Optimization of clonazepam therapy adjusted to patient's CYP3A-status and NAT2 genotype.

BACKGROUND: The shortcomings of clonazepam therapy include tolerance, withdrawal symptoms and adverse effects, such as drowsiness, dizziness and confusion leading to increased risk of falls. Inter-individual variability in the incidence of adverse events in patients partly originates from the differences in clonazepam metabolism due to genetic and non-genetic factors. METHODS: Since the prominent role in clonazepam nitro-reduction and in acetylation of 7-amino-clonazepam is assigned to CYP3A and NAT2 enzymes, respectively, the association between the patients' CYP3A-status (CYP3A5 genotype, CYP3A4 expression) or NAT2 acetylator phenotype and clonazepam metabolism (plasma concentrations of clonazepam and 7-amino-clonazepam) was evaluated in 98 psychiatric patients suffering from schizophrenia or bipolar disorders. RESULTS: The patients' CYP3A4 expression was found to be the major determinant of clonazepam plasma concentrations normalized by the dose and the bodyweight (1263.5+/-482.9 and 558.5+/-202.4 ng/ml per mg/kg bw in low and normal expressers, respectively, P<0.0001). Consequently, the dose-requirement for the therapeutic concentration of clonazepam was substantially lower in low CYP3A4 expresser patients than in normal expressers (0.029+/-0.011 vs 0.058+/-0.024 mg/kg bw, P<0.0001). Furthermore, significantly higher (about 2-fold) plasma concentration ratio of 7-amino-clonazepam and clonazepam was observed in the patients displaying normal CYP3A4 expression and slow N-acetylation than all the others. CONCLUSION: Prospective assaying of CYP3A4 expression and NAT2 acetylator phenotype can better identify the patients with higher risk of adverse reactions and can facilitate the improvement of personalized clonazepam therapy and withdrawal regimen

Optimization of clonazepam therapy adjusted to patient's CYP3A-status and NAT2 genotype

BACKGROUND: The shortcomings of clonazepam therapy include tolerance, withdrawal symptoms and adverse effects, such as drowsiness, dizziness and confusion leading to increased risk of falls. Inter-individual variability in the incidence of adverse events in patients partly originates from the differences in clonazepam metabolism due to genetic and non-genetic factors. METHODS: Since the prominent role in clonazepam nitro-reduction and in acetylation of 7-amino-clonazepam is assigned to CYP3A and NAT2 enzymes, respectively, the association between the patients' CYP3A-status (CYP3A5 genotype, CYP3A4 expression) or NAT2 acetylator phenotype and clonazepam metabolism (plasma concentrations of clonazepam and 7-amino-clonazepam) was evaluated in 98 psychiatric patients suffering from schizophrenia or bipolar disorders. RESULTS: The patients' CYP3A4 expression was found to be the major determinant of clonazepam plasma concentrations normalized by the dose and the bodyweight (1263.5+/-482.9 and 558.5+/-202.4 ng/ml per mg/kg bw in low and normal expressers, respectively, P<0.0001). Consequently, the dose-requirement for the therapeutic concentration of clonazepam was substantially lower in low CYP3A4 expresser patients than in normal expressers (0.029+/-0.011 vs 0.058+/-0.024 mg/kg bw, P<0.0001). Furthermore, significantly higher (about 2-fold) plasma concentration ratio of 7-amino-clonazepam and clonazepam was observed in the patients displaying normal CYP3A4 expression and slow N-acetylation than all the others. CONCLUSION: Prospective assaying of CYP3A4 expression and NAT2 acetylator phenotype can better identify the patients with higher risk of adverse reactions and can facilitate the improvement of personalized clonazepam therapy and withdrawal regimen

Isoform-Dependent Changes in Cytochrome P450-Mediated Drug Metabolism after Portal Vein Ligation in the Rat

Surgical removal of complicated liver tumors may be realized in two stages via selective portal vein ligation, inducing the atrophy of portally ligated lobes and the compensatory hypertrophy of nonligated liver lobes. Unlike morphological changes, functional aspects such as hepatic cytochrome P450 (CYP)-mediated drug metabolism remain vaguely understood, despite its critical role in both drug biotransformation and hepatic functional analysis. Our goal was the multilevel characterization of hepatic CYP-mediated drug metabolism after portal vein ligation in the rat.Male Wistar rats (n = 24, 210-230 g) were analyzed either untreated (controls; n = 4) or 24/48/72/168/336 h (n = 4 each) following portal vein ligation affecting approximately 80% of the liver parenchyma. Besides the weights of ligated and nonligated lobes, pentobarbital (30 mg/kg)-induced sleeping time, CYP1A(2), CYP 2B(1/2), CYP2C(6/11/13), CYP3A(1) enzyme activities, and corresponding isoform mRNA expressions, as well as CYP3A1 protein expression were determined by in vivo sleeping test, CYP isoform-selective assays, polymerase chain reaction, and immunohistochemistry, respectively.Portal vein ligation triggered atrophy in ligated lobes and hypertrophy nonligated lobes. Sleeping time was transiently elevated (p = 0.0451). After an initial rise, CYP1A, CYP2B, and CYP3A enzyme activities dropped until 72 h, followed by a potent increase only in the nonligated lobes, paralleled by an early (24-48 h) transcriptional activation only in nonligated lobes. CYP2C enzyme activities and mRNA levels were bilaterally rapidly decreased, showing a late reconvergence only in nonligated lobes. CYP3A1 immunohistochemistry indicated substantial differences in positivity in the early period.Beyond the atrophy-hypertrophy complex, portal vein ligation generated a transient suppression of global and regional drug metabolism, re-established by an adaptive, CYP isoform-dependent transcriptional response of the nonligated lobes

Early changes in Orthopteran assemblages after grassland restoration : a comparison of space-for-time substitution versus repeated-measures monitoring

Grasslands harbour significant biodiversity and their restoration is a common intervention in biodiversity conservation. However, we know very little on how grassland restoration influences arthropod groups. Here we compared orthopteran assemblages in croplands, natural grasslands and one to four-year-old grasslands restored in a large-scale restoration on former croplands in Hortobágy National Park (E-Hungary). Sampling was done by standardized sweep-netting both in a repeated measures design and space-for-time substitution (chronosequence) design. General linear models with repeated measures from five years showed that species richness, abundance and Shannon diversity of orthopterans decreased in the year following restoration but increased afterwards. By the fourth year, species richness almost doubled and abundance increased almost ten-fold in restored grasslands compared to croplands. Multivariate analyses showed that species composition in the first two years did not progress much but by the third and fourth year there was partial overlap with natural grasslands. Local restoration conditions (last crop, seed mixture) and landscape configuration (proportion of natural grasslands < 1 km away) did not influence the above patterns in either the repeated measures or the chronosequence design, whereas time since restoration affected almost all community variables. Our results suggest that generalist ubiquitous species appeared in restored grasslands first and the more sensitive species colonized the restored fields gradually in later years. The qualitative and quantitative properties of the orthopteran assemblages in restored fields did not yet reach those of natural grasslands, therefore, our study suggests that the full regeneration of the orthopteran assemblages takes more than four years

A földhasználat-változás hatásai az ízeltlábú együttesekre Egyek-Pusztakócson

A gyeprekonstrukció egyik széles körben alkalmazott módja a magvetéssel történő gyepesítés. Munkánkban habitat affinitási index segítségével jellemeztük a rekonstrukciós vizsgálatok sikerességét, ízeltlábú együtteseket (pókok, poloskák, egyenesszárnyúak és futóbogarak) vizsgálva, az Egyek-Pusztakócsi mocsárrendszer területén. Szántókat, egy éves-, két éves-, és természetes gyepeket vizsgáltunk. A fajszám nem különbözött szignifikánsan az egyes élőhelytípusok között, azonban a fajösszetétel már a gyepesítés utáni második évre jelentősen megváltozott. Megkezdődött a generalista fajok kicserélődése a gyepekhez kötődő specialista fajokra. Eredményeink azt mutatták, hogy esetünkben az élőhely-rekonstrukció sikerének nyomon követésére a fajszám nem alkalmas. Hatékonyabbak bizonyultak a sokváltozós módszerek, melyek jól tükrözik a fajösszetételbeli változásokat. A habitat affinitási index, amely a fajok identitását is figyelembe veszi, érzékenyen tükrözi a változásokat, ezért javasoljuk általános használatát a rekonstrukciós projektek sikerességének jellemzésére