Andrew John Thorpe

The diverse therapeutic actions of pregabalin: is a single mechanism responsible for several pharmacological activities?

Pregabalin is a specific ligand of the alpha2-delta (α2-δ) auxiliary subunit of voltage-gated calcium channels. A growing body of evidence from studies of anxiety and pain indicate that the observed responses with pregabalin may result from activity at the α2-δ auxiliary protein expressed presynaptically, in several different circuits of the central nervous system (CNS). The disorders that appear to be effectively treated with pregabalin are thematically linked by neuronal dysregulation or hyperexcitation within the CNS. This review proposes how binding to the α2-δ protein target in different regions of the CNS may contribute to the observed clinical activity of pregabalin, as well as to the adverse event profile of the compound. Whether this compound regulates synaptic function via α2-δ in additional conditions is yet to be discovered. The potential of pregabalin to regulate neuronal hyperactivity involving other CNS circuits will require further exploration.

Possible sites of therapeutic action in restless legs syndrome: focus on dopamine and α2δ ligands.

Restless legs syndrome (RLS) is a common sensorimotor disorder characterized by abnormal sensations that occur primarily at rest or during sleep, which are alleviated by movement of the affected limb. The pathophysiology of RLS remains unclear, although roles for dopamine dysfunction and brain iron deficiency have been proposed. The hypothalamic A11 dopaminergic circuit is used to explain the dopamine dysfunction in RLS and the potential therapeutic actions of dopamine D2 agonists. Modulation of central and peripher- al neuronal circuits may also explain the potential therapeutic sites of action of opioids, adenosine receptor ligands, and voltage-gated calcium channel α2δ ligands in RLS. The known and possible therapeutic benefits of these agents and their relationship to dopaminergic dysfunction in RLS are discussed in this review.

Oxadiazolone bioisosteres of pregabalin and gabapentin.

A series of oxadiazolone bioisosteres of pregabalin 1 and gabapentin 2 were prepared, and several were found to exhibit similar potency for the alpha(2)-delta subunit of voltage-gated calcium channels. Oxadiazolone 9 derived from 2 achieved low brain uptake but was nevertheless active in models of osteoarthritis. The high clearance associated with compound 9 was postulated to be a consequence of efflux by OAT and/or OCT, and was attenuated on co-administration with cimetidine or probenecid.

Herpes Zoster Infection in Patients With Ulcerative Colitis Receiving Tofacitinib

Abstract Background Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for ulcerative colitis (UC). Tofacitinib is approved for rheumatoid arthritis and psoriatic arthritis, where it has been shown to increase herpes zoster (HZ) risk. We evaluated HZ risk among UC patients using tofacitinib. Methods HZ cases were identified in tofacitinib phase II/III/ongoing, open-label, long-term extension (OLE) UC trials. We calculated HZ incidence rates (IRs) per 100 patient-years of tofacitinib exposure within phase III maintenance (Maintenance Cohort) and phase II/III/OLE (Overall Cohort) studies, stratified by baseline demographics and other factors. HZ risk factors were evaluated in the Overall Cohort using Cox proportional hazard models. Results Overall, 65 (5.6%) patients developed HZ. Eleven patients had multidermatomal involvement (2 nonadjacent or 3–6 adjacent dermatomes), and 1 developed encephalitis (resolved upon standard treatment). Five (7.7%) events led to treatment discontinuation. HZ IR (95% confidence interval [CI]) in the Overall Cohort was 4.07 (3.14–5.19) over a mean (range) of 509.1 (1–1606) days, with no increased risk observed with increasing tofacitinib exposure. IRs (95% CI) were highest in patients age ≥65 years, 9.55 (4.77–17.08); Asian patients, 6.49 (3.55–10.89); patients with prior tumor necrosis factor inhibitor (TNFi) failure, 5.38 (3.86–7.29); and patients using tofacitinib 10 mg twice daily, 4.25 (3.18–5.56). Multivariate analysis identified older age and prior TNFi failure as independent risk factors. Conclusions In tofacitinib-treated UC patients, there was an elevated risk of HZ, although complicated HZ was infrequent. Increased HZ rates occurred in patients who were older, Asian, or had prior TNFi failure (NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612).

Neuropathic pain: a narrative review of etiology, assessment, diagnosis, and treatment for primary care providers

Abstract Background: Neuropathic pain (NeP) is a distinct type of chronic pain that is a direct result of damage to the nervous system itself. Studies have shown that training on the topic of chronic pain in medical schools is lacking and many practitioners are not confident in their ability to effectively manage patients with such pain. Aims: The purpose of this narrative review is to provide a brief high-level overview of NeP for primary healthcare providers that includes a discussion of mechanisms, prevalence, burden, assessment, and treatment. The information provided here should help primary care providers better understand this type of chronic pain.

PTU-001 Tofacitinib, an oral jak inhibitor, in the treatment of ulcerative colitis: open-label, long-term extension study

Introduction Tofacitinib is an oral, small molecule JAK inhibitor that is being investigated for ulcerative colitis (UC). The efficacy and safety of tofacitinib was demonstrated as induction and maintenance therapy in 3 Phase 3, randomised, placebo-controlled studies (OCTAVE Induction 1, NCT01465763; OCTAVE Induction 2, NCT01458951; OCTAVE Sustain, NCT01458574) in patients (pts) with moderate to severe UC.1 Methods We present interim safety and efficacy data up to 3 years of treatment (as of 8 July 2016) from an ongoing Phase 3, multicentre, open-label, long-term extension study (OLE; NCT01470612) in pts who had completed or demonstrated treatment failure in OCTAVE Sustain, or who were non-responders after completing OCTAVE Induction 1 or 2. Pts in remission at Week 52 of OCTAVE Sustain received tofacitinib 5 mg twice daily (BID); all others received 10 mg BID. At Month 2, all pts underwent endoscopy, and non-responders from Induction were mandated to withdraw if no evidence of clinical response was shown. Remission was defined by a Mayo score ≤2 with no individual subscore >1, and rectal bleeding subscore of 0. Binary efficacy endpoints were derived from Mayo score, based on local-read endoscopic subscore. Results 914 pts (5 mg BID, n=156 [17.1%]; 10 mg BID, n=758 [82.9%]) received ≥1 dose of study drug; 381 pts (41.7%) discontinued. The most frequent AE leading to discontinuation was worsening of UC. The most frequent treatment-emergent AEs by system organ class (both doses) were ‘infections/infestations’ and ‘gastrointestinal disorders’, and by preferred term were ‘nasopharyngitis’ and ‘worsening of UC’. Serious infections AEs were reported in 4 (2.6%) and 14 (1.8%) pts with 5 and 10 mg BID, respectively. Malignancies excl. NMSC were reported in 9 (1.2%) pts in the 10 mg BID group (no clustering of malignancy type); none were reported in the 5 mg BID group. No new safety risks were identified. Data ‘as observed’ for remission and mucosal healing at Months 2, 12 and 24 are shown. Conclusions In pts with moderate to severe UC who remained in the OLE study, no new safety concerns emerged compared with those observed with tofacitinib in rheumatoid arthritis. Efficacy results from this OLE study support sustained efficacy with tofacitinib 5 and 10 mg BID. Funded by Pfizer Inc.Abstract PTU-001 Table 1 Summary of safety and efficacy is the OLE study Reference 1. Sandborn WJ, et al. N Engl J Med 2017;376:1723–36.

Pregabalin for the treatment of neuropathic pain: a narrative review for primary care providers

Abstract Background: Neuropathic pain (NeP) is a distinct type of pain caused by damage to the nervous system itself. This often severe and chronic type of pain requires specific treatments that target the underlying pain pathophysiology. Aim: The purpose of the current narrative review is to provide an overview of pregabalin (Lyrica1) for the treatment of NeP including its effects on pain, pain-related sleep interference, and other health-related outcomes, timing of therapeutic effect, safety and tolerability, and dosing. The information provided here will help primary care providers develop more effective NeP treatment strategies.