Comparison of the BASDAI and the miniBASDAI in assessing disease activity in patients with ankylosing spondylitis

The BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) is the most widely used instrument for the assessment of disease activity in ankylosing spondylitis (AS). Objective. The aims to investigate whether the alternative BASDAI, here termed as the miniBASDAI [(Question (Q) 1 fatigue + Q2 spinal pain) + mean of (Q5 strength morning stiffness + Q6 duration morning stiffness)] / 3], measures disease activity more accurately in the subgroup of AS patients without peripheral manifestations. One hundred and ten patients were included in this cross-sectional study according to the modified New York criteria for AS. Clinical and biological parameters were evaluated. The disease activity was evaluated by the BASDAI. We calculated the miniBASDAI by omitting both the peripheral joints and the enthesitis questions: questions 3 and 4. Patients were dichotomized into a “P+” group if peripheral manifestations were present (at least arthritis or enthesitis) and a “P−” group, the subgroup without peripheral involvement (with either arthritis or enthesitis). Correlation of the BASDAI and miniBASDAI with other disease parameters were examined with the Spearman's rank correlation analysis. One hundred and ten patients were recruited. The percentage of patients with pure axial disease manifestation without peripheral involvement “P − group” was 42.7%. We found a similarly good correlation of the miniBASDAI with patient global, physician on disease activity, BASFI, ESR and CRP if compared to the correlation of the original BASDAI with these disease parameters, also in the group without peripheral involvement. Our study suggests that the BASDAI remains valid in assessing disease activity in AS patients with and without peripheral manifestations.     

Silodosin: A selective α1A-adrenergic receptor antagonist for the treatment of benign prostatic hyperplasia

Background: Silodosin is a new α₁-adrenergic receptor antagonist that is selective for the α_1A-adrenergic receptor. It was approved by the US Food and Drug Administration (FDA) in 2008 for the treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH).Objective: This article reviews the pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, and dosage and administration of silodosin in adult male patients with BPH.Methods: A search of MEDLINE (1950–October 8, 2009), International Pharmaceutical Abstracts (1970–October 8, 2009), and the Iowa Drug Information Service database (1966–October 8, 2009) was conducted using the terms silodosin, KMD-3213, benign prostatic hyperplasia, and α₁-adrenergic receptor antagonist. Reports of research and review articles published in English were identified and evaluated, and the bibliographies of these articles were reviewed for additional relevant publications. A search of the FDA Web site was performed, and abstracts and posters presented at scientific meetings of the American Urological Association were reviewed.Results: By antagonizing α_1A-adrenergic receptors in the prostate and urethra, silodosin causes smooth muscle relaxation in the LUT. Silodosin has greater affinity for the α_1A-adrenergic receptor than for the α_1B-adrenergic receptor (by a factor of 583), minimizing the propensity for blood pressure-related adverse effects mediated by α_1B blockade. In 3 controlled clinical studies in patients with BPH-related LUTS (1 published; 2 presented in the prescribing information and published in a pooled analysis), patients receiving silodosin at a total daily dose of 8 mg had significant improvements in the International Prostate Symptom Score (IPSS) and maximum urinary flow rate (Q_max) compared with those receiving placebo (both, P < 0.05). The most commonly reported adverse effect was abnormal or retrograde ejaculation (>22%), and the incidence of orthostatic hypotension was low (<3%).Conclusions: In the small number of clinical trials reviewed, silodosin was associated with significant reductions in IPSS and Q_max compared with placebo. To determine whether silodosin's selectivity for the α_1A-adrenergic receptor translates into a clinical advantage relative to other available agents, long-term studies evaluating the comparative efficacy and tolerability of silodosin and other α₁-blockers (specifically tamsulosin) are necessary.     

Tigecycline prevents LPS-induced release of pro-inflammatory and apoptotic mediators in neuronal cells

Pro-inflammatory and pro-apoptotic mediators have been involved in the pathogenesis of neurodegenerative diseases. Tigecycline (Tig), a glycylcycline antibiotic and an analog of Minocycline, is shown to exert anti-inflammatory effects that are distinct from its anti-microbial activity. Its neuroprotective mechanism is unknown. In this study, we investigated the direct protective mechanisms of tigecycline against lipopolysaccharide (LPS)-induced Rat pheochromocytoma (PC12) cells. The results showed that tigecycline significantly attenuated the expression and the release of nuclear factor-kappa beta (NF-κB), tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β), as well as nitric oxide (NO) levels in LPS-induced PC12 cells. In addition, tigecycline dose-dependently decreased cytochrome c release and caspase-3 activity. This later finding corroborated the results of decreased pro-apoptotic Bad, and increased anti-apoptotic Bcl-2 protein expression thus, confirming a neuroprotective effect of the drug in differentiated PC12 cells induced with LPS. The findings of our study suggest new targets for tigecycline and support the potential for tigecycline to be investigated as a therapeutic agent for neurodegenerative disorders.     

Glomérulonéphrites aiguës postinfectieuses

Acute postinfectious glomerulonephritis are defined by an acute nonsuppurative inflammatory insult predominantly glomerular. Its current incidence is uncertain because of the frequency of subclinical forms. The most common infectious agent involved is beta hemolytic streptococcus group A. Acute postinfectious glomerulonephritis is uncommon in adults, and its incidence is progressively declining in developed countries. Humoral immunity plays a key role in the pathogenesis of kidney damage. Complement activation by the alternative pathway is the dominant mechanism, but a third way (lectin pathway) has been recently identified. The classic clinical presentation is sudden onset of acute nephritic syndrome after a free interval from a streptococcal infection. Treatment is essentially symptomatic and prevention is possible through improved hygiene and early treatment of infections.     

Disposition of ON 01210.Na (Ex-RAD(R)), a Novel Radioprotectant,in the Isolated Perfused Rat Liver: Probing Metabolic Inhibition to Increase Systemic Exposure

ON 01210.Na (Ex-RAD) is a novel benzyl styryl sulfone analog, developed as a radioprotectant by Onconova Therapeutics Inc. The objectives of this research were to evaluate the hepatobiliary disposition of ON 01210.Na in the isolated perfused rat liver (IPRL) and to determine the effect of coadministration of ethacrynic acid (EA) on the pharmacokinetic profile of ON 01210.Na. EA acid was used as a prototypical inhibitor of glutathione-S-transferase inhibitor. ON 01210.Na was highly bound in IPRL perfusate proteins, and binding was significantly lower in the presence of EA. Dose-escalation studies (bolus dose, target concentrations 10–250 μg/mL) showed that ON 01210.Na followed nonlinear pharmacokinetics with hepatic clearance decreasing from 3.14 to 1.99 mL/min with increasing dose. ON 01210.Na underwent extensive metabolic degradation to its glutathione (GSH) adduct in liver. The GSH metabolite was mainly excreted into the bile. Coadministration of EA (1 mM) significantly inhibited the conversion of ON 01210.Na to its GSH conjugate, resulting in decreased clearance (approx. fivefold lower), and prolonged elimination from the perfusate. These preclinical studies suggest that EA is a potential pharmacoenhancer that can reduce the metabolism of ON 01210.Na in vivo, thereby increasing drug exposure and boosting radioprotective activity.     

Synthesis and self‐assembly of polymers containing dicarboximide groups by living ring‐opening metathesis polymerization

Polymers with narrow molecular weight distributions and controlled architectures were generated by living ring‐opening metathesis polymerization of exo‐7‐oxabicyclo[2.2.1]hept‐5‐ene‐2,3‐dicarboximide. The dicarboximide units have been previously shown to exhibit biological activity, can selectively bind to the nucleic acid base adenine by hydrogen‐bonding, and are readily functionalizable. Block copolymers containing these moieties were generated, and underwent self‐assembly into nanoscale spherical aggregates, with surface localized molecular recognition motifs.