Comprehensive long-term safety of adalimumab from 18 clinical trials in adult patients with moderate-to-severe plaque psoriasis

Adalimumab is a powerful drug used to treat psoriasis, that has been specially designed to mimic normal human molecules, and for this reason it is classed as a ‘biological’ drug. It reduces inflammation by inhibiting the activity of a chemical ‘cytokine’ in the body called ‘tumour necrosis factor alpha’ (TNF-alpha). The aim of this study, from the USA, was to assess long-term safety for patients with psoriasis receiving adalimumab. The authors looked at data from 3727 patients receiving the drug as part of 18 different clinical trials in which adverse events (AEs, meaning unwanted side effects while on the drug) were recorded. Overall, there were 16,536 AEs during 5429.7 patient years (304.6 AEs for every 100 patient years). Patient years (PYs) means the number of patients, multiplied by the amount of time they were included in the study. Most common AEs were nasopharyngitis (a common throat complaint), upper respiratory infection, and headache (23.7, 12.9, and 7.9 AEs per 100 PYs, respectively). Incidence rates for serious infections, tuberculosis, and opportunistic infections were 1.8, 0.3, and 0.02 AEs per 100 PYs, respectively. Incidence of malignancy (cancer) excluding non-melanoma skin cancer (NMSC) was 0.8 AEs per 100 PYs. Incidences of NMSC and melanoma were 0.6 and 0.2 AEs per 100 PYs, respectively. The authors conclude that AE rates remained stable in this analysis of patients with psoriasis receiving adalimumab; no new safety signals (such as increased AEs) were identified compared with earlier studies.     

Misidentification of mental health symptoms in presence of organic diseases and delirium during psychiatric liaison consulting

Objective: To identify predictors of misidentification of organic mental disorders and delirium in patients undergoing psychiatric liaison consultation.

Methods: Data were collected at Santa Casa de São Paulo between July of 2009 and March of 2013. We included in our analysis all inpatients for whom the requesting service judged that a psychiatric consultation was required for a possible mental health condition. Outcomes of interest were the instances of misidentification where a condition was initially deemed to be of a psychiatric nature, whereas the final diagnosis by the liaison psychiatric team was of an organic disease or delirium. Our predictors were the clinical specialty of the requesting service, requester and patient characteristics. A series of generalised linear models were used to evaluate misidentification risks.

Results: A total of 947 subjects met our inclusion criteria, 14.6% having a final liaison diagnosis of organic mental disorder and 8.1% of delirium. Older patients were significantly associated with increased risk of misidentification for both organic conditions (OR 3.01 – 95% CI 2.01, 4.5) and delirium (OR 3.92 – 2.4, 6.39).

Conclusions: Educational interventions in general hospitals focused on preventing psychiatric misdiagnosis should target in-hospital services where patients tend to be older.     

Cardiovascular effects elicited by milonine, a new 8,14-dihydromorphinandienone alkaloid

Abstract: The mechanisms underlying the cardiovascular responses evoked by milonine (i.v.), an alkaloid, were investigated in rats. In normotensive rats, milonine injections produced hypotension and tachycardia, which were attenuated after N^w‐nitro‐l ‐arginine methyl esther (l ‐NAME; 20 mg/kg, i.v.). In phenylephrine (10 μM), pre‐contracted mesenteric artery rings, milonine (10^?10 M to 3 × 10^?4 M) caused a concentration‐dependent relaxation (EC₅₀ = 1.1 × 10^?6 M, E_max = 100 ± 0.0%) and this effect was rightward shifted after either removal of the vascular endothelium (EC₅₀ = 1.6 × 10^?5, p < 0.001), or after l ‐NAME 100 μM (EC₅₀ = 6.2 × 10^?5, p < 0.001), hydroxocobalamin 30 μM (EC₅₀ = 1.1 × 10^?4, p < 0.001) or ODQ 10 μM (EC₅₀ = 1.9 × 10^?4p < 0.001). In addition, in rabbit aortic endothelial cells, milonine increased NO₃^? levels. The relaxant effect induced by milonine was attenuated in the presence of KCl (20 mM), a modulator efflux K⁺ (EC₅₀ = 1.2 × 10^?5, p < 0.001), or different potassium channel blockers such as glibenclamide (10 μM) (EC₅₀ = 6.3 × 10^?5, p < 0.001), TEA (1 mM) (EC₅₀ = 2.3 × 10^?5 M, n = 6) or Charybdotoxin (0.2 μM) plus apamin (0.2 μM) (EC₅₀ = 3.9 × 10^?4 M, n = 7). In addition, pre‐contraction with high extracellular potassium concentration prevented milonine‐induced vasorelaxation (EC₅₀ = 1.0 × 10^?4, p < 0.001). Milonine also reduced CaCl₂‐induced contraction in Ca²⁺‐free solution containing KCl (60 mM). In conclusion, using combined functional and biochemical approaches, we demonstrated that the hypotensive and vasorelaxant effects produced by milonine are, at least in part, mediated by the endothelium, likely via nitric oxide release, activation of nitric oxide‐cGMP pathway and opening of K⁺ channels.     

A Kunitz proteinase inhibitor from corms of Xanthosoma blandum with bactericidal activity

Bacterial infections directly affect the world's population, and this situation has been aggravated by indiscriminate use of antimicrobial agents, which can generate resistant microorganisms. In this report, an initial screening of proteins with antibacterial activity from corms of 15 species of the Xanthosoma genus was conducted. Since Xanthosoma blandum corms showed enhanced activity toward bacteria, a novel protein with bactericidal activity was isolated from this particular species. Edman degradation was used for protein N-termini determination; the primary structure showed similarities with Kunitz inhibitors, and this protein was named Xb-KTI. This protein was further challenged against serine proteinases from different sources, showing clear inhibitory activities. Otherwise, no hemolytic activity was observed for Xb-KTI. The results demonstrate the biotechnological potential of Xb-KTI, the first proteinase inhibitor with antimicrobial activity described in the Xanthosoma genus.     

Effect of fluid resins on the surface roughness and topography of resin composite restorations analyzed by atomic force microscope

The aim of the study was to verify the influence of surface sealants on the surface roughness of resin composite restorations before and after mechanical toothbrushing, and evaluate the superficial topography using atomic force microscope. Five surface sealers were used: Single Bond, Opti Bond Solo Plus, Fortify, Fortify Plus and control, without any sealer agent. The lowest values of surface roughness were obtained for control, Single Bond and Fortify groups before toothbrushing. Fortify and Fortify Plus were the sealer agents that support the abrasive action caused by the toothbrushing although Fortify Plus group remained with high values of surface roughness. The application of specific surface sealants could be a useful clinical procedure to maintain the quality of resin-based composite restorations.     

Involvement of monoamine oxidase B on models of postoperative and neuropathic pain in mice

In this study we assessed the involvement of monoamine oxidase B (MAO-B), a key enzyme implicated in monoamine metabolism, on postoperative (plantar incision) and neuropathic (partial sciatic nerve ligation) pain models in mice. Paw incision submitted mice showed a significant decrease in mechanical threshold compared with the sham-operated mice, characterizing the development of mechanical allodynia. The selective and irreversible MAO-B inhibitor selegiline, at a dose sufficient to selectively inhibit MAO-B activity (10mg/kg), showed an anti-allodynic effect from 0.5 to 6h after incision. Likewise, partial sciatic nerve ligation submitted mice also developed mechanical allodynia, which was reversed by selegiline (10mg/kg) from 2 to 6h after treatment. In addition, a significant increase on striatal MAO-B activity was observed in neuropathic mice compared with the sham-operated animals, which was reversed by selegiline treatment. Taken together, our results showed that MAO-B seems to exert a critical role in the development of postoperative and neuropathic pain.     

The 2-nitrate-1,3-dibuthoxypropan, a new nitric oxide donor, induces vasorelaxation in mesenteric arteries of the rat

The reduced availability of nitric oxide (NO) is associated with cardiovascular diseases. Therefore, NO donors such as organic nitrates are useful for the treatment of these disorders. The 2-nitrate-1,3-dibuthoxypropan (NDBP) is an organic nitrate synthesized from glycerin, which the pharmacological effects have not been investigated. In this study we evaluated the vasorelaxant effect induced by NDBP in superior mesenteric artery from rats. In phenylephrine pre-contracted artery rings, NDBP (10(-8)-10(-4)M) elicited concentration-dependent and endothelium-independent relaxation, which were attenuated by hydroxocobalamin-HDX (30μM), a NO extracellular scavenger, and 1-H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one-ODQ (10μM), an inhibitor of soluble guanylyl cyclase (sGC). In addition, the NDBP-induced relaxation was reduced by non-selective K(+) channels blocker KCl (20mM) or selective K(+) channels blockers such as tetraethylammonium-TEA (B(KCa), 1mM), charybdotoxin-ChTX (B(KCa), 100nM), glibenclamide (K(ATP), 1μM) and 4-aminopyridine-4-AP (K(V), 1mM). In preparations with ODQ (10μM) plus TEA (1mM), the response was virtually abolished. In rat smooth muscle cells culture, NDBP (10(-6)-10(-4)M) caused concentration-dependent increases in NO levels. These findings suggest that NDBP causes vasorelaxation through NO generation and activation of the sCG/cGMP/PKG pathway.