Association between CYP2B6 genetic variability and cyclophosphamide therapy in pediatric patients with neuroblastoma.

Cyclophosphamide, an oxazaphosphorine prodrug is frequently used in treatment of neuroblastoma, which is one of the most prevalent solid organ malignancies in infants and young children. Cytochrome P450 2B6 (CYP2B6) is the major catalyst and CYP2C19 is the minor enzyme in bioactivation and inactivation pathways of cyclophosphamide. CYP-mediated metabolism may contribute to the variable pharmacokinetics of cyclophosphamide and its toxic byproducts leading to insufficient response to the therapy and development of clinically significant side effects. The aim of the study was to reveal the contribution of pharmacogenetic variability in CYP2B6 and CYP2C19 to the treatment efficacy and cyclophosphamide-induced side effects in pediatric neuroblastoma patients under cyclophosphamide therapy (N = 50). Cyclophosphamide-induced hematologic toxicities were pivotal in all patients, whereas only moderate hepatorenal toxicity was developed. The patients' CYP2B6 metabolizer phenotypes were associated with the occurrence of lymphopenia, thrombocytopenia, and monocytopenia as well as of liver injury, but not with kidney or urinary bladder (hemorrhagic cystitis) toxicities. Furthermore, the patients' age (< 1.5 years, P = 0.03) and female gender (P ≤ 0.02), but not CYP2B6 or CYP2C19 metabolizer phenotypes appeared as significant prognostic factors in treatment outcomes. Our results may contribute to a better understanding of the impact of CYP2B6 variability on cyclophosphamide-induced side effects.

CYP2B6 allelic variants and non-genetic factors influence CYP2B6 enzyme function.

Human CYP2B6 enzyme although constitutes relatively low proportion (1-4%) of hepatic cytochrome P450 content, it is the major catalyst of metabolism of several clinically important drugs (efavirenz, cyclophosphamide, bupropion, methadone). High interindividual variability in CYP2B6 function, contributing to impaired drug-response and/or adverse reactions, is partly elucidated by genetic polymorphisms, whereas non-genetic factors can significantly modify the CYP2B6 phenotype. The influence of genetic and phenoconverting non-genetic factors on CYP2B6-selective activity and CYP2B6 expression was investigated in liver tissues from Caucasian subjects (N = 119). Strong association was observed between hepatic S-mephenytoin N-demethylase activity and CYP2B6 mRNA expression (P < 0.0001). In less than one third of the tissue donors, the CYP2B6 phenotype characterized by S-mephenytoin N-demethylase activity and/or CYP2B6 expression was concordant with CYP2B6 genotype, whereas in more than 35% of the subjects, an altered CYP2B6 phenotype was attributed to phenoconverting non-genetic factors (to CYP2B6-specific inhibitors and inducers, non-specific amoxicillin + clavulanic acid treatment and chronic alcohol consumption, but not to the gender). Furthermore, CYP2B6 genotype-phenotype mismatch still existed in one third of tissue donors. In conclusion, identifying potential sources of CYP2B6 variability and considering both genetic variations and non-genetic factors is a pressing requirement for appropriate elucidation of CYP2B6 genotype-phenotype mismatch.

Novel mitochondrial transition pore inhibitor N-methyl-4-isoleucine cyclosporin is a new therapeutic option in acute pancreatitis.

KEY POINTS: •Bile acids, ethanol and fatty acids affect pancreatic ductal fluid and bicarbonate secretion via mitochondrial damage, ATP depletion and calcium overload. •Pancreatitis-inducing factors open the membrane transition pore (mPTP) channel via cyclophilin D activation in acinar cells, causing calcium overload and cell death; genetic or pharmacological inhibition of mPTP improves the outcome of acute pancreatitis in animal models. •Here we show that genetic and pharmacological inhibition of mPTP protects mitochondrial homeostasis and cell function evoked by pancreatitis-inducing factors in pancreatic ductal cells. •The results also show that the novel cyclosporin A derivative NIM811 protects mitochondrial function in acinar and ductal cells, and it preserves bicarbonate transport mechanisms in pancreatic ductal cells. •We found that NIM811 is highly effective in different experimental pancreatitis models and has no side-effects. NIM811 is a highly suitable compound to be tested in clinical trials. ABSTRACT: Mitochondrial dysfunction plays a crucial role in the development of acute pancreatitis (AP); however, no compound is currently available with clinically acceptable effectiveness and safety. In this study, we investigated the effects of a novel mitochondrial transition pore inhibitor, N-methyl-4-isoleucine cyclosporin (NIM811), in AP. Pancreatic ductal and acinar cells were isolated by enzymatic digestion from Bl/6 mice. In vitro measurements were performed by confocal microscopy and microfluorometry. Preventative effects of pharmacological [cylosporin A (2 µm), NIM811 (2 µm)] or genetic (Ppif-/- /Cyp D KO) inhibition of the mitochondrial transition pore (mPTP) during the administration of either bile acids (BA) or ethanol + fatty acids (EtOH+FA) were examined. Toxicity of mPTP inhibition was investigated by detecting apoptosis and necrosis. In vivo effects of the most promising compound, NIM811 (5 or 10 mg kg-1 per os), were checked in three different AP models induced by either caerulein (10 × 50 µg kg-1 ), EtOH+FA (1.75 g kg-1 ethanol and 750 mg kg-1 palmitic acid) or 4% taurocholic acid (2 ml kg-1 ). Both genetic and pharmacological inhibition of Cyp D significantly prevented the toxic effects of BA and EtOH+FA by restoring mitochondrial membrane potential (Δψ) and preventing the loss of mitochondrial mass. In vivo experiments revealed that per os administration of NIM811 has a protective effect in AP by reducing oedema, necrosis, leukocyte infiltration and serum amylase level in AP models. Administration of NIM811 had no toxic effects. The novel mitochondrial transition pore inhibitor NIM811 thus seems to be an exceptionally good candidate compound for clinical trials in AP.

[Fear of falling among community-living older adults]. / Az eleséstol való félelem otthon élo idosek körében.

INTRODUCTION: Due to fear of falling, older people may restrict their activities, causing muscle weakness and impaired balance and, consequently, admission to an institute. Accordingly, fear of falling is a common and serious health problem among older individuals. The prevalence of the fear of falling and its associated factors as well as possible preventive and therapeutic methods have been widely investigated in geriatrics. AIM: The aim of our study was to describe the prevalence of the fear of falling and its associations with demographic (age, gender) and health factors (age-related chronic diseases, functional mobility, falling in the previous year, medications) among community-living older adults. METHOD: Two-hundred individuals participated in the study. The fear of falling was diagnosed based on the cut-off value of the short Falls Efficacy Scale - International (FES-I). Logistic regression analysis was used to assess associations. In total, 61 participants were diagnosed with fear of falling. RESULTS: In our sample, the fear of falling was associated with age, the number of diseases and functional mobility. CONCLUSION: The short FES-I is simple, easy to fill-out and has a validated Hungarian version as well. By its use, people of higher age affected by multiple chronic illnesses are primarily worth of screening in order to identify those who are in need for further more detailed examinations and, if needed, more targeted interventions. Orv Hetil. 2019; 160(5): 191-197.

Gait parameters in physically active and inactive elderly as well as young community-living people.

BACKGROUND: This study aimed to reveal the effects of a complex exercise program on gait among older people through analyzing the gait parameters in three groups: 1) older individuals participating in complex exercise program called 60+; 2) older individuals who were physically inactive; and 3) young individuals. METHODS: Fifty-seven community-living individuals were enrolled in this study. Variability of step length, step time, step width, and double support ratio as well as automaticity were measured. RESULTS: We found that the variability of step length, step time, and double support ratio, as well as the cognitive automaticity index of physically inactive elderly individuals were significantly worse compared to both physically active elderly (step length P=0.007; step time P=0.002; double support ratio P=0.036; cognitive automaticity index P=0.006) and young individuals (step length P<0.001; step time P<0.001; double support ratio P=0.001; cognitive automaticity index P=0.003). However, the variability of gait step width did not differ among the three groups. CONCLUSIONS: This study demonstrated that 60+ program has beneficial effects on gait parameters. Thus, the 60+ program can enrich the range of geriatric exercise programs aiming to improve gait safety.

Cross-cultural validation of the Falls Efficacy Scale-International to assess concerns about falls among Hungarian community-living older people.

PURPOSE: The Falls Efficacy Scale-International (FES-I) is a reliable and valid tool for assessing concerns about falling. Our aims were to translate, culturally adapt, and evaluate the main psychometric characteristics (internal consistency, reproducibility, and convergent construct validity) of the Hungarian version of the FES-I on a sample of community-living older adults. METHODS: After translating and culturally adapting the original scale, 165 community-living older adults (aged 60 years or over) participated in the measurements and filled in the questionnaire. After two weeks, a subsample of 64 persons filled in the FES-I again to determine the test-retest reliability. RESULTS: The test-retest analysis showed excellent reliability: Intraclass Correlation Coefficient was 0.831. The FES-I Hungarian consisted of two factors that showed good internal consistency: Cronbach's alpha 0.95 (Factor 1), 0.89 (Factor 2), and 0.93 (whole scale). The FES-I was able to discriminate the participants based on gender and fall history. It showed a significant correlation with the Timed Up and Go test (r = 0.740) and the general health perception (r = -0.713). CONCLUSIONS: Translation and cultural adaptation of the original scale were successful. The Hungarian version proved to be a reliable, valid tool confirming that it can be used in future clinical and scientific work with Hungarian older people. Implications for rehabilitation Excessive concerns about falls may lead to avoidance of activities, decreasing functional abilities, increasing of risk of a future fall, ultimately premature nursing home admission. The Falls Efficacy Scale-International is a widespread tool for assessing concerns about falls. The Hungarian version of Falls Efficacy Scale-International has an excellent test-retest reliability, good internal consistency, and acceptable construct validity. The Hungarian version of Falls Efficacy Scale-International is a valid and reliable tool for measuring the concerns about falls among Hungarian-speaking community-living older people in everyday clinical practice and scientific studies.