Allergan (Germany)

ObjectiveTo review the literature on the mechanism of action of onabotulinumtoxinA in chronic migraine.BackgroundOnabotulinumtoxinA is a chronic migraine preventive treatment that significantly reduces headache frequency. The traditional mechanism described for onabotulinumtoxinA – reducing muscle contractions – is insufficient to explain its efficacy in migraine, which is primarily a sensory neurological disease.MethodsA narrative literature review on the mechanism of action of onabotulinumtoxinA in chronic migraine.ResultsFollowing injection into tissues, onabotulinumtoxinA inhibits soluble N‐ethylmaleimide‐sensitive fusion attachment protein receptor (SNARE)‐mediated vesicle trafficking by cleaving one of its essential proteins, soluble N‐ethylmaleimide‐sensitive fusion attachment protein (SNAP‐25), which occurs in both motor and sensory nerves. OnabotulinumtoxinA inhibits regulated exocytosis of motor and sensory neurochemicals and proteins, as well as membrane insertion of peripheral receptors that convey pain from the periphery to the brain, because both processes are SNARE dependent. OnabotulinumtoxinA can decrease exocytosis of pro‐inflammatory and excitatory neurotransmitters and neuropeptides such as substance P, calcitonin gene‐related peptide, and glutamate from primary afferent fibers that transmit nociceptive pain and participate in the development of peripheral and central sensitization. OnabotulinumtoxinA also decreases the insertion of pain‐sensitive ion channels such as transient receptor potential cation channel subfamily V member 1 (TRPV1) into the membranes of nociceptive neurons; this is likely enhanced in the sensitized neuron. For chronic migraine prevention, onabotulinumtoxinA is injected into 31‐39 sites in 7 muscles of the head and neck. Sensory nerve endings of neurons whose cell bodies are located in trigeminal and cervical ganglia are distributed throughout the injected muscles, and are overactive in people with migraine. Through inhibition of these sensory nerve endings, onabotulinumtoxinA reduces the number of pain signals that reach the brain and consequently prevents activation and sensitization of central neurons postulated to be involved in migraine chronification.ConclusionOnabotulinumtoxinA likely acts via sensory mechanisms to treat chronic migraine.

Objective: The objective was to characterize psoriasis treatment patterns, including estimating persistence and describing subsequent events (i.e. switching and restarting) for all systemic therapies.Methods: This retrospective cohort study utilized Truven MarketScan databases from 1 January 2014 to 31 December 2016 to investigate persistence, switching and restarting in new users of systemic psoriasis medications. Descriptive statistics, time-to-event analyses and a Cox proportional hazards regression were conducted.Results: A total of 5205 patients met inclusion criteria. Regardless of treatment type, >50% lost persistence by 12 months. Patients newly initiating acitretin or non-TNF biologic experienced the highest loss of persistence (85.2%, 73.8%, respectively). Patients initiating a TNF-α inhibitor or apremilast experienced the lowest loss (51.8%, 56.4% respectively). Treatment type had a statistically significant effect on persistence loss (adjusted hazard ratio: 0.86, 95% CI: 0.81, 0.91). Restarting was the most commonly observed event for patients on an oral or biologic (60.2%, 79.9%, respectively). The most common switch from an oral was to a TNF-α inhibitor, while apremilast often followed biologics.Conclusion: Most patients lost persistence on initial treatment by 12 months, and the majority restarted treatment. This may indicate poor compliance or the cyclical nature of psoriasis. More patients switched from an oral to biologic than vice versa, likely due to formulary design and preference for orals. Studies are needed to investigate underlying reasons and patient characteristics that differentiate treatment utilization.

Ischemic and pharmacologic preconditioning have great clinical potential, but it remains unclear whether their effects can be maintained over time during repeated exposure.We have previously demonstrated that the acute protective effect of nitroglycerin (GTN) is attenuated during repeated daily administration. Pentaerythrityl tetranitrate (PETN) is an organic nitrate with different hemodynamic and biochemical properties. The purpose of the current experiment was to study the preconditioning-like effects of PETN and GTN during repeated daily exposure. In a randomized, investigator-blind parallel trial, 30 healthy (age 25-32) volunteers were randomized to receive (1) transdermal GTN (0.6 mg/h) administered for 2 h a day for 6 days; (2) oral PETN (80 mg) once a day for 6 days; or (3) no therapy. One week later, endothelium-dependent flow-mediated dilation was assessed before and after exposure to ischemia and reperfusion (IR). IR caused a significant blunting of the endothelium-dependent relaxation in the control group (FMD before IR: 5.8 ± 2.1%; after IR 1.0 ± 2.1%; P < 0.01). Daily, 2-h exposure to GTN partially prevented IR-induced endothelial dysfunction (FMD before IR: 7.7 ± 2.4%; after IR 4.3 ± 3.0%; P < 0.01 compared to before IR). In contrast, daily PETN administration afforded greater protection from IR-induced endothelial injury (FMD before IR: 7.9 ± 1.7%; after IR 6.4 ± 5.3%, P = ns; P < 0.05 ANOVA across groups). In vitro, incubation of human endothelial cells with GTN (but not PETN) was associated with inhibition (P < 0.01) of aldehyde dehydrogenase, an enzyme that is important for both nitrate biotransformation and ischemic preconditioning. We previously showed that upon repeated administration, the preconditioning-like effects of GTN are attenuated. The present data demonstrate a gradient in the extent of protection afforded by the two nitrates, suggesting that PETN-induced preconditioning is maintained after prolonged administration in a human in vivo model of endothelial dysfunction induced by ischemia. Using isolated human endothelial cells, we propose a mechanistic explanation for this observation based on differential effects of GTN versus PETN on the activity of mitochondrial aldehyde dehydrogenase.

ABSTRACTObjective: At the introduction of the fixed-combination of brimonidine/timolol in Germany in 2006, a non-interventional, multicenter, observational, open-label study was initiated to evaluate efficacy, tolerability, and safety of this preparation in a broad patient population.Methods: The study population comprised patients with bilateral primary open-angle glaucoma or ocular hypertension with insufficient intraocular pressure (IOP) control who participating physicians determined required a change of medication, and who switched to exclusive use of the new fixed-combination brimonidine 0.2%/timolol 0.5%. Patient demographics and information on specific risk factors were collected. IOP readings were recorded for each eye at treated baseline (previous therapy), 4 to 6 weeks, and 12 weeks after changing to twice-daily brimonidine/timolol. Tolerability was measured using a four-step scale ranging from excellent to poor. All adverse events were recorded.Results: Mean treated baseline IOP (±SD) for all patients (N = 861) was 20.8 ± 3.5 mmHg. Five hundred sixty-five patients switched from monotherapy, 138 patients switched from other fixed combinations, and 158 patients had been using non-fixed combinations of up to four different active agents. The brimonidine/timolol fixed combination provided an additional IOP decrease in most pretreatment subgroups, with an overall reduction to 16.9 ± 2.6 mmHg after 4 to 6 weeks and to 16.5 ± 2.7 mmHg after 12 weeks. Both of these values were significantly lower than baseline IOP (p < 0.001). A target pressure of <18 mmHg was achieved in 79.5% of all eyes at week 12. Tolerability of fixed-combination brimonidine/timolol was rated excellent or good by the physicians for 97.1% of patients, and by 93.4% of the patients themselves. Few adverse events occurred during the treatment period.Conclusions: Although this study was limited by its observational design, our results show that the fixed combination of brimonidine 0.2%/timolol 0.5% was effective, well tolerated, and safe in a broad POAG patient population.

Plant biology is currently experiencing a growing demand for easy and reliable mRNA and protein localisation techniques. Here, we present novel whole mount in situ hybridisation and immunolocalisation protocols, suitable to localise mRNAs and proteins in Arabidopsis seedlings. We demonstrate that these methods can be used in different organs of Arabidopsis seedlings as well as in other plant species. In order to achieve better reproducibility and higher throughput, we modified these protocols for automation to be performed by a liquid handling robot. In addition, we show that other procedures such as reporter enzyme assays and tissue clearing can be similarly automated. We present examples of application of our protocols including mRNA localisation and proteins and epitope tag (co)localisations which demonstrate that these methods provide reliable and versatile tools for expression, localisation and anatomical studies in plants.