Pharmacogenetics: data, concepts and tools to improve drug discovery and drug treatment

Variation in the human genome is a most important cause of variable response to drugs and other xenobiotics. Susceptibility to almost all diseases is determined to some extent by genetic variation. Driven by the advances in molecular biology, pharmacogenetics has evolved within the past 40 years from a niche discipline to a major driving force of clinical pharmacology, and it is currently one of the most actively pursued disciplines in applied biomedical research in general. Nowadays we can assess more than 1,000,000 polymorphisms or the expression of more than 25,000 genes in each participant of a clinical study -- at affordable costs. This has not yet significantly changed common therapeutic practices, but a number of physicians are starting to consider polymorphisms, such as those in CYP2C9, CYP2C19, CYP2D6, TPMT and VKORC1, in daily medical practice. More obviously, pharmacogenetics has changed the practices and requirements in preclinical and clinical drug research; large clinical trials without a pharmacogenomic add-on appear to have become the minority. This review is about how the discipline of pharmacogenetics has evolved from the analysis of single proteins to current approaches involving the broad analyses of the entire genome and of all mRNA species or all metabolites and other approaches aimed at trying to understand the entire biological system. Pharmacogenetics and genomics are becoming substantially integrated fields of the profession of clinical pharmacology, and education in the relevant methods, knowledge and concepts form an indispensable part of the clinical pharmacology curriculum and the professional life of pharmacologists from early drug discovery to pharmacovigilance.     

The Role of Haematological Parameters in Predicting the Response To Radical Chemoradiotherapy in Patients with Anal Squamous Cell Cancer

BackgroundHistorically, the treatment of choice for anal cancer had been abdominoperineal resection (APR). Radical radiotherapy with concurrent 5-fluorouracil plus mitomycin C chemotherapy was later established as standard therapy, although with a failure rate of 20–30%. The aim of this study was to evaluate the outcomes after radical chemoradiotherapy (CRT), prognostic and predictive factors and patterns of failure.Patients and methodsThis study included 47 patients treated with radical CRT for patohistologicaly confirmed anal squamous cell carcinoma. Analysed haematological parameters included: neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and haemoglobin level. The final logistic regression model included treatment break period. Tumour response was assessed at 24 weeks from CRT completion. Follow-up was performed every 3 months during the first two years, and every 6 months thereafter.ResultsA complete clinical response (CR) was detected in 30 patients (63.8%). Patients who did not achieve a 6-months CR and those who had a CR after 6 months but then relapsed were referred to surgical treatment. With combined CRT and surgical salvage treatment the CR rate was 80.9%. Patients with CR after 6 months had significantly longer disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS). A significant effect on the 6-month response was confirmed for PLR (p = 0.03).ConclusionsImportant prognostic factors associated with CR were baseline haemoglobin level and period of treatment interruptions. Potential haematological prognostic factors could be PLR and NLR, which can be routinely determined by low-cost and minimally invasive methods.Key words: anal cancer, chemoradiotherapy, haematological parameters     

Uric Acid and Antioxidant Effects of Wine

The aim of this article is to review the role of uric acid in the context of antioxidant effects of wine and its potential implication to human health. We described and discussed the mechanisms of increase in plasma antioxidant capacity after consumption of moderate amounts of wine. Because this effect is largely contributed by acute elevation in plasma uric acid, we paid special attention to wine constituents and metabolic processes that are likely to be involved in uric acid elevation.The association between light-to-moderate wine consumption and risk reduction of cardiovascular diseases and/or reduction of all-cause mortality was confirmed by numerous epidemiological studies (1-7). Among other beneficial biological effects, it has been shown that wine can increase antioxidant capacity in humans (8-12) and reduce susceptibility of human plasma to lipid peroxidation (11,13). These effects of wine attracted significant research interest, as oxidative stress is implicated in the pathogenesis of various diseases such as cancer and cardiovascular and neurodegenerative diseases (14-19).     

Increased ammonium in culture medium reduces the development of human embryos to the blastocyst stage

The objective of this prospective study was to evaluate the effect of ammonium accumulated in sequential media and determined by enzymatic spectrophotometric method on the blastocyst development in 281 human embryos from 100 stimulated and natural in vitro fertilization (IVF) cycles. Ammonium concentration was increased in 62% of cycles and was correlated negatively with the blastocyst development after classical IVF, but not after intracytoplasmic sperm injection (ICSI).     

Esophagogastric anastomosis in rats: Improved healing by BPC 157 and L-arginine,aggravated by L-NAME

AIM To cure typically life-threatening esophagogastric anastomosis in rats, lacking anastomosis healing and sphincter function rescue, in particular. METHODS Because we assume esophagogastric fistulas represent a particular NO-system disability, we attempt to identify the benefits of anti-ulcer stable gastric pentadecapeptide BPC 157, which was in trials for ulcerative colitis and currently for multiple sclerosis, in rats with esophagocutaneous fistulas. Previously, BPC 157 therapies have promoted the healing of intestinal anastomosis and fistulas, and esophagitis and gastric lesions, along with rescued sphincter function. Additionally, BPC 157 particularly interacts with the NOsystem. In the 4 d after esophagogastric anastomosis creation, rats received medication(/kg intraperitoneallyonce daily: BPC 157(10 μg, 10 ng), L-NAME(5 mg), or L-arginine(100 mg) alone and/or combined or BPC 157(10 μg, 10 ng) in drinking water). For rats underwent esophagogastric anastomosis, daily assessment included progressive stomach damage(sum of the longest diameters, mm), esophagitis(scored 0-5), weak anastomosis(m L H2 O before leak), low pressure in esophagus at anastomosis and in the pyloric sphincter(cm H2O), progressive weight loss(g) and mortality. Immediate effect assessed blood vessels disappearance(scored 0-5) at the stomach surface immediately after anastomosis creation. RESULTS BPC 157(all regimens) fully counteracted the perilous disease course from the very beginning(i.e., with the BPC 157 bath, blood vessels remained present at the gastric surface after anastomosis creation) and eliminated mortality. Additionally, BPC 157 treatment in combination with L-NAME nullified any effect of L-NAME that otherwise intensified the regular course. Consistently, with worsening(with L-NAME administration) and amelioration(with L-arginine), either L-arginine amelioration prevails(attenuated esophageal and gastric lesions) or they counteract each other(L-NAME + L-arginine); with the addition of BPC 157(L-NAME + L-arginine + BPC 157), there was a marked beneficial effect. BPC 157 treatment for esophagogastric anastomosis, along with NOS-blocker L-NAME and/or NOS substrate L-arginine, demonstrated an innate NO-system disability(as observed with L-arginine effectiveness). BPC 157 distinctively affected corresponding events: worsening(obtained with L-NAME administration that was counteracted); or amelioration(L-arginine + BPC 157-rats correspond to BPC 157-rats).CONCLUSION Innate NO-system disability for esophagogastric anastomoses, including L-NAME-worsening, suggests that these effects could be corrected by L-arginine and almost completely eliminated by BPC 157 therapy.