Acceptability, safety and perceived impact of providing a fact sheet to young people about cognitive symptoms in depression.

AIM: Cognitive deficits are common in young people, aged 15-25, with depression. Nevertheless, these symptoms are not routinely addressed in clinical care. This study examined the acceptability, safety, and reported impact on cognitive knowledge and strategy use, of a newly developed fact sheet (Thinking about Thinking Skills in Depression) for young people with depression. METHOD: Twenty-three participants, aged 15-25 years old (M = 19.6, SD = 3.2), receiving community-based treatment for a depressive disorder were delivered the fact sheet by their case manager and completed pre- and post-assessments conducted 3 weeks apart. Primary outcomes included: acceptability, safety, subjective distress, knowledge of cognition and use of, and confidence in using, cognitive strategies. Exploratory outcomes included depression symptoms, perceived cognitive difficulties, self-efficacy and self-esteem. Case manager perspectives were obtained using an anonymous online survey. RESULTS: Participant experiences of the fact sheet were favourable. Most reported that the amount of content provided was appropriate (91%), looked at the fact sheet again after receiving it (83%), and tried at least one strategy (57%). Participants reported significant improvements in their knowledge of cognitive difficulties and a greater use of, and confidence in using, cognitive strategies. Distress did not change following fact sheet delivery, supporting safety. Perceived improvements in depression symptoms and cognitive deficits, but not self-esteem or self-efficacy, were revealed. Case manager perspectives were also positive. CONCLUSION: Written fact sheet resources are an acceptable, safe and pragmatic method of delivering information about cognitive difficulties to young people with depression.

An Enhanced Social Networking Intervention for Young People with Active Suicidal Ideation: Safety, Feasibility and Acceptability Outcomes.

Online social networking interventions have potential to support young people who experience suicidal thoughts by specifically addressing interpersonal risk factors for suicide, but may also pose a risk of harm. This uncontrolled, single-group pilot study aimed to evaluate the safety, feasibility, and acceptability of an enhanced online social networking intervention ("Affinity") among a sample of young people who experienced active suicidal ideation, and to explore potential changes in clinical outcomes and the therapeutic targets of the intervention. Twenty young people with current or recent suicidal ideation who were receiving treatment for depression at a tertiary-level mental health service were given access to Affinity for two months. Participants were assessed at baseline and 8-week follow-up; 90 percent reported clinical suicidal ideation at baseline. A priori criteria related to feasibility, safety and acceptability were satisfied. In terms of potential clinical effects, significant and reliable pre-post improvements were found on self-report outcomes including suicidal ideation. This study provides initial world-first evidence to support the use of an online intervention incorporating social networking as an adjunct to treatment for young people who experience suicidal ideation. The effectiveness of Affinity needs to be evaluated in a randomised controlled trial.

Sulfonamides as Selective NaV1.7 Inhibitors: Optimizing Potency, Pharmacokinetics, and Metabolic Properties to Obtain Atropisomeric Quinolinone (AM-0466) that Affords Robust in Vivo Activity.

Because of its strong genetic validation, NaV1.7 has attracted significant interest as a target for the treatment of pain. We have previously reported on a number of structurally distinct bicyclic heteroarylsulfonamides as NaV1.7 inhibitors that demonstrate high levels of selectivity over other NaV isoforms. Herein, we report the discovery and optimization of a series of atropisomeric quinolinone sulfonamide inhibitors [ Bicyclic sulfonamide compounds as sodium channel inhibitors and their preparation . WO 2014201206, 2014 ] of NaV1.7, which demonstrate nanomolar inhibition of NaV1.7 and exhibit high levels of selectivity over other sodium channel isoforms. After optimization of metabolic and pharmacokinetic properties, including PXR activation, CYP2C9 inhibition, and CYP3A4 TDI, several compounds were advanced into in vivo target engagement and efficacy models. When tested in mice, compound 39 (AM-0466) demonstrated robust pharmacodynamic activity in a NaV1.7-dependent model of histamine-induced pruritus (itch) and additionally in a capsaicin-induced nociception model of pain without any confounding effect in open-field activity.

Selective antagonism of TRPA1 produces limited efficacy in models of inflammatory- and neuropathic-induced mechanical hypersensitivity in rats.

The transient receptor potential ankyrin 1 (TRPA1) channel has been implicated in pathophysiological processes that include asthma, cough, and inflammatory pain. Agonists of TRPA1 such as mustard oil and its key component allyl isothiocyanate (AITC) cause pain and neurogenic inflammation in humans and rodents, and TRPA1 antagonists have been reported to be effective in rodent models of pain. In our pursuit of TRPA1 antagonists as potential therapeutics, we generated AMG0902, a potent (IC90 of 300 nM against rat TRPA1), selective, brain penetrant (brain to plasma ratio of 0.2), and orally bioavailable small molecule TRPA1 antagonist. AMG0902 reduced mechanically evoked C-fiber action potential firing in a skin-nerve preparation from mice previously injected with complete Freund's adjuvant, supporting the role of TRPA1 in inflammatory mechanosensation. In vivo target coverage of TRPA1 by AMG0902 was demonstrated by the prevention of AITC-induced flinching/licking in rats. However, oral administration of AMG0902 to rats resulted in little to no efficacy in models of inflammatory, mechanically evoked hypersensitivity; and no efficacy was observed in a neuropathic pain model. Unbound plasma concentrations achieved in pain models were about 4-fold higher than the IC90 concentration in the AITC target coverage model, suggesting that either greater target coverage is required for efficacy in the pain models studied or TRPA1 may not contribute significantly to the underlying mechanisms.

Inhibition of Inactive States of Tetrodotoxin-Sensitive Sodium Channels Reduces Spontaneous Firing of C-Fiber Nociceptors and Produces Analgesia in Formalin and Complete Freund's Adjuvant Models of Pain.

While genetic evidence shows that the Nav1.7 voltage-gated sodium ion channel is a key regulator of pain, it is unclear exactly how Nav1.7 governs neuronal firing and what biophysical, physiological, and distribution properties of a pharmacological Nav1.7 inhibitor are required to produce analgesia. Here we characterize a series of aminotriazine inhibitors of Nav1.7 in vitro and in rodent models of pain and test the effects of the previously reported "compound 52" aminotriazine inhibitor on the spiking properties of nociceptors in vivo. Multiple aminotriazines, including some with low terminal brain to plasma concentration ratios, showed analgesic efficacy in the formalin model of pain. Effective concentrations were consistent with the in vitro potency as measured on partially-inactivated Nav1.7 but were far below concentrations required to inhibit non-inactivated Nav1.7. Compound 52 also reversed thermal hyperalgesia in the complete Freund's adjuvant (CFA) model of pain. To study neuronal mechanisms, electrophysiological recordings were made in vivo from single nociceptive fibers from the rat tibial nerve one day after CFA injection. Compound 52 reduced the spontaneous firing of C-fiber nociceptors from approximately 0.7 Hz to 0.2 Hz and decreased the number of action potentials evoked by suprathreshold tactile and heat stimuli. It did not, however, appreciably alter the C-fiber thresholds for response to tactile or thermal stimuli. Surprisingly, compound 52 did not affect spontaneous activity or evoked responses of Aδ-fiber nociceptors. Results suggest that inhibition of inactivated states of TTX-S channels, mostly likely Nav1.7, in the peripheral nervous system produces analgesia by regulating the spontaneous discharge of C-fiber nociceptors.

A rapid approach to the preliminary assessment of the physical stability of pharmaceutical hydrates.

Pharmaceutical hydrates have been used as clinical development candidates and in marketed products. The physical stability of hydrates can pose unique challenges to their development because of their particular sensitivity to the moisture levels in their surroundings. By conducting simple experiments early during the form selection phase of a drug candidate's development, a basic understanding of the thermodynamic and kinetic aspects of a hydrate form's stability can be attained that can facilitate the successful navigation of these challenges. Differential scanning calorimetry was used to determine the thermal and kinetic properties of a number of pharmaceutically relevant hydrates. The activation energy (E(a)) of dehydration and dehydration onset temperature (T(onset)) of survey compounds were compiled and analyzed. A significant number of compounds possessed both high E(a) and high T(onset) of dehydration, suggesting that these hydrate crystal forms were particularly stable. The results of these studies suggest that dehydration E(a) and dehydration T(onset) together can be used as early indicators of a crystalline hydrate's physical stability and can alert to potential challenges in developing hydrate crystal forms of drug candidates.