European Medicines Agency initiatives and perspectives on pharmacogenomics

Pharmacogenomics, the study of variations of DNA and RNA characteristics as related to drug response, has become an integral part of drug development and pharmacovigilance, as reflected by the incorporation of pharmacogenomic data in EU product information. In this short review article, we describe recent European Medicines Agency initiatives intended to support further the implementation of pharmacogenomics in drug development and surveillance so that patients and the public can benefit from advances in genomic science and technology.     

Brachytherapy and fertility

Fertility is a major part of the global care of patients treated for cancer. A new discipline known as oncofertility has emerged in some countries. Although the relationship between chemotherapy and external radiotherapy and fertility has been studied and reported, there is only scarce data available on brachytherapy. This systematic review aims to report available knowledge on the impact of brachytherapy on fertility. Specific consultations should be considered before brachytherapy to inform patients about their fertility preservation options.     

Hemolysis parameters of St. Jude Medical: Hemodynamic Plus and Regent valves in aortic position

BACKGROUND: Elevated plasma lactate dehydrogenase (LDH) concentration may reflect hemolysis due to mechanical heart valve dysfunction. Thus, knowledge of LDH levels in patients with properly working prostheses is required. Because hemolysis parameters for the SJM Hemodynamic Plus (HP) and Regent series are currently not available, the purpose of our study was to determine these data. METHODS: At 12-19 months follow-up after isolated aortic valve replacement with SJM HP(R) or Regent prostheses, we examined 102 patients by transthoracic echocardiography and determined plasma LDH, haptoglobin, bilirubin and hemoglobin. RESULTS: Five patients with properly working prostheses were excluded because of increased LDH due to non-cardiac reasons. In four patients with paravalvular leakage, LDH was 244, 307, 446 and 628 U/l, respectively. In patients with properly working prostheses, LDH was 287+/-52 (range: 163-374) U/l for HP(R) (n=33) and 274+/-48 (151-386) U/l for Regent valves (n=60, p=0.2). Haptoglobin was <1g/l in all patients; in 91% of HP and 75% of Regent valves, haptoglobin was below detection limit. Bilirubin and hemoglobin as well as red blood cell count (RBC) were normal in all patients except for five patients with renal anemia, two patients with paravalvular leakage and four patients with macrocytosis due to alcohol abuse. There was no correlation between LDH and transvalvular gradient (r=-0.02) or valve size (r=0.25). CONCLUSIONS: In patients with SJM HP(R) or Regent valves in aortic position, LDH values > 400 U/l indicate valvular dysfunction or leakage if non-cardiac causes for hemolysis are excluded. However, paravalvular leakage can be present without substantially increased LDH. Haptoglobin has no diagnostic value as it is almost always markedly reduced. Hemolysis does not correlate with transvalvular gradient or prosthesis size.     

Growth requirements,growth factor responsiveness,and growth factor secretion of three human embryonal carcinoma cell lines

Summary The in vitro growth requirements of three human embryonal carcinoma cell lines (H 12.7, 2102 EP, 1428 A) were investigated. The basal medium DME/F12 supplemented with insulin, transferrin, and low-density and high-density lipoproteins was sufficient to support substantial multiplication of all three lines. The most efficient attachment factor was either fibronectin (for 2102 EP and 1428 A) or collagen type I (H 12.7). In a serum-free system the influence of epidermal growth factor (EGF), insulin-like growth factor I, multiplication stimulating activity (MSA), a platelet extract, and the glucocorticoids dexamethasone and hydrocortisone, as determined by the DNA synthesis rate of the cells, was generally minimal. However, the DNA synthesis rate of cell lines H 12.7 and 2102 EP was increased by MSA, and the line with the highest potential to differentiate (H 12.7) was stimulated by EGF. All three cell lines secreted growth factors in a heterologous stimulation assay. Insulin-like growth factors I and II were not part of the growth promoting activity. The inhibitory effect of a monoclonal anti-EGF antibody on the ³H-thymidine incorporation of cell line 2102 EP might indicate autocrine secretion of EGF or an EGF-like factor by this cell line.     

Long-term clearance from small airways in patients with cystic fibrosis.

Impaired mucociliary clearance is a hallmark of cystic fibrosis (CF). Early morphological changes first appear in the small airways. Lung clearance was investigated in 11 young CF adults with mild-to-moderate lung disease using a method depositing particles mainly in the small airways. Radiolabelled Teflon particles (6 microm) were inhaled with an extremely slow inhalation flow, 0.05 L x s(-1). Lung retention was measured immediately following inhalations and, on four occasions up to 21 days. The results were compared with data from healthy subjects. The lung retention at 24 h in % of deposition was 67% (95% confidence interval 58-76) in the CF patients, compared to 48% (42-53) in the healthy subjects. Clearance on days 1-7 was larger in the CF patients, 22% (15-29) compared to the healthy subjects, 14% (12-16). No difference was observed between the CF patients and the healthy subjects in the slow clearance phase at day 7 to day 21, representing small airway clearance. Impaired mucociliary clearance in CF patients results in increased 24-h retention and a prolonged rapid clearance phase. The results of the study do not support the current authors' hypothesis that clearance from small airways is slower in cystic fibrosis patients compared to healthy subjects. Furthermore, the data suggest that mucociliary transport is not the dominant clearance mechanism in small airways.