Increased importance of the documented development stage in process validation

Current trends in pharmaceutical quality assurance moved when the Federal Drug Administration (FDA) of the USA published its new guideline on process validation in 2011. This guidance introduced the lifecycle approach of process validation. In this short communication some typical changes from the point of view of practice of API production are addressed in the light of inspection experiences. Some details are compared with the European regulations.     

Integrity® bare-metal coronary stent-induced platelet and endothelial cell activation results in a higher risk of restenosis compared to Xience® everolimus-eluting stents in stable angina patients

Drug-eluting stenting (DES) has become a reliable tool for coronary stenting; however, its direct effects on platelet and endothelium function differ from those of bare-metal stenting (BMS). This study involved a periprocedural analysis of various biomarkers of cellular activation after elective DES (Xience^®, Abbott Vascular, Santa Clara, CA, USA) or BMS (Integrity^®, Medtronic, Minneapolis, MI, USA). Forty-nine stable angina patients were recruited: 28 underwent BMS, and 21 received everolimus-eluting stents. Samples were collected (i) prior to stenting, (ii) at 24 hours after procedure, and (iii) after 1 month of dual antiplatelet therapy. Platelet activation was analyzed by surface P-selectin positivity in parallel with plasma levels of soluble P-selectin, CD40L and platelet-derived growth factor (PDGF). Endothelial cell (EC) activation was detected by measuring markers of early (von Willebrand factor) and delayed response (VCAM-1, ICAM-1, E-selectin). Patients were followed for 6 months for the occurrence of restenosis or stent thrombosis. Increased platelet activation was sustained regardless of stent type or antiplatelet medication. Concentrations of most EC markers were more elevated after BMS than after DES. No stent thrombosis was seen, but six BMS subjects displayed restenosis with significantly higher sCD40L (779 [397–899] vs. 381 [229–498] pg/mL; p = 0.032) and sICAM-1 (222 [181–272] vs. 162 [153–223] ng/mL; p = 0.046) levels than in those without complication, while DES patients exhibited significantly decreased PDGF (572 [428–626] vs. 244 [228–311] pg/mL; p = 0.004) after 1 month. Nonresponsiveness to antiplatelet drugs did not influence these changes. In conclusion, the degree of platelet and EC activation suggests that Xience^® DES may be regarded a safer coronary intervention than Integrity^® BMS, with a lower risk of in-stent restenosis.     

Treatment of Chronic Migraine with OnabotulinumtoxinA: Mode of Action,Efficacy and Safety

Background: Chronic migraine is a common, highly disabling, underdiagnosed and undertreated entity of migraine. It affects 0.9%–2.2% of the general adult population. The present paper overviews the preclinical and clinical data regarding the therapeutic effect of onabotulinumtoxinA in chronic migraineurs. Methods: A literature search was conducted in the database of PubMed up to 20 May 2015 for articles related to the pathomechanism of chronic migraine, the mode of action, and the efficacy, safety and tolerability of onabotulinumtoxinA for the preventive treatment of chronic migraine. Results: The pathomechanism of chronic migraine has not been fully elucidated. The mode of action of onabotulinumtoxinA in the treatment of chronic migraine is suggested to be related to the inhibition of the release of calcitonin gene-related peptide and substance P in the trigeminovascular system. Randomized clinical trials demonstrated that long-term onabotulinumtoxinA fixed-site and fixed-dose (155–195 U) intramuscular injection therapy was effective and well tolerated for the prophylactic treatment of chronic migraine. Conclusions: Chronic migraine is a highly devastating entity of migraine. Its exact pathomechanism is unrevealed. Two-third of chronic migraineurs do not receive proper preventive medication. Recent clinical studies revealed that onabotulinumtoxinA was an efficacious and safe treatment for chronic migraine.     

Hyperuricemia predicts adverse clinical outcomes after cardiac resynchronization therapy

Abstract

Objectives: Changes in the levels of serum creatinine and N-terminal of prohormone brain natriuretic peptide (NT-proBNP) are useful risk markers after cardiac resynchronization therapy (CRT). The diagnostic value of changes in serum uric acid levels has been established in chronic heart failure, but no data are available on the prognostic value of hyperuricemia in a CRT population. Design: We measured markers of renal function [creatinine, blood urea nitrogen (BUN) and uric acid] and NT-proBNP levels of 129 heart failure patients undergoing CRT in a prospective, observational study. The 5-year all-cause mortality and the 6-month clinical response (≥ 15% increase in the left ventricular ejection fraction) were considered as study end points. Results: In multivariable analyses, the uric acid was found to be a statistically significant predictor of the outcome. Uric acid levels exceeding 386?mmol/L before CRT increased the chances of mortality [n?=?55, hazard ratio?=?2.39 (1.30-4.39), p?<?0.01] and poor clinical response [n?=?37, odds ratio?=?2.89 (1.22-6.87), p?=?0.01] independently of serum NT-proBNP and other factors. Conclusions: Elevated uric acid concentrations in patients with CRT are associated with an increased risk of mortality and poor clinical response independently of the NT-proBNP levels and other relevant clinical factors.     

The role of metabolic ecosystem in cancer progression — metabolic plasticity and mTOR hyperactivity in tumor tissues

Cancer and Metastasis Reviews - Despite advancements in cancer management, tumor relapse and metastasis are associated with poor outcomes in many cancers. Over the past decade, oncogene-driven...     

Prevalence of human papillomaviruses in the healthy oral mucosa of women with high‐grade squamous intra‐epithelial lesion and of their partners as compared to healthy controls

Oral human papillomavirus (HPV) carriage rates were investigated in relation to genital HPV carriage in women with HPV‐associated cervical lesions and male partner of such women, including several couples, in comparison with healthy individuals. Buccal and lingual mucosa of 60 males and 149 females with healthy oral mucosa and without known genital lesion, genital and oral mucosa of further 40 females with cervical high‐grade squamous intraepithelial lesion (HSIL) and 34 male sexual partners of women with HSIL (including 20 couples) were sampled. HPV DNA was detected using MY/GP PCR. Genotype was determined by sequencing or restriction fragment length polymorphism. Virus copy numbers were determined by real‐time PCR. Overall, oral HPV carriage rate was 5.7% (12/209) in healthy individuals; average copy number was 5.8 × 10² copies/1 μg DNA; male and female rates were comparable. Oral carriage in women with HSIL was significantly higher, 20.0% (8/40, P = 0.003); males with partners with HSIL showed a carriage rate of 17.6% (6/34), copy numbers were similar to the healthy controls. In contrast, genital carriage rate (52.9%, 18/34 vs. 82.5%, 33/40; P = 0.006) and average copy number were lower in males (5.0 × 10⁵ vs. 7.8 × 10⁵ copies/1 μg DNA; P = 0.01). Oral copy numbers in these groups and in healthy individuals were comparable. High‐risk genotypes were dominant; couples usually had the same genotype in the genital sample. In conclusion, genital HPV carriage is a risk factor of oral carriage for the individual or for the sexual partner, but alone is not sufficient to produce an oral HPV infection in most cases.