Secukinumab improves patient-reported psoriasis symptoms of itching, pain, and scaling: results of two phase 3, randomized, placebo-controlled clinical trials.

BACKGROUND: Secukinumab is a human interleukin-17A antagonist indicated for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. The objective of this analysis was to measure the treatment response on psoriasis-related itching, pain, and scaling via the Psoriasis Symptom Diary (PSD)(©). METHODS: ERASURE (n = 738) and FIXTURE (n = 1306) were double-blind, multicenter phase 3 studies in adults randomized to secukinumab (300, 150 mg, n = 1144) or placebo (n = 574) (administered at Weeks 0, 1, 2, 3, and 4, followed by dosing every 4 weeks) or a biologic active control (FIXTURE only). Patient-reported itching, pain, and scaling were assessed during the first 12 weeks of treatment using the PSD. The results reported here are limited to subjects in the secukinumab and placebo treatment groups who completed the PSD. The proportions of subjects achieving prespecified responses (improvement:reduction of at least 2.2 points for itching, 2.2 points for pain, or 2.3 points for scaling) were compared for secukinumab versus placebo. RESULTS: Overall, 39% of subjects completed the PSD at baseline and Week 12 (n = 453 secukinumab; 225 placebo). Subjects treated with secukinumab achieved significantly greater improvements in itching, pain, and scaling at Week 12 versus placebo (all P < 0.0001) and had significantly greater proportions of itching, pain, and scaling responders at Week 12 versus placebo (all P < 0.05). CONCLUSION: Secukinumab significantly improves patient-reported itching, pain, and scaling in adults with moderate to severe psoriasis compared with placebo.

Denosumab densitometric changes assessed by quantitative computed tomography at the spine and hip in postmenopausal women with osteoporosis.

FREEDOM was a phase 3 trial in 7808 women aged 60-90yr with postmenopausal osteoporosis. Subjects received placebo or 60 mg denosumab subcutaneously every 6mo for 3yr in addition to daily calcium and vitamin D. Denosumab significantly decreased bone turnover; increased dual-energy X-ray absorptiometry (DXA) areal bone mineral density (aBMD); and significantly reduced new vertebral, nonvertebral, and hip fractures. In a subset of women (N=209), lumbar spine, total hip, and femoral neck volumetric BMD (vBMD) were assessed by quantitative computed tomography at baseline and months 12, 24, and 36. Significant improvement from placebo and baseline was observed in aBMD and vBMD in the denosumab-treated subjects at all sites and time points measured. The vBMD difference from placebo reached 21.8%, 7.8%, and 5.9%, respectively, for the lumbar spine, total hip, and femoral neck at 36mo (all p≤0.0001). Compared with placebo and baseline, significant increases were also observed in bone mineral content (BMC) at the total hip (p<0.0001) largely related to significant BMC improvement in the cortical compartment (p<0.0001). These results supplement the data from DXA on the positive effect of denosumab on BMD in both the cortical and trabecular compartments.

[Effect of hypodynamic stress on the adrenaline-induced contraction of the smooth muscles of the thoracic aorta]. / Hipodinaminio streso itaka krutines aortos lygiuju raumenu adrenalino sukeltam susitraukimui.

UNLABELLED: Aim of the study was to investigate the influence of hypodynamic stress on the contractile responses of the smooth muscles to adrenaline. MATERIAL AND METHODS: Hypodynamic stress was induced by fixation of Chinchilla rabbits (n=8) in the metal hutches for 48 days (B. M. Fiodorov method). Rabbits in the control group (n=8) were kept in ordinary conditions of vivarium for the same period of time. Isolated preparations of the thoracic aorta were obtained from both groups of the rabbits. The contractile responses of the thoracic aorta preparations to 10(-7)mol/l and 10(-6)mol/l of adrenaline were registered in vitro by micromechanographic device under isometric conditions. RESULTS: The contractile responses of the thoracic aorta preparations under the influence of adrenaline at concentration 10(-7)mol/l were not significantly higher (p>0.05) and at concentration 10(-6)mol/l they were significantly higher (p=0.021) in rabbits after hypodynamic stress than in control ones. CONCLUSION: Long-term hypodynamic stress in rabbits leads to the significantly increased adrenaline-induced contraction of the smooth muscles of the thoracic aorta.

[Trace elements, cholesterol and ultrastructural alterations of aorta in hypodynamic stress]. / Mikroelementu, cholesterolio ir aortos intimos strukturiniai pakitimai esant hipodinamijai.

Hypodynamic stress of 48-day duration was provoked by permanent and periodically recurrent intervention (the hypodynamics periodically exchanged to physically activity) for Chinchilla rabbits (weight 2.5-3.0 kg) (n=19) by placing them in metal hutches according to B. V. Fiodorow. Rabbits (n=10) of the control group which had no intervention were kept in vivarium conditions. The concentration of trace elements (Zn, Mn, Cu) in the blood plasma and thoracic aorta was assessed by atomic absorption spectrophotometer (Perkin-Elmer 503, USA). The level of cholesterol was determined by enzymatic analysis. Ultrathin sections of thoracic aorta were examined with electron microscope "Tesla BS-500" (Italy). After 48 days of permanent hypodynamic stress the concentration of Zn and Mn in blood plasma of rabbits was found to be significantly decreased while the cholesterol and Cu level was greater than before the stress. In case of permanent stress significant decrease also was found in the concentration of Cu and Mn in aorta in comparison with that in the case of periodically recurrent stress. The mentioned changes of the trace elements and cholesterol concentration in tissues of rabbits in case of permanent hypodynamic stress were accompanied by ultrastructural alterations in endothelium--desintegration of cells, and winding and fragmentation of internal elastic lamina, accumulation of lipids. In case of periodically recurrent hypodynamic stress of the some duration these changes were less expressed.

[The significance of zinc for contractility of smooth muscles and ultrastructure of their microfilaments in case of hypodynamic stress]. / Cinko itaka lygiuju raumenu kontraktiliskumui ir ju mikrofilamentu ultrastrukturai hipodinaminio streso metu.

The aim of the study was to investigate the significance of zinc (added to food of the rabbits) for contractility of smooth muscles (effected by acetylcholine) and ultrastructure of their microfilaments in case of hypodynamic stress. Hypodynamic stress of 48-day duration was provoked for Chinchilla rabbits (n=20) by placing them in metal hutches. Every day (48 days) 10 rabbits, which had intervention received doses of zinc 0.3 mg/kg body wt (in form of zinc acetate). The rabbits (n=10) of the control group, which had no intervention were kept in vivarium conditions. The relaxation of smooth muscles from thoracic aorta as mediated by acetylcholine at a concentration from 10(-8) mol/l to 10(-4) mol/l was detected by means of a 6MXIC mechanotron in isometric regime. Response was expressed as the percentage of relaxation to prostaglandin F(2alpha) (10(-5) mol/l)-induced precontraction. The ultrastructure of the microfilaments of smooth muscles was evaluated by electron microscopy "Philips-300". In rabbits that received no zinc the relaxation of smooth muscles under the influence of acetylcholine was significantly lower than in rabbits that received zinc and lower in control rabbits. Also in rabbits without zinc supplement the investigation of ultrastructure of microfilaments revealed their damage (such change as irregular formation, drop out in flakes, microfilaments becoming shorter and thicker). In rabbits receiving zinc ultrastructure of microfilaments did not change.

The effect of zinc on endothelium-dependent relaxation of blood-vessels and on the ultrastructure of endothelial cells under immobilization stress.

We investigated the effects of zinc on the function and ultrastructure of endothelial cells in the case of a 48-day immobilization stress provoked in Chinchilla male rabbits (n=18) by placing them in metal hutches. Half of those rabbits (n=9) received an daily oral supplement of zinc at a dose of 0.3 mg/kg body weight (in the form of zinc acetate). The control rabbits had no intervention and received no supplement of zinc. The relaxation of smooth muscles from thoracic aorta as mediated by acetylcholine at concentrations from 10(-8) mol/L to 10(-4) mol/L was determined in isometric regime. Responses were expressed as the percentage of relaxation to prostaglandin F2alpha (2.10(-5) mol/L)-induced precontraction. The ultrastructure of endothelial cells was evaluated by electron microscopy. The level of total cholesterol and zinc in the blood serum was determined by an enzymatic method and by atomic absorption spectrometry, respectively. In rabbits receiving no zinc supplement, the relaxation of smooth muscles under the influence of acetylcholine concentrations from 10(-8) mol/L to 10(-4) mol/L was significantly (P < 0.05-0.01) lower than in rabbits receiving a supplement of zinc and lower than in control rabbits. Also, in the rabbits not receiving the zinc supplement, the level of total blood serum cholesterol was increased, but the concentration of zinc decreased. In rabbits receiving the zinc supplement, the contractility of the smooth muscles effected by acetylcholine did not change as compared with control rabbits, and we found a normal structure of endothelial cells and a normal level of total cholesterol and zinc in their blood serum. Thus, zinc played an important role in the maintenance of the normal ultrastructure and function of the endothelial cells in the rabbits receiving zinc under immobilization stress.