involved in these effects have not been characterized, but NT receptors are coupled to the phospholipase C pathway and Ca(2+) mobilization. However, an enhancement of intracellular Ca(2+) concentration ([Ca(2+)](i)) evoked by NT in DAergic neurons has yet to be demonstrated. Furthermore, the hypothesis that the excitatory effects of NT in DAergic neurons are Ca(2+) dependent is currently untested. In whole-cell recording experiments, DAergic neurons in culture were identified by their selective ability to express a cell-specific green fluorescent protein reporter construct. These experiments confirmed that NT increases firing rate in cultured DAergic neurons. This effect was Ca(2+) dependent because it was blocked by intracellular dialysis with BAPTA. Using Ca(2+) imaging, we showed that NT caused a rapid increase in [Ca(2+)](i) in DAergic neurons. Most of the Ca(2+) originated from the extracellular medium. NT-induced excitation and Ca(2+) influx were blocked by SR48692, an antagonist of the type 1 NT receptor. Blocking IP(3) receptors using heparin prevented the excitatory effect of NT. Moreover, Zn(2+) and SKF96365 both blocked the excitatory effect of NT, suggesting that nonselective cationic conductances are involved. Finally, although NT can also induce a rise in [Ca(2+)](i) in astrocytes, we find that NT-evoked excitation of DAergic neurons can occur independently of astrocyte activation.