Anti‐Tumor Effects and Pharmacokinetics of S‐40542, a Novel Non‐Steroidal Anti‐Androgen,in Mice

Objectives: The current study was undertaken to explore novel anti‐androgens. We investigated a series of tetrahydroquinoline compounds and identified 1‐(8‐nitro‐3a,4,5,9b‐tetrahydro‐3H‐cyclopenta[c]quinolin‐4‐yl)ethane‐1,2‐diol (S‐40542). Methods: Affinity for androgen receptor of S‐40542 was evaluated in receptor binding assay. Effects of repeated treatment with S‐40542 and bicalutamide on prostate weight were examined in mice subcutaneously treated for 14days. Efficacy of S‐40542 and bicalutamide against prostate cancer was evaluated in an androgen‐dependent prostate cancer xenograft model using KUCaP‐2 cell line. Plasma concentrations of these agents in mice after oral and subcutaneous administration were measured by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) system. Results: S‐40542 displayed twofold higher affinity to androgen receptor than bicalutamide in vitro. Subcutaneous repeated administration of S‐40542 (10–100 mg/kg) significantly reduced the prostate weight. Oral repeated treatment with S‐40542 (30, 100 mg/kg) for 28 days significantly suppressed growth of KUCaP‐2 tumor. Similar administration of bicalutamide also exerted significantly anti‐tumor effect in the model. The serum prostate‐specific antigen level was little influenced by the S‐40542 treatment, while significantly decreased by bicalutamide. Oral treatment with S‐40542 resulted in a dose‐dependent elevation of the plasma concentration, and its C_max and AUC were much lower than those of bicalutamide. The pharmacokinetic study showed that this agent had relatively short plasma half‐life and low oral bioavailability. Conclusion: S‐40542 as well as bicalutamide has shown as an anti‐androgen by reducing the prostate weight of mice. Repeated oral treatment with S‐40542 was shown to significantly suppress tumor growth in the KUCaP‐2 xenograft model.     

Chronobiology,endocrinology, and energy‐ and food‐reward homeostasis

Energy‐ and food‐reward homeostasis is the essential component for maintaining energy balance and its disruption may lead to metabolic disorders, including obesity and diabetes. Circadian alignment, quality sleep and sleep architecture in relation to energy‐ and food‐reward homeostasis are crucial. A reduced sleep duration, quality sleep and rapid‐eye movement sleep affect substrate oxidation, leptin and ghrelin concentrations, sleeping metabolic rate, appetite, food reward, hypothalamic‐pituitary‐adrenal (HPA)‐axis activity, and gut‐peptide concentrations, enhancing a positive energy balance. Circadian misalignment affects sleep architecture and the glucose‐insulin metabolism, substrate oxidation, homeostasis model assessment of insulin resistance (HOMA‐IR) index, leptin concentrations and HPA‐axis activity. Mood disorders such as depression occur; reduced dopaminergic neuronal signaling shows decreased food reward. A good sleep hygiene, together with circadian alignment of food intake, a regular meal frequency, and attention for protein intake or diets, contributes in curing sleep abnormalities and overweight/obesity features by preventing overeating; normalizing substrate oxidation, stress, insulin and glucose metabolism including HOMA‐IR index, and leptin, GLP‐1 concentrations, lipid metabolism, appetite, energy expenditure and substrate oxidation; and normalizing food reward. Synchrony between circadian and metabolic processes including meal patterns plays an important role in the regulation of energy balance and body‐weight control. Additive effects of circadian alignment including meal patterns, sleep restoration, and protein diets in the treatment of overweight and obesity are suggested.     

Atacicept in patients with rheumatoid arthritis: Results of a multicenter,phase ib,double‐blind,placebo‐controlled,dose‐escalating,single‐ and repeated‐dose study

Objective

Atacicept is a recombinant fusion protein that binds and neutralizes B lymphocyte stimulator and a proliferation‐inducing ligand. The purpose of this study was to investigate the tolerability, pharmacokinetics, and pharmacodynamics of atacicept treatment in patients with rheumatoid arthritis (RA) and to collect exploratory data on clinical outcomes.

Methods

In this multicenter, phase Ib, randomized, placebo‐controlled, dose‐escalating trial, 73 patients were enrolled into 6 escalating‐dose cohorts. Patients received atacicept or placebo as single doses (70, 210, or 630 mg) or as repeated doses given at 2‐week intervals (3 doses of 70 mg, 3 doses of 210 mg, or 7 doses of 420 mg), followed by 10 weeks of trial assessments, with a followup assessment at 3 months after the final dose.

Results

Atacicept was well tolerated, with few differences between treatment groups and no obvious safety concerns. The pharmacokinetics profile was nonlinear, but was consistent and predictable across all doses and regimens. Treatment‐related decreases in immunoglobulin (particularly IgM) and rheumatoid factor levels were evident, and a clear decrease in anti–citrullinated protein antibodies was observed in the cohort that received 7 doses of 420 mg. The B cell response was biphasic, with an initial transient increase (dominated by memory B cells) followed by a dose‐related decrease (dominated by mature B cells). Clinical assessments showed trends toward improvement with the 3‐month treatment. Little effect on the erythrocyte sedimentation rate or C‐reactive protein levels was seen.

Conclusion

Atacicept was well tolerated both systemically and locally. The results demonstrated that the biologic activity of atacicept was consistent with its mechanism of action.

     

Self‐care versus self‐harm: piercing,tattooing, and self‐injuring in eating disorders

Eating disordered patients seem to have a love–hate relationship with their bodies. Why do some decorate their bodies by means of tattooing and piercing, while others deliberately injure themselves and make parts of their body unattractive? We have explored this question in 101 eating‐disordered patients by means of self‐reporting questionnaires about the presence and characteristics of tattooing, piercing and self‐injuring as well as the underlying motives. Furthermore, we studied the co‐occurrence of impulsive behaviours as well as personality traits. In our patient sample, 11.9 per cent had one or more tattoos, 25.7 per cent a piercing and 64.9 per cent showed some form of self‐injurious behaviour (SIB). Tattooing and piercing are clearly driven by esthetical reasons, whereas SIB can have various explanations. All three behaviours were significantly more often linked to substance (ab)use. With respect to personality traits, piercing was positively linked to extraversion (positive affectivity) and openness, and negatively to conscientiousness. SIB, on the contrary, was positively linked to neuroticism (negative affectivity) and conscientiousness, and negatively to extraversion and openness. Tattooing did not show significant correlations with particular personality traits (probably due to the small number of tattooed patients). In summary, piercing and tattooing seem to reflect more self‐care, and might protect some patients against more self‐harm. Copyright © 2005 John Wiley & Sons, Ltd and Eating Disorders Association.     

Melatonin enhances L‐DOPA therapeutic effects,helps to reduce its dose,and protects dopaminergic neurons in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐induced parkinsonism in mice

L‐3,4‐dihydroxyphenylalanine (L‐DOPA) reduces symptoms of Parkinson's disease (PD), but suffers from serious side effects on long‐term use. Melatonin (10–30 mg/kg, 6 doses at 10 hr intervals) was investigated to potentiate L‐DOPA therapeutic effects in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced parkinsonism in mice. Striatal tyrosine hydroxylase (TH) immunoreactivity, TH, and phosphorylated ser 40 TH (p‐TH) protein levels were assayed on 7th day. Nigral TH‐positive neurons stereology was conducted on serial sections 2.8 mm from bregma rostrally to 3.74 mm caudally. MPTP caused 39% and 58% decrease, respectively, in striatal fibers and TH protein levels, but 2.5‐fold increase in p‐TH levels. About 35% TH neurons were lost between 360 and 600 μm from 940 μm of the entire nigra analyzed, but no neurons were lost between 250 μm rostrally and 220 μm caudally. When L‐DOPA in small doses (5–8 mg/kg) failed to affect MPTP‐induced akinesia or catalepsy, co‐administration of melatonin with L‐DOPA attenuated these behaviors. Melatonin administration significantly attenuated MPTP‐induced loss in striatal TH fibers (82%), TH (62%) and p‐TH protein (100%) levels, and nigral neurons (87–100%). Melatonin failed to attenuate MPTP‐induced striatal dopamine depletion. L‐DOPA administration (5 mg/kg, once 40 min prior to sacrifice, p.o.) in MPTP‐ and melatonin‐treated mice caused significant increase in striatal dopamine (31%), as compared to L‐DOPA and MPTP‐treated mice. This was equivalent to 8 mg/kg L‐DOPA administration in parkinsonian mouse. Therefore, prolonged, effective use of L‐DOPA in PD with lesser side effects could be achieved by treating with 60% lower doses of L‐DOPA along with melatonin.     

Clinical trials update from the American College of Cardiology 2009: ADMIRE‐HF,PRIMA, STICH,REVERSE, IRIS,partial ventricular support,FIX‐HF‐5, vagal stimulation,REVIVAL‐3, pre‐RELAX‐AHF,ACTIVE‐A,HF‐ACTION,JUPITER, AURORA,and OMEGA

This article provides information and a commentary on trials relevant to the pathophysiology, prevention and treatment of heart failure presented at the American College of Cardiology meeting in 2009. Unpublished reports should be considered as preliminary, since analyses may change in the final publication. ¹²³I‐mIBG myocardial scintigraphy was a good predictor of mortality in patients with heart failure in ADMIRE‐HF. In PRIMA, use of individualized target NT‐proBNP levels failed to improve outcomes compared with usual care in patients hospitalized with symptomatic heart failure. In the STICH trial, additional ventricular reconstruction surgery failed to improve outcomes in patients with ischaemic heart failure undergoing CABG. Cardiac resynchronization therapy may modify disease progression in patients with mild heart failure, according to data from REVERSE. Implantation of a defibrillator early after MI in high‐risk patients in the IRIS study failed to improve outcomes compared with usual care. Cardiac contractility modulation showed some beneficial effects on symptoms and exercise capacity in the unblinded FIX‐HF‐5 study. Data from pre‐RELAX‐AHF show that relaxin may have potential as a treatment for acute heart failure. HF‐ACTION showed that patients who complied with an exercise training regime achieved a better outcome, although this may be confounded by the ability of patients with a good prognosis to exercise for longer.     

Metformin extended‐release versus immediate‐release: An international,randomized, double‐blind,head‐to‐head trial in pharmacotherapy‐naïve patients with type 2 diabetes

This international, randomized, double‐blind trial (NCT01864174) compared the efficacy and safety of metformin extended‐release (XR) and immediate‐release (IR) in patients with type 2 diabetes. After a 4‐week placebo lead‐in, pharmacotherapy‐naïve adults with glycated haemoglobin (HbA1c) at 7.0% to 9.2% were randomized (1:1) to receive once‐daily metformin XR 2000 mg or twice‐daily metformin IR 1000 mg for 24 weeks. The primary endpoint was change in HbA1c after 24 weeks. Secondary endpoints were change in fasting plasma glucose (FPG), mean daily glucose (MDG) and patients (%) with HbA1c <7.0% after 24 weeks. Overall, 539 patients were randomized (metformin XR, N = 268; metformin IR, N = 271). Adjusted mean changes in HbA1c, FPG, MDG and patients (%) with HbA1c <7.0% after 24 weeks were similar for XR and IR: ?0.93% vs ?0.96%; ?21.1 vs ?20.6 mg/dL (?1.2 vs ?1.1 mmol/L); ?24.7 vs ?27.1 mg/dL (?1.4 vs ?1.5 mmol/L); and 70.9% vs 72.0%, respectively. Adverse events were similar between groups and consistent with previous studies. Overall, metformin XR demonstrated efficacy and safety similar to that of metformin IR over 24 weeks, with the advantage of once‐daily dosing.     

Anti–N‐methyl‐D‐aspartate receptor antibodies,cognitive dysfunction,and depression in systemic lupus erythematosus

Objective

To assess the association of cognitive dysfunction and depression with serum antibodies to N‐methyl‐D ‐aspartate (NMDA) receptor (anti‐NR2) and analyze clinical and neuroimaging correlates in patients with systemic lupus erythematosus (SLE).

Methods

Sixty patients underwent neurocognitive assessment, evaluation for depression with the Beck Depression Inventory II (BDI‐II) and psychiatric interview (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM‐IV] criteria), brain magnetic resonance imaging, and proton magnetic resonance spectroscopy imaging (¹H‐MRSI). Cognition was assessed in 5 domains: memory, attention/executive, visuospatial, motor, and psychomotor, and adjusted to each individual's best level of prior cognitive functioning estimated from the reading subtest of the Wide Range Achievement Test–3 (WRAT‐3). Serum anti‐NR2 antibodies were measured by enzyme‐linked immunosorbent assay using a pentapeptide from the human NMDA receptor.

Results

Cognitive dysfunction was found in 28 of 60 patients (mild in 8, moderate in 20) before adjustment for WRAT‐3 and in 35 of 60 patients (mild in 15, moderate in 11, and severe in 9) after adjustment for WRAT‐3. The changes were most pronounced in the memory and visuospatial domains. There was no significant association between anti‐NR2 antibody levels and cognition. On ¹H‐MRSI, patients with moderate or severe cognitive dysfunction had significantly higher choline:creatine ratios in the dorsolateral prefrontal cortex and the white matter, compared with patients with mild or absent cognitive dysfunction. Anti‐NR2 antibodies were significantly correlated with BDI scores; patients with BDI‐II scores of ≥14 had higher serum levels of anti‐NR2 antibodies (P = 0.005, 95% confidence interval 0.83, 4.31), and there was a trend toward higher anti‐NR2 antibody levels among patients who fulfilled the DSM‐IV criteria for major depression.

Conclusion

Serum anti‐NR2 antibodies are associated with depressive mood but not with cognitive dysfunction in SLE at a given time point. Larger longitudinal studies are needed to address the possible association between anti‐NR2 antibodies and depression in SLE.