Interaktionen kardialer und antiretroviraler Medikation

Zusammenfassung: Neue therapeutische Optionen der hochaktiven antiretroviralen Therapie (HAART) haben die Morbidität und Mortalität von HIV-infizierten Patienten deutlich gesenkt, so dass nun vermehrt die altersspezifischen Erkrankungen manifest werden, wie z. B. kardiovaskuläre Erkrankungen. Zusätzlich verursacht die HIV-Erkrankung selber eine gewisse kardiovaskuläre Morbidität. Aus diesem Grund gewinnt die Behandlung der kardiovaskulären Symptome eine zunehmende Bedeutung. Die Pharmakotherapie dieser HIV-positiven Patienten ist sehr komplex, da sie durch eine Polypharmazie aus Medikamenten mit einem hohen Interaktionspotential geprägt is

UPLC TOF MS for sensitive quantification of naturally occurring pyrrolizidine alkaloids in Petasites hybridus extract (Ze 339)

AbstractDue to increasing regulatory awareness of their hepatotoxic, genotoxic and possibly carcinogenic potential, pyrrolizidine alkaloid (PA) content has to be thoroughly monitored in herbal medicinal preparations. Recently, new very low PA regulatory threshold concentrations have been requested by the authorities. Therefore, a highly sensitive and reproducible UPLC TOF MS method for the quantification of the PAs senkirkine, senecionine, seneciphylline, senecionine-N-oxide and seneciphylline-N-oxide in a CO2-extract of Petasites hybridus leaves (Ze 339) has been developed.The limit of quantification (LOQ) was 2ppb for all PAs. Recovery at the LOQ was between 88.9 and 141.9%, the repeatability precision between 3.5 and 13.6%. Linearity of the five PAs showed correlation coefficients between 0.9995 and 0.9998 and coefficients of variation between 7.44 and 8.56%. A working range between 2 ppb and 200 ppb could be fixed. In the tested batches of the P. hybridus extract Ze 339, the absence of PAs could be demonstrated. In conclusion, this assay allows to determine trace PA concentrations in P. hybridus extract Ze 339, making it suitable for analytical PA monitoring in accordance with regulatory requirements

Pharmacokinetics and metabolism of idebenone in healthy male subjects

Purpose: Idebenone is a synthetic analogue of ubiquinone that may be beneficial in the treatment of Friedreich's ataxia. Since in previous pharmacokinetic trials only lower doses were studied, it was the aim of this study to evaluate the pharmacokinetics of idebenone in higher doses of up to 2,250mg/day. Methods: In this open, randomized trial, 25 healthy male subjects received first either a single oral dose of 150mg or 750mg of idebenone, then the same dose given at 8-h intervals for 14days. Results: Idebenone and its metabolites appeared in the plasma quickly. Over 99% of parent idebenone was metabolized, indicating a high first-pass effect. Cmax and AUC0−t values for parent idebenone and its metabolites increased in a dose-proportional manner. There was virtually no accumulation of parent drug or metabolites following multiple dosing. Conclusions: Idebenone exhibited dose-dependent pharmacokinetics in daily doses up to 2,250mg. In 6/14 subjects, adverse events of mild to moderate severity were observe

Modulation of transendothelial permeability and expression of ATP-binding cassette transporters in cultured brain capillary endothelial cells by astrocytic factors and cell-culture conditions

Confluent cell monolayers of brain capillary endothelial cells (BCEC) are used widely as an in vitro cell culture model of the blood-brain barrier. The present study describes the influence of cell-culture conditions on tight junctions, filamentous-actin cytoskeleton, and expression of ATP-binding cassette (ABC) transporters in primary cell cultures of porcine BCEC. Astrocyte as well as C6 glioma-conditioned cell culture medium was used in combination with retinoic acid, dexamethasone, cyclic adenosine monophosphate (cAMP) analogs, or 1,25-dihydroxyvitamin D3. It was shown that C6-conditioned medium led to a reorganization of filamentous actin and to an improved staining of zonula occludens-associated protein-1 (ZO-1). Further optimization of these culture conditions was achieved with cAMP analogs and dexamethasone. Retinoic acid, as well as 1,25-dihydroxyvitamin D3, did not improve cellular tight junctions as judged by filamentous actin, ZO-1 rearrangement, and transcellular electrical resistance (TER) measurements. However, these morphological changes did not influence the paracellular permeability of the extracellular marker sucrose. Expression of ABC transporters such as P-glycoprotein, multidrug resistance-associated protein-1( MRP1), and MRP2 were compared by measuring messenger RNA (mRNA) levels in whole-brain tissue, isolated brain capillaries, and cultured cells. In freshly isolated BCEC, mRNA levels of MRP2 and P-glycoprotein dropped by two- to sevenfold, respectively, whereas MRP1 mRNA levels were slightly increased. During cell culture, mRNA levels of MRP1 and MRP2 decreased by up to fivefold, while P-glycoprotein levels remained constant. These results were unaltered by different cell-culture conditions. In conclusion, the present study suggests that paracellular permeability, as well as mRNA expression of the studied ABC transporters in primary cultures, of porcine BCEC are insensitive toward changes in cell-culture condition

Effects of carbohydrate sugars and artificial sweeteners on appetite and the secretion of gastrointestinal satiety peptides

In vitro, both carbohydrate sugars and artificial sweeteners (AS) stimulate the secretion of glucagon-like peptide-1 (GLP-1). It has been suggested that the gut tastes sugars and AS through the same mechanisms as the tongue, with potential effects on gut hormone release. We investigated whether the human gut responds in the same way to AS and carbohydrate sugars, which are perceived by lingual taste as equisweet. We focused on the secretion of gastrointestinal (GI) satiety peptides in relation to appetite perception. We performed a placebo-controlled, double-blind, six-way, cross-over trial including twelve healthy subjects. On separate days, each subject received an intragastric infusion of glucose, fructose or an AS (aspartame, acesulfame K and sucralose) dissolved in 250ml of water or water only (control). In a second part, four subjects received an intragastric infusion of the non-sweet, non-metabolisable sugar analogue 2-deoxy-d-glucose. Glucose stimulated GLP-1 (P=0·002) and peptide tyrosine tyrosine (PYY; P=0·046) secretion and reduced fasting plasma ghrelin (P=0·046), whereas fructose was less effective. Both carbohydrate sugars increased satiety and fullness (albeit not significantly) compared with water. In contrast, equisweet loads of AS did not affect gastrointestinal peptide secretion with minimal effects on appetite. 2-Deoxy-d-glucose increased hunger ratings, however, with no effects on GLP-1, PYY or ghrelin. Our data demonstrate that the secretion of GLP-1, PYY and ghrelin depends on more than the detection of (1) sweetness or (2) the structural analogy to glucos

Effect of the inhibition of CYP3A4 or CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone

Purpose: The main metabolic pathways of oxycodone, a potent opioid analgetic, are N-demethylation (CYP3A4) to inactive noroxycodone and O-demethylation (CYP2D6) to active oxymorphone. We performed a three-way, placebo-controlled, double-blind cross-over study to assess the pharmacokinetic and pharmacodynamic consequences of drug interactions with oxycodone. Methods: The 12 participants (CYP2D6 extensive metabolizers) were pre-treated with placebo, ketoconazole or paroxetine before oral oxycodone ingestion (0.2mg/kg). Results: Pre-treatment with ketoconazole increased the AUC for oxycodone 2- to 3-fold compared with placebo or paroxetine. In combination with placebo, oxycodone induced the expected decrease in pupil diameter. This decrease was accentuated in the presence of ketoconazole, but blunted by paroxetine. In comparison to pre-treatment with placebo, ketoconazole increased nausea, drowsiness, and pruritus associated with oxycodone. In contrast, the effect of pre-treatment with paroxetine on the above-mentioned adverse events was not different from that of placebo. Ketoconazole increased the analgetic effect of oxycodone, whereas paroxetine was not different from placebo. Conclusions: Inhibition of CYP3A4 by ketoconazole increases the exposure and some pharmacodynamic effects of oxycodone. Paroxetine pretreatment inhibits CYP2D6 without inducing relevant changes in oxycodone exposure, and partially blunts the pharmacodynamic effects of oxycodone due to intrinsic pharmacological activities. Pharmacodynamic changes associated with CYP3A4 inhibition may be clinically important in patients treated with oxycodon

Non-immunological toxicological mechanisms of metamizole-associated neutropenia in HL60 cells

Metamizole is an  analgesic and  antipyretic , but can cause  neutropenia and  agranulocytosis . We investigated the toxicity of the metabolites N-methyl-4-aminoantipyrine (MAA),  4-aminoantipyrine (AA), N-formyl-4-aminoantipyrine (FAA) and N-acetyl-4-aminoantipyrine (AAA) on neutrophil granulocytes and on HL60 cells (granulocyte precursor cell line). MAA, FAA, AA, and AAA (up to 100 µM) alone were not toxic for HL60 cells or granulocytes. In the presence of the  myeloperoxidase substrate H2O2, MAA reduced cytotoxicity for HL60 cells at low concentrations (<50 µM), but increased cytotoxicity at 100 µM H2O2. Neutrophil granulocytes were resistant to H2O2 and MAA. Fe2+ and Fe3+ were not toxic to HL60 cells, irrespective of the presence of H2O2 and MAA. Similarly, MAA did not increase the toxicity of  lactoferrin ,  hemoglobin or  methemoglobin for HL60 cells.  Hemin (hemoglobin degradation product containing a  porphyrin ring and Fe3+) was toxic on HL60 cells and cytotoxicity was increased by MAA.  EDTA , N-acetylcystein and  glutathione prevented the toxicity of hemin and hemin/MAA. The absorption spectrum of hemin changed concentration-dependently after addition of MAA, suggesting an interaction between Fe3+and MAA. NMR revealed the formation of a stable MAA reaction product with a reaction pathway involving the formation of an electrophilic intermediate. In conclusion, MAA, the principle metabolite of metamizole, increased cytotoxicity of hemin by a reaction involving the formation of an electrophilic metabolite. Accordingly, cytotoxicity of MAA/hemin could be prevented by the  iron chelator EDTA and by the electron donors NAC and glutathione. Situations with increased production of hemin may represent a risk factor for metamizole-associated  granulocytopenia

TRANSPORT OF THE ␤-LACTAM ANTIBIOTIC BENZYLPENICILLIN AND THE DIPEPTIDE GLYCYLSARCOSINE BY BRAIN CAPILLARY ENDOTHELIAL CELLS IN VITRO

This paper is available online at http://www.dmd.org ABSTRACT: Peripherally administered ␤-lactam antibiotics, which are structural analogs of tripeptides, may cause neurotoxic reactions or induce seizures. Previous in vivo studies provided evidence for brain uptake of these antibiotics. In the present work, we studied the extent and mechanism of the uptake of benzylpenicillin and glycylsarcosine by brain microvessel endothelial cells in vitro, using freshly isolated and cultured porcine brain capillary endothelial cells. Characterization of the cell culture model demonstrated the functional expression of the system transporting the neutral amino acids leucine and phenylalanine. The initial rate of uptake of benzylpenicillin was >3-fold greater than the rate of uptake of the extracellular marker sucrose (ratio, 3.29 ؎ 0.37), whereas uptake of glycylsarcosine did not differ from that of sucrose. The differences in cellular uptake correlated with the octanol/buffer partition coefficients for glycylsarcosine and benzylpenicillin (1.16 ؋ 10 ؊3 for glycylsarcosine and 6.83 ؋ 10 ؊2 for benzylpenicillin). The concentration-dependent uptake of benzylpenicillin (1-2000 M) was not saturable and was not sensitive to shifts in pH or temperature. The permeability-surface area product for the uptake of benzylpenicillin at pH 7.4 was determined from these experiments and was found to be 8.1 ؋ 10 ؊5 ml/sec/g of brain. This value was very close to the value determined in in vivo studies. Uptake of benzylpenicillin and glycylsarcosine was not reduced in the presence of 1 mM ceftibuten or 100 M probenecid. The findings with cultured cell monolayers were confirmed using freshly isolated endothelial cells. These in vitro data are compatible with benzylpenicillin, but not glycylsarcosine, being able to penetrate endothelial cells. Uptake of benzylpenicillin by brain capillary endothelial cells occurs by a slow nonsaturable process, with no evidence for carriermediated transport