Delivery of Dihydroergotamine Mesylate to the Upper Nasal Space for the Acute Treatment of Migraine: Technology in Action.

Oral tablets account for the majority of medications used to acutely treat migraine, but relief can be limited by their rates of dissolution and absorption. The nose is an attractive alternative route of drug delivery since it provides patient convenience of at-home use, gastrointestinal (GI) avoidance, and rapid absorption of drugs into systemic circulation because of its large surface area. However, the site of drug deposition within the nasal cavity should be considered since it can influence drug absorption. Traditional nasal devices have been shown to target drug delivery to the lower nasal space where epithelium is not best-suited for drug absorption and where there is an increased likelihood of drug clearance due to nasal drip, swallowing, or mucociliary clearance, potentially resulting in variable absorption and suboptimal efficacy. Alternatively, the upper nasal space (UNS) offers a permeable, richly vascularized epithelium with a decreased likelihood of drug loss or clearance due to the anatomy of this area. Traditional nasal pumps deposit <5% of active drug into the UNS because of the nasal cavity's complex architecture. A new technology, Precision Olfactory Delivery (POD®), is a handheld, manually actuated, propellant-powered, administration device that delivers drug specifically to the UNS. A dihydroergotamine (DHE) mesylate product, INP104, utilizes POD technology to deliver drug to the UNS for the acute treatment of migraine. Results from clinical studies of INP104 demonstrate a favorable pharmacokinetic profile, consistent and predictable dosing, rapid systemic levels known to be effective (similar to other DHE mesylate clinical programs), safety and tolerability on the upper nasal mucosa, and high patient acceptance. POD technology may have the potential to overcome the limitations of traditional nasal delivery systems, while utilizing the nasal delivery benefits of GI tract avoidance, rapid onset, patient convenience, and ease of use.

Collaboration in pharmacovigilance: lamotrigine and fatal severe cutaneous adverse reactions - a review of spontaneous reports.

Pharmacovigilance presents many challenges, particularly when managing unpredictable, rare conditions, eg, severe cutaneous adverse reactions (SCARs). Such rare events are often only detected from spontaneous reports, which present their own limitations, particularly during a prolonged global launch schedule. GlaxoSmithKline's routine pharmacovigilance includes regular reviews of global adverse event (AE) reports and aggregate data from a central safety database. Lamotrigine is one of the several antiepileptic drugs associated with SCARs. After identification of increased rates of fatal SCAR cases with lamotrigine in Japan between September and December 2014, this analysis investigated the global incidence of fatal SCARs with lamotrigine and explored whether known risk factors may have contributed to these cases. Global fatal SCAR cases reported with lamotrigine administration from launch until January 2015 were reviewed for evidence of temporal association with dosing and the presence of risk factors, including comorbidities, concomitant medications, and noncompliance with the prescribing information (PI). Worldwide, the estimated cumulative exposure to lamotrigine was >8.4 million patient-years. Globally, there were 54,513 AE reports for lamotrigine, of which 3,454 (6.3%) concerned SCARs. Of these, 122 (3.5%) had a fatal outcome (attributable and nonattributable to lamotrigine), equating to 0.01 fatal SCARs per 1,000 patient-years. In Japan (estimated cumulative exposure 141,000 patient-years), 17 fatal SCARs were reported (attributable and nonattributable), equating to 0.12 per 1,000 patient-years. Seventy-one percent of fatal SCAR cases in Japan showed evidence of noncompliance with the recommended dosing regimen; in 65% of the cases, a delay in discontinuation of lamotrigine after early signs of hypersensitivity was reported. Despite a number of limitations inherent in comparing spontaneous report data, this analysis highlights the need for adherence to the lamotrigine PI and emphasizes the importance of collaboration between global and local pharmacovigilance departments, to promptly identify and reduce the risk of rare and serious events, such as SCARs.

Flexible and stretchable power sources for wearable electronics.

Flexible and stretchable power sources represent a key technology for the realization of wearable electronics. Developing flexible and stretchable batteries with mechanical endurance that is on par with commercial standards and offer compliance while retaining safety remains a significant challenge. We present a unique approach that demonstrates mechanically robust, intrinsically safe silver-zinc batteries. This approach uses current collectors with enhanced mechanical design, such as helical springs and serpentines, as a structural support and backbone for all battery components. We show wire-shaped batteries based on helical band springs that are resilient to fatigue and retain electrochemical performance over 17,000 flexure cycles at a 0.5-cm bending radius. Serpentine-shaped batteries can be stretched with tunable degree and directionality while maintaining their specific capacity. Finally, the batteries are integrated, as a wearable device, with a photovoltaic module that enables recharging of the batteries.

Infants Born to Opioid-Dependent Women in Ontario, 2002-2014.

BACKGROUND: There is a paucity of data characterizing mother-infant pairs with prenatal opioid dependence in Canada. We therefore conducted a study of relevant births in Ontario from 2002 to 2014. METHODS: We used data from the Institute for Clinical Evaluative Sciences, the linked databases of coded population-based Ontario health services records. Differences in characteristics of opioid-dependent mother-neonate pairs and infant hospital costs by year were assessed using linear regression, and we calculated rates of preterm birth, low birth weight, birth defects, mortality, and neonatal abstinence syndrome. RESULTS: The number of infants born to opioid-dependent women in Ontario rose from 46 in 2002 to almost 800 in 2014. Methadone was most frequently used for prenatal opioid dependence; there was little buprenorphine or buprenorphine + naloxone use. Rates of preterm birth and low birth weight were high. The proportion of neonates with neonatal abstinence syndrome (58%) was stable over the study period. The mean length of neonatal hospital stay was 13.96 days. Infant hospital costs increased from $724 774 in 2003 to $10 539 988 in 2013, and the mean cost per infant grew from $9928 to $12 917. Birth defect prevalence was 75.84/1000 live births (95% CI 68.12/1000 to 84.10/1000). The stillbirth rate was 11.39/1000 births (95% CI 8.47/1000 to 14.99/1000), and the infant mortality rate was 12.21/1000 live births (95% CI 9.16/1000 to 15.95/1000). CONCLUSION: We observed a 16-fold increase in the number of mother-infant pairs affected by opioid dependence in Ontario over the past decade. Adverse birth outcome rates were high. Expanded services for opioid-dependent women and their children are needed.

Fetal femur fracture and external cephalic version.

BACKGROUND: Femoral fractures due to birth trauma are extremely rare. External cephalic version is considered a relatively safe alternative when dealing with breech presentation, but it can be associated with complications. CASE: This patient underwent elective cephalic version for breech presentation at 36 weeks of gestation. Due to concerns of fetal distress after the version, a cesarean delivery was performed. The newborn had a bruised leg at delivery, and X-ray studies confirmed a distal femoral corner fracture. CONCLUSION: This case demonstrates another risk of external cephalic version. Physicians and patients should be aware of this potential complication.